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Schizophr Bull. 2009 January; 35(1): 256–278.
Published online 2008 January 31. doi:  10.1093/schbul/sbm147
PMCID: PMC2643957

Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia


In recent years, numerous substances have been identified as so-called “endocrine disruptors” because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis. The review shows similarities exist between the effects of exposure to BPA and other related chemicals with schizophrenia. These similarities can be observed in 11 broad categories of abnormality: physical development, brain anatomy, cellular anatomy, hormone function, neurotransmitters and receptors, proteins and factors, processes and substances, immunology, sexual development, social behaviors or physiological responses, and other behaviors. Some of these similarities are sexually dimorphic and support theories that sexual dimorphisms may be important to schizophrenia pathogenesis. Research recommendations for further elaboration of the theory are proposed.

Keywords: chemical, pathology, psychosis, environment, neuropathology, estrogen, phytoestrogens, phthalates, neurosteroids, environmental, toxins, bisphenol-A, endocrine disruption, schizophrenia


Several theories of schizophrenia pathogenesis have been proposed including genetic abnormalities, infectious diseases, poor nutrition, and stress. These theories have led to major advances in both treatment and understanding of the neurochemical and anatomical underpinnings of the disease, but there remains the possibility that alternative routes of disease pathogenesis exist that have not been fully elucidated. The current study proposes a mechanism of so-called “endocrine disruption” that possibly causes an abnormal endocrine environment, predominantly in fetal life, that leads to schizophrenia. Endocrine and neuroendocrine causes of schizophrenia have been proposed before, but the notion of endocrine disruption as it has been used in recent years to describe certain exposures to environmental contaminants offers a new paradigm and class of risk factors in schizophrenia research.

Endocrine and neuroendocrine abnormalities in schizophrenia have been extensively described in the past.1,2 These abnormalities have included impaired growth hormone (GH) regulation, prolactin abnormalities especially related to antipsychotic medications, various changes in adrenocorticotropic hormone and cortisol, effects on vasopressin and oxytocin, and possible neuroprotective roles of estrogen and progesterone (PG).1 Many of these studies have concentrated on the neuroendocrine status of adults with schizophrenia. Others have reported on neuroendocrine changes from prenatal stress that causes alterations of glucocorticoid function in developing fetuses.3

One recent theory has proposed that factors involved in the normal development of sexual dimorphisms in the human brain may also interact with risk factors associated with schizophrenia.4 As these dimorphisms develop at the same critical fetal stages associated with schizophrenia vulnerability, research on factors that influence sexual dimorphisms was suggested for future schizophrenia research.4 That schizophrenia and abnormal sexual development share at least one risk factor associated with endocrine disruption is demonstrated by hypospadias, the abnormality in which the male urethra opens on the underside of the penis or on the perineum. Some investigators suggest that exposure to endocrine-disrupting chemicals (EDCs) in the environment is the most likely explanation for the worldwide increase in hypospadias in the last 3 decades.5 Concurrently, the risks of hypospadias and schizophrenia are both significantly correlated with maternal influenza in the first 3 months of pregnancy.6,7

The following discussion will propose endocrine disruption such as that caused by the endocrine disruptor bisphenol-A (BPA) as a putative cause of schizophrenia with 5 objectives in mind. First, estrogen and steroids will be reviewed as to their possible roles in schizophrenia. This will include a discussion of research that suggests dysregulation of hormones could be involved in the pathogenesis of schizophrenia. Second, BPA will be described as to its basic history, possible known involvement with psychiatric illness, and its commercial and environmental significance. Third, the effects on animals of BPA and other selected endocrine disruptors will be compared with parallel literature in schizophrenia research. The comparison will show these chemicals cause 11 categories of pathological abnormalities with similar findings in schizophrenia. Fourth, the comparison will include a description and summary of sexually dimorphic changes in brain and behavior induced by BPA that have relevance to schizophrenia. Finally, an endocrine disruption theory of schizophrenia is presented using BPA as a model of how estrogenic endocrine disruptors could cause schizophrenia. The theory will describe that while BPA exposure is a possible model of schizophrenia, BPA is just one possible endocrine disruptor that could cause schizophrenia. The theory will propose that other chemical exposures and certain genetic, infectious, nutritional, and stress-related risk factors for schizophrenia could also be acting through endocrine disruption.

Estrogen and Schizophrenia

The majority of studies of estrogen in schizophrenia indicate that estrogen may prevent but not necessarily treat schizophrenia. Low estrogen levels are associated with schizophrenia symptoms in males810 and females.1114 The later age of onset of schizophrenia in women compared with men has been correlated with protective effects of higher levels of estrogen in women,15,16 and estrogen variations through the menstrual cycle correlate with schizophrenia symptom severity.17 Hypoestrogenism in schizophrenia has been attributed to medication side effects such as hyperprolactinemia, but hypoestrogenism can occur with and without antipsychotic-induced hyperprolactinemia.18

Estrogen exerts a protective role in sensorimotor gating deficits,1921 serotonin transporter and receptor function,2225 and N-methyl-D-aspartate (NMDA) receptor binding in schizophrenia models.26 However, studies of the efficacy of treating schizophrenia with estrogen have had mixed results. A recent Cochrane Database review27 and 2 double-blind, placebo-controlled trials of estrogens as adjuvant therapy to antipsychotics in treating schizophrenia did not find any beneficial effect from the addition of estrogen.28,29

Evidence that prenatal estrogen exposure may have the opposite effect than in adulthood emerged from reports of psychosis in patients prenatally exposed to the synthetic estrogen, diethylstilbestrol (DES).30 Attempts to produce animal models of schizophrenia with synthetic estrogens have had variable results.31 One study of prenatal exposure to 17alpha-ethinylestradiol in rats did not find abnormalities in prepulse inhibiton of the startle reflex in offspring, which argued against prenatal estrogen exposure as a cause of schizophrenia.31 That study exposed the fetuses for only 6 days (gestational day 9–14), a brief time compared with endocrine-disruption studies that commonly expose pregnant animals from mating to weaning. Exposure times and duration must be long enough to ensure exposure occurs on days of brain development. Variability of outcomes from endocrine disruption may be explained by the exquisite sensitivity of the developing brain to the dose, timing, and durations of exposures to hormones.32

Other indications that estrogen may be involved in schizophrenia have been found in genetic conditions that cause abnormal estrogenic function. Turner (XO) and Klinefelter's syndromes (XXY) are possible genetic models of endocrine disruption although not directly comparable to chemical exposures as entire chromosomes are involved in these syndromes. Turner syndrome, in which there is a missing X gene causing an absence of estrogen during prenatal/perinatal life, is associated with cognitive problems and psychosis.3335 One study found Turner syndrome patients have 3 times the risk for schizophrenia as normal controls.36 Klinefelter's syndrome, which often presents with hypogonadism, has been proposed as a genetic model of psychotic disorders.37

Stress-Related Hormones and Schizophrenia

Although mood disorders are frequently associated with the hypothalamic-pituitary-adrenal (HPA) axis, recent research has found HPA axis involvement in schizophrenia.38 Research on the role of the HPA axis in schizophrenia generally focuses on the effects of glucocorticoid elevations from stress. A recent study found that chronic glucocorticoid elevation in rats leads to neurotoxic structural changes in hippocampal dendritic arbors.39 Corticosterone exposure of rats also causes degeneration of the prefrontal cortex.40 Further evidence of the role of the HPA axis in schizophrenia is that corticosterone modulates prepulse inhibition in rodents, an animal model of schizophrenia.41,42 The HPA axis is potentially vulnerable to disruption by estrogenic EDCs as estrogen directly and indirectly regulates the fetal HPA in baboons.43,44

Other steroids that may be involved in the HPA axis include neurosteroids such as pregnenolone, allopregnanolone, and dehydroepiandrosterone (DHEA). Neurosteroids are important in the regulation of neuroexcitability during early development.45 The neuroprotective and neurotrophic effects of neurosteroids on inhibitory GABA(A) and excitatory NMDA receptors may have potential treatment applications for several neurological and psychiatric diseases including schizophrenia and bipolar disorder.46,47

The effect of EDCs on DHEA has not been significantly researched, although EDCs do affect other neurosteroids involved in schizophrenia as discussed below. The neurosteroid allopregnanolone, a metabolite of PG, regulates GABA(A) inhibitory receptors strongly implicated in several psychiatric diseases.48 Allopregnanolone concentrations are altered in various brain regions in schizophrenia and bipolar disorder,46 and neonatal allopregnanolone administration disrupts normal brain development in rats.49 The efficacy of certain antipsychotic medications including olanzapine and clozapine involves these GABAergic effects.50,51

The effects of plastic-related endocrine disruptors on allopregnanolone have not been studied, but allopregnanolone synthesis can be disrupted through changes in estrogen,52 PG,5355 and the primary enzymes involved in allopregnanolone synthesis, 5alpha reductase type 1 and 3alpha-hydroxysteroid dehydrogenease.56 The control by estrogen and PG of allopregnanolone modulation of striatal N-methyl-D-aspartic acid–evoked dopaminergic activity57,58 also implies vulnerability to endocrine disruption. Examples of endocrine disruption of these pathways include several naturally occurring endocrine disruptors (phytoestrogens) that inhibit not only 5alpha reductase type 1 but also 3alpha-hydroxysteroid activity.5961 The endocrine disruptor, tributyltin, which causes “imposex” (male sex organs on females) in marine invertebrates also inhibits 5alpha reductase type 1,62 and the phytoestrogen, genistein, inhibits allopregnanolone in invertebrates.63

BPA and Other EDCs

Because several lines of evidence suggest a possible role of estrogenic endocrine disruption in schizophrenia as described above, the author examined the literature of EDCs to determine which EDCs have a research base sufficient to compare to schizophrenia research. Major EDCs in the present environment include commercial chemicals such as BPA, phthalates, nonylphenol, octylphenol, organotins, polychlorinated biphenyl (PCB), and other organohalogens; and the naturally occurring substances, cadmium, genistein, and other phytoestrogens. The author chose to compare the endocrine-disrupting effects of BPA and a few other selected endocrine disruptors to schizophrenia primarily because there is substantial BPA-related literature available for review, and highly controversial claims have been made that BPA could be involved in other mental problems or psychiatric illnesses such as autism and attention-deficit hyperactivity disorder (ADHD).64,65 In addition, a recent government-sponsored panel expressed concern that BPA can impair normal neural and behavior development in fetuses, infants, and children.66

BPA is a common ingredient of many plastic and resin products including food and drink containers, internal linings of food cans, and dental enamels.67 Also known as 2,2-bis(4-hydroxyphenyl) propane, BPA was invented in the 20th century68 and is manufactured by combining acetone and phenol.69 Emerging research indicates BPA is an estrogenic EDC that alters or interferes with normal endocrine development in various vertebrate and invertebrate species.70

Because BPA leaches from containers to food, the estimated daily human BPA intake is some amount less than 1 μg/kg body weight/day.69 BPA is found in various human fluids including fetal serum and full-term amniotic fluid indicating the ability of BPA to pass through the placenta.71 One study found a 5-fold higher concentration of BPA in human 15- to 18-week amniotic fluid compared with other fluids.71 A partial fetal-maternal barrier to BPA exists in the second trimester as another study found that in the majority of pregnant women, maternal serum levels of BPA were higher than amniotic fluid levels.72 Measured over a span of 10 years in pregnant women in Japan, the yearly BPA median level in amniotic fluid ranged from 0 to 2.98 nM, which is environmentally significant as mouse embryo development is altered at BPA concentrations ranging from 1 to 3 nM.72

Comparison of the Effects of BPA and Other EDCs to Schizophrenia

The current study compares the effects of BPA and selected other EDCs in 11 broad categories of pathology to schizophrenia (table 1). These categories do not presume to include all abnormalities reported in either schizophrenia or from BPA exposure but rather to organize the literature where parallels in the 2 areas of research can be found. Research is rapidly evolving in both fields, and information is lacking in some of the categories described below. In 2 such instances, the discussion utilizes literature about endocrine disruption in invertebrates. By doing this, the author intends to suggest that similarities could exist in vertebrates although such assumptions are prone to error. In other instances of emerging evidence, psychiatric diseases other than schizophrenia such as autism, bipolar disorder, depression, dementia, and others are mentioned as possible indicators of what might be important to schizophrenia as psychiatric illnesses often share risk factors or be risks for other psychiatric illnesses.

Table 1.
Categories of Comparison

Abnormalities of Physical Development

A relationship between schizophrenia and BPA exposure exists in the involvement of retinoic acid and transforming growth factor-beta (TGFB) in one type of minor physical abnormality (MPA) that is associated with psychosis. MPAs possibly reflect an insult during the first trimester of pregnancy73 and include cleft palate74 that is associated with upregulated mRNA expression of retinoic acid and TGFB.75 Upregulation of retinoic acid receptor alpha (RARalplha) also results from in utero BPA exposure of mice,76 and in utero BPA exposure of rats causes upregulation of TGFB-3 in the medial preoptic area of the brain.77

Another area of parallel between schizophrenia and endocrine disruption related to physical development can be found in the changes of the estrogen-associated finger digit ratio in schizophrenia. Schizophrenia is associated with a more “feminized” 2nd to 4th finger digit ratio (2D-to-4D).7880 This ratio is normally sexually dimorphic and reflects prenatal androgen/estrogen levels that could be vulnerable to disruption and act as a predisposing factor in schizophrenia.79 Several studies have described prenatal and neonatal BPA-induced disruption of estrogen in the rodent brain,68,8185 which, if occurring in humans, could influence sexual dimorphisms such as the 2D-to-4D ratio.

Abnormalities of Brain Anatomy


Effects of BPA exposure on the cerebellum are similar to cerebellar changes found in schizophrenia. Abnormalities of the cerebellum in several functional domains are reported in schizophrenia.86 The abnormalities include reduced cerebellar inhibition and reduced Purkinje cell size87,88 and alterations of factors controlling synaptogenesis.89 BPA, acting as an estrogen mimic, inhibits and disrupts estrogen-induced signaling in rats that regulates cell growth and death in the cerebellum.90 BPA also induces Purkinje dendritic growth in neonatal mice, the same effect that estrogen has on mouse Purkinje dendritic growth.91,92

Locus Coeruleus.

Alterations of the locus coeruleus (LC) in schizophrenia can be compared with those observed from BPA exposure in animals. In schizophrenia, there is a trend for reduced LC volume, and the human LC expresses both estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), the latter of which is reduced in persons committing suicide.93 One postmortem study of the LC in schizophrenia found no abnormality.94 That study was a case-control study that combined males and females, with roughly two-thirds of the groups being male, a male-to-female ratio that could have possibly veiled gender-related LC sizes.

Sexually dimorphic responses occur in the LC in response to BPA. Prenatal and neonatal exposure to BPA in rats causes increased LC volume in males and decreased volumes in females ultimately resulting in reversal of the sex differences normally observed in the rat LC.81 The reversal likely results from BPA's estrogenic effect on ERalpha and ERbeta that are expressed in the LC.

Abnormalities at the Cellular Level

Neuronal Differentiation, Migration, Cell Growth, and Apoptosis.

Parallels are found between schizophrenia and BPA exposure in neuronal differentiation, migration, and apoptosis. Both decreased and increased proliferation and/or migration of neural stem cells are described in schizophrenia95 and in BPA exposure.96,97 BPA interferes with differentiation of ectodermal tissues, including neural tissues, in cynomolgus monkeys.98 In tadpoles, BPA also induces apoptosis in central neurons of Xenopus laevis resulting in head, vertebral, and abdominal developmental defects.99

Increased neurogenesis in a rat ketamine model of schizophrenia100 parallels increased cortical and hippocampal neuronal growth from BPA exposure that affects caspase-3, a protein involved in the apoptosis process, in rat brains.101 BPA interferes with normal brain development by inhibiting caspase-3 thus preventing desirable neuronal cell death. A different study determined that high levels of BPA activate caspase-3 and cause cell death.102 Similar opposing variations in caspase-3 activity have been observed in schizophrenia. Caspase-3 is activated by both phencyclidine (PCP)-induced neuronal death103 and treatment with antipsychotic medication.104 In chronic schizophrenia, normal caspase-3 levels are reported,105 indicating apoptosis is not active in the chronic phase although the chronic phase exhibits a higher Bax-to-Bcl-2 ratio (proteins that regulate apoptosis), suggesting cortical vulnerability to apoptosis. BPA might also alter the Bax-to-Bcl-2 ratio as in male offspring of dams fed BPA during gestation to weaning, caspase-3 increases, and bcl-2 decreases.106

Possible models of apoptosis in schizophrenia have included transferase-mediated dUTP nick end-labeling (TUNEL)–positive hippocampal neurons in rats treated with neonatal kainic acid.107 Cells that are TUNEL positive are apoptotic. In neonatal rats injected with BPA, a reduction in the midbrain of tyrosine hydroxylase (TH) immunoreactivity occurred with the appearance of TUNEL-positive cells indicating neurodegeneration.108 In that study, BPA also increased gene expression of dopamine (DA) transporter in adult rats after neonatal exposure. The exposed rats were hyperactive, and the investigators proposed the hyperactive rats as possible models of autism or ADHD.

Abnormalities in synaptogenesis are found in both schizophrenia and BPA exposure. The mitogen-activated kinase (MAPK) cascade likely influences estrogen-induced CA1 pyramidal dendrite spine synapse density109 and may be involved in the pathogenesis of schizophrenia.110 BPA exposure in rats impairs estrogen-induced hippocampal synaptogenesis that may occur through inhibition of MAPK.109 BPA also exerts estrogenic protective effects on hippocampus cells, providing neuroprotection against glutamate and amyloid beta protein toxicity.111

In schizophrenia and BPA exposure, similar abnormalities in cortical neurons are observed. In schizophrenia and other psychiatric illnesses, neuronal size is decreased, and neuronal density is increased in cortical layers 5 and 6 of the anterior cingulate cortex.112 Prenatal BPA exposure also affects layers 5 and 6 in mice in which BPA increases neuron growth in the 5th and 6th cortical layers and disrupts thalamocortical projections.113


Pathological changes in oligodendrocytes are observed in both schizophrenia and BPA exposure. Abnormalities of oligodendrocyte survival and differentiation as well as abnormal expressions of oligodendrocyte and myelin genes are reported in schizophrenia.114,115 Reductions in oligodendrocyte numbers and abnormalities of myelin sheaths also occur in schizophrenia.116 BPA inhibits differentiation of oligodendrocyte precursor cells in rodents117 and impairs the expression of myelin basic protein.117


Astrocytes are affected in both schizophrenia and BPA exposure. In a schizophrenia animal model, leukemia inhibitory factor (LIF)–treated rats have decreased motor activity and prepulse inhibition in the acoustic startle test at adolescence, an abnormality that may involve glial cells.118 LIF is a IL-6 cytokine, a class that is elevated in schizophrenia, Alzheimer's disease (AD), and autoimmune diseases.118122 When astrocyte progenitor cells are exposed to LIF, then treated with BPA, the expression of glial fibrillary acid protein (GFAP) is enhanced.123 BPA treatment of LIF-stimulated cells enhances GFAP expression through activation of excessive “signal transducer and activator of transcription 3” (STAT3) and “mothers against decapentaplegic homolog 1” (Smad1).124 This effect on GFAP may be due to the “cross-talk” reported between STAT3 and estrogen receptor (ER) signaling.125 LIF, like BPA, also induces STAT3 phosphorylation and increases GFAP.118 A cross-talk also exists between Smad proteins and MAPKs (mentioned above under the section on cell growth) that has been linked with the pathogenesis of AD.126

The increase of GFAP expression by BPA is important to schizophrenia because treatment of rat brain with the NMDA antagonist, MK-801, also increases GFAP-positive astroglial cells that are believed to play a role in schizophrenia pathology. This increase in GFAP-positive astroglial cells, a reaction that is suppressed by the antipsychotic medication clozapine, probably represents glial cell activation in response to glutamate toxicity that activates peptidase activity.127

Activations of astrocytes in schizophrenia and AD are also reflected by subpopulations of patients with increased S100B serum concentrations.128,129 S100B is an astrocytic protein that regulates calcium homeostasis. BPA activates mouse astrocytes as shown by BPA induction of stellate morphology and increased GFAP.102 Nonylphenol, another commercial chemical identified as an endocrine disruptor, also increases GFAP in cultured rat hypothalamic cells.130 Although BPA's effect on S100B expression has not been reported, BPA does impact calcium homeostasis through other pathways discussed below.

Abnormalities of Hormone Function


BPA is an estrogenic endocrine disruptor, and BPA exposure causes estrogen-associated changes relevant to schizophrenia. As described above, various lines of evidence support a role of estrogen or estrogen-related abnormalities in schizophrenia. ERs may also play a role in neuropsychiatric disorders as ERalpha mRNA is decreased in the amygdala, frontal cortex, and hippocampus in major psychiatric illnesses.93,131,132 The human forebrain has discrete ERalpha mRNA expression,133 and synapses in the hippocampus depend on estrogen.134,135 Estrogen also regulates the growth-associated protein, GAP-43, in the rat hypothalamus, and GAP-43 is abnormal in schizophrenia.136138

In rodent models, the effect of BPA exposure on ERs is often complex and sex related. Neonatal and pubertal exposure to BPA alters or disrupts hypothalamic ERalpha transcription in a sexually dimorphic manner.82,85 Neonatal BPA exposure of female animals causes increases of ERalpha but not ERbeta in the medial basal hypothalamus but not in the anterior pituitary.84 In males, BPA increases both ERalplha and ERbeta in the pituitary but not in the hypothalamus.84 BPA treatment causes delayed and sustained hyperprolactinemia in both sexes of offspring,84 which could explain some portion of these changes in ERs.

Another study of sexually dimorphic responses to BPA examined the effects in rats of postnatal BPA exposure on hypothalamic ERs by the time of puberty.85 By postnatal day 37, BPA exposure increased ER-labeled neurons in the ventromedial nucleus of the hypothalamus of males compared with exposed females and control groups. But by postnatal day 90, BPA-exposed females had higher ER-labeled neurons in the ventromedial nucleus and medial preoptic area of the hypothalamus. Other research found that in postnatally treated rats, BPA “defeminized” (a word commonly used in the literature to describe the estrogenic effects of endocrine disruptors) double-labeled cells of ERalpha and TH in the medial region of the anteroventral periventricular nucleus (AVPV) of the hypothalamus.68


As with estrogen, PG changes from BPA exposure could be important to schizophrenia pathogenesis despite the lack of association of PG with symptom severity or stress in males.139,140 Although PG's link with schizophrenia may be less direct than that of estrogen, endocrine disruption of PG could be involved in schizophrenia through PG's effects on neurosteroids, especially allopregnanolone, as discussed above. Other involvement of PG in schizophrenia could occur through augmentation of estrogen. For example, estrogen or estrogen plus PG protects against 8-hydroxy-2-dipropylaminotetralin–induced disruption of prepulse inhibition of acoustic startle, an animal model of schizophrenia.20 Estrogen and PG also restore TH innervation following reductions in fiber density in the dorsolateral prefrontal cortex in ovariectomized female macaque monkeys,141 and subtle “miswirings” of TH-immunoreactive varicose fibers in the cingulate gyrus have been reported in schizophrenia.142 PG with estrogen also augments DA D5 receptor expression in certain hypothalamic neurons.143 D5 receptors are D1 like, and decreases in D1-like receptors are associated with schizophrenia.143

Reports of PG changes from BPA exposure mostly concern the effects on hypothalamic PG receptors. For the following discussion, the effects of other EDCs on PG have been added for additional detail. The information reflects a sexually dimorphic variation of EDCs on PG expression that would, like with estrogen, have relevance to sexually dimorphic abnormalities. Perinatal exposure of rats to diisononyl phthalate downregulates hypothalamic PG receptors in females but not in males.144 Perinatal exposure to the phytoestrogen, genistein, also reduces PG levels in mature females but not in males.145

BPA injection of only female rats causes dose-dependent increases in PG receptor cells in the preoptic and ventromedial areas of the hypothalamus.146,147 BPA also increases PG receptor mRNA in the frontal cortex of ovariectomized female rats.148

Luteinizing Hormone and Testosterone.

Schizophrenia and BPA exposure both have mostly negative effects on luteinizing hormone (LH) and testosterone (T). Although women with schizophrenia treated with conventional and atypical antipsychotic medications have low levels of estrogen and LH due to medication effects on prolactin, the low estrogen and LH are not always associated with hyperprolactinemia.18 In chronic schizophrenia, reductions of basal LH have been reported.149 LH levels in male suicide attempters have been found marginally elevated, but T levels were decreased, and the lowest T levels were in the subgroup with schizophrenia.150

One study examined the effects of BPA exposure on LH and T when exposure occurred during the postnatal period in rats.67 BPA exposure suppressed serum LH and T and decreased LHbeta and ERbeta pituitary mRNA. Treatment of adult Leydig cells also decreased the steroidogenic enzyme, 17alpha-hydroxylase/17-20 lyase. Another portion of the same study found decreased T in the testicular interstitial fluid of adult offspring from BPA-exposed pregnant and nursing dams. Because rats exposed to BPA develop sustained hyperprolactenimia,84 the reduced LH possibly results from its suppression by prolactin like in other species.151


The literature concerning somatostatin in both BPA exposure and schizophrenia is limited but specific. One study of schizophrenia found altered somatostatin/neuropepetide Y-containing GABA neurons and GABA(A) receptors.152 BPA exposure of rats causes layer V of the frontoparietal cortex to have decreased somatostatin receptor subtype 3 mRNA especially in the presence of GABA(A) subunits alpha (1,5).153 The estrogen-like effects of BPA are also promoted by somatostatin receptor subtype 2 alpha in association with the GABA(A) receptor.154


Oxytocin is implicated in animal models of schizophrenia, and central oxytocin function is affected by BPA exposure. In an animal model of schizophrenia, prenatally stressed rats exhibit social withdrawal similar to schizophrenia that is reversible with oxytocin administration.155 Stressed male rats have less oxytocin mRNA in the paraventricular nucleus and increased oxytocin receptor binding in the central amygdala.155 Other studies have also found that the central oxytocinergic system may be responsible for social impairments in schizophrenia.156 Reduced oxytocin receptors downregulate reelin that may contribute to social behaviors of schizophrenia and autism.157 Oral BPA exposure reduces certain maternal behaviors such as licking-grooming and arched back posture related to oxytocin.158 These effects are likely related to BPA's effect on estrogen-inducible central oxytocin receptors.158

Corticotropin-Releasing Hormone.

Schizophrenia and BPA may be related through effects on corticotropin-releasing hormone (CRH) and the bed nucleus of the stria terminalis (BST). This information highlights the sexually dimorphic effects of BPA previously mentioned. Alterations of the BST and/or CRH neurons may be involved in schizophrenia. In rat models of schizophrenia, rats with brain lesions to induce deficits in prepulse inhibition of the startle reflex, blood perfusion is increased in several brain areas including the BST.159 In both rats and mice, CRH reduces prepulse inhibition associated with schizophrenia.160,161 Upregulation of CRH by lipopolysaccharide injection in pregnant rats indicates activation of the fetal stress axis described above as probably involved in schizophrenia.162

One study examined CRH in the brains of offspring of rats prenatally and perinatally exposed to BPA.163 Ordinarily, this study reported there are more CRH neurons in the preoptic area and BST in females than in males. After BPA exposure, no change in neurons was observed in the preoptic area, but CRH neurons in the BST of males increased while they decreased in females resulting in an equalization of CRH neurons in the BST. The researchers concluded the BST is more sensitive to endocrine disruption than the preoptic area regardless of sex.

Growth Hormone.

GH regulation appears abnormal in schizophrenia although the changes are subtle and influenced by several neurotransmitters.1

In ovine pituitary cells, BPA suppresses basal and growth hormone–releasing hormone (GHRH)–stimulated GH release.164 This study also demonstrated that BPA reduces cellular GH content and cell number, suppresses GHmRNA, and eliminates GHRH-induced increases in cAMP and Ca2+.

Abnormalities of Neurotransmitters and Receptors

TH, DA, and Related Effects.

Several studies have investigated the effects of BPA exposure on TH and DA, and research on TH and DA in schizophrenia is extensive. There is a well-known association of enhanced DA D2 function in schizophrenia, and the D1A receptor function may also be abnormal in schizophrenia.165 The level of expression of DA transporter is possibly an illness trait in schizophrenia,166 and mouse models of schizophrenia have reduced expression of DA transporter.167 Increased transcription of TH in the substantia nigra is also found in schizophrenia,168 and transgenic mice used as animal models of schizophrenia have reduced density and numbers of TH neurons in the substantia nigra pars compacta.169

Much of the BPA literature concerning TH continues to emphasize the recurring theme of prenatal BPA causing sexual dimorphisms. In mice, populations of TH neurons in the rostral periventricular preoptic area are normally sexually dimorphic.170 Mice exposed to BPA from gestation through lactation lose this sexual dimorphism due to fewer TH neurons in the exposed brains.170 Other sexually dimorphic responses are observed in the substantia nigra in which BPA increases TH neurons in female but not male rats.171 Likewise, in the medial AVPV of the hypothalamus, double-labeled cells for ERalpha and TH are defeminized in number in postnatal rats treated with BPA.68 These researchers noted that females normally would have 3 times as many of these double-labeled cells than were observed.

Other studies relevant to schizophrenia examined the effect of BPA on TH and DA functions in the developing animal brain. Some studies focus on how BPA exposure causes hyperactivity. In the midbrain of rats injected with BPA at 5 days of age, DA transporter gene expression increases and is associated with hyperactivity.172 These rats were additionally assessed following treatment in the midbrain at 5 days of age with other synthetic endocrine disruptors including dibutylphthalate (DBP), dicyclohexylphthalate (DCHP), and diethylhexylphthalate (DEHP). These substances reduced DA receptor D1A. Similar treatment with the endocrine disruptors, nonylphenol and DBP, increased DA D2. Another study that administered BPA to 5-day-old rats correlated the onset of hyperactivity at 4–5 weeks of age with increased DA D4 receptor expression and reduced DA transporter expression in the midbrain.173 One study of only male mice exposed to BPA prenatally and neonatally did not find changes in DA transporter,174 although a similar study found BPA increased TH and DA transporter immunoreactivity in the limbic area.175

The effects of BPA on DA have been observed in other experimental settings. BPA rapidly releases DA from PC12 cells,176 and treatment of mouse astrocyte/neuronal cells with BPA enhances Ca2+ response to DA.102 In males exposed prenatally and neonatally to BPA, DA D1 receptor mRNA is upregulated in the whole brain.174

BPA also attenuates DA D3 receptor–mediated G-protein activation by 7-OH-DPAT in the mouse limbic forebrain.177 In this case, BPA acts more as an antipsychotic,178 but attenuation of prenatal DA D3 may have entirely different effects than enhanced D3 activation in adult life. A possible difference between effects on D3 in prenatal versus adult life is supported by the finding that D3 appears early in murine development and is believed to have an important role in prenatal development.179 D3R-deficient mice also have decreased TH, increased DA transporter mRNAs, and increased DA reuptake,180 which parallel the effects of BPA. Brain-derived neurotrophic factor (BDNF), discussed below, controls the expression of DA D3 receptor, and a link has been proposed between BDNF and DA neurotransmission in schizophrenia.181

Peroxisome Proliferator–Activated Receptor gamma.

Similarities exist between peroxisome proliferator–activated receptor gamma (PPAR-gamma) in schizophrenia and the effect of endocrine disruption on PPAR-gamma. Several lines of evidence show antagonism of PPAR-gamma would be detrimental for normal brain functioning. PPAR-gamma agonists regulate brain inflammation and microglial activation,182 regulate neural stem-cell proliferation and differentiation,183 confer neuroprotection in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease,184 protect cerebellar cells from apoptosis by reducing the expression of nitric oxide synthase,185,186 increase glucose utilization in the rat cortex and reduce oxidative damage from stress,187 reduce the risk of AD,188 and are useful in treating multiple sclerosis (MS) and other neurodegenerative disorders.189,190 PPAR-gamma antagonism enhances behavioral sensitization to methamphetamine in mice.191 Polymorphism of the PPAR-gamma gene appears to impact the susceptibility to both younger age and late-onset AD.192,193

No studies have shown whether BPA interacts with PPAR-gamma but a product likely formed endogenously from BPA does. Bisphenol A diglycidyl ether (BADGE), formed by a coreaction of BPA with epichlorohydrin, is a PPAR-gamma antagonist and endocrine disruptor used in liquid epoxy resins.194 BADGE has potential as an antitumor drug that induces apoptosis through Bax, caspases-2 and -8, and stimulation of mitochondrial release of apoptosis-inducing factor.195 BADGE may form BPA endogenously as shown in BADGE-exposed workers.196 BADGE induces several cellular reactions through antagonism of PPAR-gamma including disruption of microtubule networks,197 increase of the severity and duration of experimental allergic encephalomyelitis which is a Th1 cell–mediated autoimmune disease model of MS,198,199 induction of cell death in astrocytomas,200 and blockage of 15-dioxy-PGJ(2)–induced neuronal differentiation of rat embryonic midbrain cells.201

Norepinephrine Transporter.

An indirect link may be found between schizophrenia and BPA through the norepinephrine transporter (NT) gene. Although genetic linkage studies have not demonstrated a clear relationship between schizophrenia and NT, the repression of a polymorphism of the NT gene is associated with ADHD.202 ADHD is a risk factor for velocardiofacial syndrome (22q11.2 deletion syndrome), which carries a risk of psychosis and mania.203 The effect of BPA on NT function has not been studied in animal brains, but BPA inhibits NT function in cultured bovine adrenal medullary cells.204

Choline Acetyltransferase.

Choline acetyltransferase (ChAt) is reduced in the nucleus accumbens and pontine tegmentum in schizophrenia and correlates with cognitive measures of the individuals.205 BPA induces memory impairment and dramatic reductions of ChAt-like immunoreactivity in the hippocampus of mice exposed prenatally and perinatally.206 ChAt is also reduced by neonatal exposure to the endocrine disruptor, PCB, which induces hypothyroidism that causes reduced ChAt.207

GABA and Neurosteroids.

The importance of neurosteroids and GABA(A) receptors in schizophrenia was discussed above. Additional evidence indicates that BPA's effects on GABA and neurosteroids are similar in schizophrenia. As previously described, endogenous neurosteroids modulate inhibitory transmission by GABA(A) receptors,208 and abnormal steroid regulation of GABA is implicated in several psychiatric diseases including schizophrenia.48

BPA influences hippocampal neurosteroid synthesis and completely suppresses the estradiol enhancement of long-term potentiation through a mechanism involving steroidogenic proteins and ERalpha.209 BPA also increases GABA-induced currents that are decreased by GABA(A) receptor modulators in dissociated rat CA3 pyramidal neurons.210 BPA further reduces the amplitude of GABAergic miniature inhibitory postsynaptic currents (GabaMIPC).210 Reduced GabaMIPCs are associated with seizure-prone rats in which there are abnormal GABA subunit expressions compared with normal rats.208 Reduced GabaMIPCs are also associated with alterations of the growth factor, neuregulin1, which may contribute to schizophrenia and epilepsy.211 BPA's GABA effects could relate to the known relationship between epilepsy, infantile spasms, and schizophrenia that is based on the effects of neurosteroids and GABA(A) receptors.212

Abnormalities of Proteins and Factors

Sonic Hedgehog.

The signaling molecule and dopaminergic neuron development factor, sonic hedgehog (SH), is involved in embryonic development of the brain, eyes, limbs, and foregut. A relationship between schizophrenia and BPA disruption of SH is suggested because disruption of SH is associated with developmental disorders of the brain, especially holoprosencephaly (HPE).213 HPE is a brain malformation associated with facial and cerebral malformations, developmental delay, epilepsy, and endocrine abnormalities.214 HPE is believed to result from combined environmental and genetic factors; one gene in particular being Zic2.214 The Zic2 knockdown mouse is an animal model for HPE. The Zic2kd/+ mouse is an animal model for diseases of sensorimotor gating abnormalities which would include schizophrenia.215 Chronic and prenatal BPA exposures both produce a significant decrease and disruption of SH.175

Glial Cell Line–Derived Neurotrophic Factor.

Glial cell line–derived neurotrophic factor (GDNF) may play a role in schizophrenia as certain GDNF alleles appear to protect against schizophrenia.216 GDNF, a dopaminergic neuron development factor, protects DA neurons from toxic effects of amphetamine in animal models.217 Chronic and prenatal BPA exposures both significantly decrease GDNF.175


Parallel changes of the neuropeptide, galanin, can be found in schizophrenia and BPA exposure. Galanin has modulating and inhibitory effects on serotonergic and dopaminergic neurotransmission, respectively.218,219 Decreased galanin-R2 may be involved in schizophrenia as galanin reduces glutamate toxicity and modulates neurotoxicity in hippocampal cells.220 Galanin is upregulated in Alzheimer's,221 and galanin-R1 and -R2 inhibit kindling epileptogenesis. Galanin receptor 2 null mutant mice also exhibit an anxiogenic-like phenotype,222,223 which parallels the effects of BPA, DBP, DCHP, and DEHP injection in the midbrain of rats at 5 days of age that reduces gene expression of galanin receptor 2.172


Ketamine and PCP, often used as selective NMDA receptor antagonists in animal models of schizophrenia, increase GTPgamma-S binding, a G-protein–activating protein.224,225 DA induction of [(35))S]GTP-gamma-S is markedly stimulated by BPA in prenatally and neonatally exposed male mice.174


The effect of BPA on calbindin is another example of BPA's disruption of sexual dimorphisms. These dimorphic effects can be directly compared with schizophrenia. First, in an animal model of schizophrenia using female rats, calbindin immunoreactive cells are decreased in isolation-reared rats, an alteration that resembles neuronal abnormalities in schizophrenia.226 Second, a case-control study of schizophrenic and normal brains found reduced densities of calbindin-immunoreactive interneurons in the planum temporale. That study used brains from both male and female subjects, and the investigators noted that mean calbindin cell size was increased in female and decreased in male patients.227

Postnatal exposure of rats to BPA has sexually dimorphic effects and increases the number of calbindin neurons in the sexually dimorphic nucleus (SDN) of the preoptic area of male rats compared with females used as controls.32 The authors of that study referred to this BPA response as “hypermasculinizing” the number of neurons as if the SDN had been exposed to estrogen (in fetal male mammals, T activates estradiol that masculinizes the male brain). They further observed that no change occurred in the volume of the brain area. Their conclusion was that “lack of a morphometric disruption does not necessarily indicate lack of functional disruption.” This same study found that genistein, but not BPA, “demasculinized” the AVPV volume demonstrating differential prenatal effects of 2 endocrine disruptors on different parts of the hypothalamus.

Retinoids, Neurogranin, and Thyroid Proteins.

Retinoids, thyroid proteins, and neurogranin are combined in this discussion as they are best described together in their relation to both schizophrenia and BPA. In schizophrenia, evidence supports a role of retinoids. RARalplha is increased 2-fold in schizophrenia,228 and retinoid X receptor gamma1 is known to modulate DA-mediated processes.229 There is also evidence of retinoid and thyroid hormone gene interactions with the environment in schizophrenia.230 Thyroid hormones regulate both neurogranin and retinoids, and thyroid hormones also regulate neuronal calmodulin-Ca(2+) downstream of the NMDA receptor.231 In schizophrenia, the prefrontal cortex has reduced neurogranin in area 9 and 32,232 and there is an association of the neurogranin gene in males with schizophrenia.231 The schizophrenia candidate gene, HOPA, codes a member of thyroid receptor coactivator protein (TRAP) that is associated with psychosis, autism, and hypothyroidism.233235 The association of hypothyroidism induced by PCB and its effect on ChAt and potential relationship with schizophrenia was discussed above.

BPA exposure impacts the same systems. BPA increases RARalpha and retinoid X receptor alpha mRNA expression in the cerebrum and cerebellum of male and female mouse embryos.76 In Xenopus (tadpole) tail culture, BPA upregulates thyroid hormone receptor alpha and beta and downregulates RXRgamma.236 When rats are fed BPA during pregnancy and lactation, total thyroid hormone T4 increases in the dentate gyrus of offspring without effect on thyroid-stimulating hormone.237 These changes are accompanied by upregulation of the thyroid hormone-response gene that encodes RC3/neurogranin.237 Another study of perinatal BPA exposure found RC3/neurogranin expression was unchanged by BPA administration, but steroid receptor coactivator-1 was upregulated in the hippocampus of male pups.238 In that study, exposed dams developed temporary hypothyroidism, but male pups developed transient hyperthyroidism followed by hypothyroidism. Thyroid hormone receptor alpha and beta were not changed. BPA also impairs thyroid function by inhibiting T3 binding to the thyroid receptor.239 In uterine tissue, BPA activates ER transcription in association with TRAP220.240

Protein Disulfide Isomerase.

The effects of BPA exposure on protein disulfide isomerase (PDI) are more relevant to neurodegenerative disorders in general than specifically to schizophrenia. PDI provides neuroprotection by facilitating protein folding and preventing misfolding.241 PDI is believed to prevent nitrosative stress that leads to protein misfolding and neuronal cell death that causes degenerative brain disorders.241 Several neurodegenerative disorders are linked to protein misfolding including dementia with Lewy bodies.242 BPA binds to PDI and inhibits its activity.243 The deactivation of PDI may be responsible for various effects of BPA,243 and one could speculate that inhibition of PDI by BPA would increase the risk of neurodegenerative disorders.

Brain-Derived Neurotrophic Factor.

A relationship between BDNF in schizophrenia and BPA may be found through BDNF involvement with DA, glutamatergic, and c-fos functions. As mentioned previously, BDNF and DA neurotransmission appear linked in schizophrenia.181 Increased BDNF associated with hyperactive glutamatergic neurons has been found in cerebellar granule cells in schizophrenia.244 Another study of schizophrenia found reduced plasma levels of BDNF in first-episode psychosis compared with normal.245 In mouse cerebellar granule cells, BPA decreases induction of both BDNF and c-fos mRNA.246 These results are difficult to interpret as induction of c-fos may be altered in similar directions by amphetamine, PCP, and antipsychotic treatment depending on brain region, dose, timing, and environment.247250

cAMP-Responsive Element-Binding Protein and Mitogen-Activated Protein.

The discussion of abnormalities in synaptogenesis discussed above described the possible role of MAPK in BPA impairment of estrogen-induced hippocampal synaptogenesis.109 Schizophrenia and BPA exposure may be further related through MAPK by BPA's effects on the transcription factor cAMP-responsive element-binding protein (CREB). CREB stimulates the expression of several genes and influences signal transduction of DA and serotonin receptor subtypes. Novel variants of CREB genes have been associated with schizophrenia.251 Increased CREB-stained cells have been found in the amygdalar nuclei of subjects who died by suicide252 and has been found in the cerebellar vermis in schizophrenia.253

In pancreatic islet cells, low-dose BPA activates CREB through a nonclassical ER-related mechanism.254 There is some controversy as to whether and how BPA influences mitogen-activated protein (MAP) although CREB may be a downstream target of MAP.253 One study found only the brominated form of BPA, tetrabromobisphenol A (TBBPA), influences MAPKs in a cell-specific and dose-dependent manner.255 Another study found that in cultured rat hypothalamic cells, BPA increases both MAP2 and synapsin I.130 Synapsin I has not been associated with schizophrenia, and generally synapsin reductions instead of increases are found in schizophrenia.256 However, reductions in synapsin are associated with developmental thyroid insufficiency. Thyroid insufficiency may contribute to persistent behavioral abnormalities257 and was mentioned above as possibly related to other abnormalities of endocrine disruption.

Epidermal Growth Factor.

What effect BPA may directly have on epidermal growth factor (EGF) is unknown, but a comparison with schizophrenia is made below by using the effects of the endocrine disruptor, 4-tert-octyphenol (OP) on EGF. EGF and EGF receptor abnormalities are reported in schizophrenia, and EGF administered to rats causes abnormalities of prepulse inhibition of acoustic startle.258 The age of onset in males with schizophrenia may be related to a polymorphism of the EGF gene.259

Embryonic ERbeta modulates EGF that influences calretinin-immunoreactive GABEergic interneurons and neuronal migration.260 This would suggest that estrogenic disruption involving ERbeta would alter EGF. OP increases estrogen-responsive gene expression including that of EGF.261 One study of calretinin neurons in the cerebral cortex of neonatally and perinatally BPA–exposed mice did not find any differences between exposed and controls.171

Abnormalities of Miscellaneous Processes and Substances


There is evidence that hypomethylation occurs in both schizophrenia and BPA exposure. DNA methylation in general may influence gene-environment interactions associated with schizophrenia.262 Hypomethylation in particular has been proposed as an epigenetic modification involved in schizophrenia.263,264 BPA hypomethylates DNA by decreasing cytosine-guanine dinucleotide methylation (CpG) that changes the coat color of mice offspring.265 CpG methylation and hypomethylation are found in schizophrenia,266268 AD,269 Huntington disease,270 and bipolar disorder.271

Calcium Signaling.

Calcium signaling is a broad field with numerous possible avenues of involvement in schizophrenia and BPA. The following discussion highlights particular involvements of calcium signaling in schizophrenia and certain findings of BPA's effects on calcium signaling. In schizophrenia, Ca2+ abnormalities may be the link through which elevations of calcyon and neuronal calcium sensor-1 protein influence the development of schizophrenia.272274 The calcium sensor protein caldendrin, with an important role in brain Ca2+ signaling, is reduced in cortical neurons in chronic schizophrenia.275,276

BPA enhances Ca2+ signaling in NMDA-responsive neurons through a pathway involving ERs.277 In astrocyte/neuron cocultures, BPA also increases Ca2+ response to DA.102 One study suggested BPA has a role in neurodegenerative disorders based on BPA's purported Ca2+-based potentiation of 1-methyl-4-phenylpyridinium ion–induced hydroxyl radical (•OH) in rat striatum.278 The previously mentioned brominated form of BPA, TBBPA, also disrupts calcium homeostasis.279

Glutathione Redox.

Abnormalities of glutathione-related functions can be found in both schizophrenia and BPA exposure. There is evidence of both altered antioxidant status in schizophrenia280 and a decreased glutathione to glutathione disulfide ratio (GSH-to-GSSG) in schizophrenia compared with controls.281 Glutathione deficit may cause hypofunction of NMDA receptors and be associated with cognitive deficits in schizophrenia.282,283 Male mice injected with BPA develop increased GSSG in the brain with a decreased GSH-to-GSSG ratio.284

Thiobarbituric Acid–Reactive Substances.

Increased thiobarbituric acid–reactive substances (TBARS) are found in never-medicated individuals with schizophrenia and correlate with symptom severity.285 BPA exposure of mice during fetal life and infancy results in increased TBARS in the brain, kidney, and testis.286

Abnormalities of the Immune System

There are parallels between immunological hypotheses in schizophrenia and BPA exposure. Immune hypotheses have been proposed for schizophrenia,287289 and genetic studies have identified IL-2 and IL-4 polymorphisms as candidate genes in schizophrenia.290 A correlation between schizophrenia and autoimmune diseases is well known.291

Several studies have demonstrated the immunological effects of BPA exposure in animals. BPA increases antibody response to protein antigens in vivo292 and enhances autoantibody production by B1 cells that may influence the development of autoimmune diseases.293 Th1 greater than Th2 cytokine induction is nearly universal in immunological studies of mice exposed to BPA tending to support an autoimmune response.294298 One study found BPA exposure suppressed the Th-2 (IL-4) response.299 Another found that BPA impairs lymphocyte proliferation.295

A shift to Th2 with reduced Th1 is usually observed in schizophrenia,291 which is the reverse of BPA exposure although interferon-gamma production has also been reported as either increased or decreased by BPA exposure.295,299 However, the maternal immune environment may be more important to the pathogenesis of schizophrenia through an immune response involving IL-6.300 In the section above concerning astrocytes, the stimulating effect of BPA on the effects of IL-6 (LIF) was discussed. The stimulation of LIF by BPA would afford one pathway through which BPA could alter the maternal immune environment. Another pathway would involve the sexual dimorphism of the immune function in which androgens and estrogens influence the Th1/Th2 balance.301304

BPA also enhances IL-4 production by antigen-primed CD4+ T cells that is mediated by a Ca2+/calcineurin/nuclear factor-AT signaling pathway.299 Schizophrenia research has found a genetic association between altered calcineurin signaling with schizophrenia.305 The same research identified the early growth-responsive-3 (EGR-3) gene as the possible susceptibility gene. EGR3 is a novel estrogen-responsive gene,306 which suggests vulnerability to disruption by estrogenic compounds like BPA.

Abnormalities of Sexual Development

The effect of BPA on sexual dimorphisms has been a recurrent theme in this discussion. Sexual differentiation of the brain, sexual dimorphism, and the vulnerability of schizophrenia have been linked in previous studies.4 One study described these so-called “gender effects in schizophrenia” as “the most robust phenomena of the disease, yet they have defied explanation ….”1 The effect of BPA and other endocrine disruptors on sexual development in animals has been reported by numerous investigators. Some studies have focused on the effects on actual behaviors whereas others have evaluated the effect on the sexual differentiation of brains in animals. Many of the latter findings have been discussed above.

The sensitivity of the developing brain to the timing, duration, and dose of endocrine influences has been previously mentioned, and a difference in timing by 1 or 2 days of exposure has been described as causing different outcomes of brain development.32 The correct timing and duration of these influences are vital for normal development in mammals as female brain and anatomy will develop without aromatization of testicular T to estradiol that induces male brain development.68

Several examples of BPA-induced sexually dimorphic behavioral changes have been reported that can be associated with disrupted brain development. BPA eliminates the normally sexually dimorphic differences in mouse sexual behaviors in open-field tests, indicating disruption of brain development.170 Sexual behaviors of offspring of pregnant rats exposed during pregnancy and lactation to BPA are also changed. Female behaviors are increased whereas male behaviors are decreased.307 The opposite effect for females, that is, defeminization of some aspects of behavior, was observed in another study.308 Male offspring of rats exposed from pregnancy through lactation with BPA exhibit feminized levels of impulsive behavior.309 Female offspring of rats exposed from pregnancy through lactation develop altered estrous cycles including persistent estrous.310

Abnormalities of Behavior or Physiological Response


Symptoms of schizophrenia include paranoia, and paranoid schizophrenia is one type of schizophrenia.311 Male offspring of pregnant rats exposed to prenatal and perinatal BPA exhibit changes in normal responses to fear-inducing stimuli.312 These investigators suggested BPA “may render male offspring exceedingly vulnerable to intolerable levels of fear.”

Pain Sensation.

Changes of pain sensitivity are observed in both schizophrenia and BPA exposure. In schizophrenia, pain sensitivity appears altered in some patients and in experimental animals treated with subchronic ketamine.224 Changes in pain sensitivity in animal models of schizophrenia result from modifications of the mu opioid receptor.224 There is also a suggestion that abnormalities of opiate-DA interactions are involved in schizophrenia.313

Pre- and perinatal BPA administration to pregnant rats alters pain perception in male and female offspring.314 Specifically, BPA increases flexing and licking hyperalgesia, the licking more prominent in females suggestive of a dimorphic effect. The researchers concluded these responses likely resulted from BPA's estrogen-like effects on supraspinal neural or opioid effects. Postnatal BPA, however, decreased paw-jerk frequency in both males and females suggesting a greater tolerance of pain.

Abnormalities of Other Behaviors

The following behavioral changes caused by BPA in animals are not specific to schizophrenia but are frequently observed in the clinical setting. Socially important behaviors with parallels in endocrine disruption research include “neophobia,” or the aversion to new or novel stimuli, changes in exploratory behaviors, aggression, and drug- or reward-seeking behaviors. Some of the behaviors show sexual dimorphisms like others discussed above. For example, female but not male rats prenatally and/or perinatally exposed to BPA exhibit increased neophobia.309 Female Mongolian gerbils exposed to varying levels of BPA display decreased exploratory behaviors,315 and perinatal BPA exposure of mice results in the decrease or elimination of sexual differences exhibited by mice in exploration and emotional response tests.316 Male rat offspring exposed prenatally to BPA exhibit greater aggression before but not after puberty.317

Sex-related differences are also observed in the behavioral effects of prenatal and/or perinatal BPA exposure that impacts the rewarding or activating effects of drugs on offspring. Male rats prenatally and perinatally exposed to BPA display less drug-induced activity in response to amphetamine challenge than controls.309 BPA exposure of female mice exposed prenatally eliminates expected amphetamine-induced place conditioning,318 but in male mouse offspring BPA enhances methamphetamine-induced place preference174 that is accompanied by increased methamphetamine-induced hyperlocomotion.

BPA also enhances the rewarding effect of morphine indicated by altered place preference in mice whose mothers were exposed to BPA in the prenatal or neonatal stage.102,319 Increased place preference for morphine in BPA-exposed animals was accompanied by increased morphine-induced hyperlocomotion.319

Similar changes of place preference have been applied as models of schizophrenia. One study used place preference as a model for the reduction in reward-seeking behaviors observed in anhedonia or negative symptoms of schizophrenia.320 Rats treated with EGF during the neonatal period have higher conditioned place preference and exhibit abnormalities in prepulse inhibition.258 Neonatal hippocampal lesions in rats result in abnormalities of amphetamine-induced place preference,320 and PCP treatment of adult rats but not neonatal rats disturbs place preference.321

Summary of the Sexually Dimorphic Effects of BPA Relevant to Schizophrenia

Table 2 lists the sexually dimorphic effects of BPA relevant to schizophrenia that were discussed in preceding sections. Sexual dimorphisms that were discussed above and are specific to schizophrenia include the “feminized” finger-to-digit ratio, and sexually dimorphic calbindin neurons in schizophrenia which are directly comparable to the effects of BPA. Table 2 does not include literature regarding the effects of other EDCs. Table 2 demonstrates that endocrine disruption by BPA induces sexual dimorphisms, and if sexual dimorphisms are related to schizophrenia, there is evidence for BPA to be related to schizophrenia through this mechanism.

Table 2.
Sexual Dimorphisms Induced by BPA


Although the review above may have important implications for the current controversy over the toxicity and permissible levels of human exposure to BPA, the focus of this study has been whether endocrine disruption like that from BPA might be involved in schizophrenia. However, the current debate over the safety of human BPA exposure has raised the question whether endocrine disruption increases the incidence of diseases such as autism and ADHD, diseases that may have associated risk with schizophrenia. For this reason, perhaps the current study may apply to other diseases like autism and ADHD. Because schizophrenia epidemiology has similarities to that of MS,322,323 the role of BPA in promoting autoimmune reactions and repressing myelin basic protein described above supports the addition of diseases like MS to the list of diseases as possibly related to endocrine disruption. The primary goal of the foregoing discussion was, however, to emphasize the several lines of evidence suggesting a possible role of endocrine disruption in the pathogenesis of schizophrenia.

The author does not suggest that BPA is the only purported cause of endocrine disruption leading to schizophrenia. The review above demonstrates that an estrogen mimic or other endocrine signal from some source in prenatal life could be reduced, delayed, increased, or premature which disrupts brain development so as to cause schizophrenia. The theory's validity also does not depend on whether experiments with BPA and other EDCs have used environmentally significant levels of exposure. The purpose of the review was to show the similarities of endocrine disruption to schizophrenia at whatever dose is necessary to induce disruption regardless of the specific agent involved.

The proposed theory is also not limited to suggesting that only fetal or neonatal exposures to EDCs are psychiatrically pathogenic. BPA tissue levels, or exposures to any other major EDCs, have not been studied in children or adults with schizophrenia or other major mental illnesses. It is possible that such studies could reveal previously unsuspected exposures or undiscovered metabolic and/or other abnormalities that would render children or adults with schizophrenia more susceptible to EDCs. It is also possible that exposure of adults with schizophrenia to EDCs could explain certain adverse reactions to medications or disease states believed to have been traits.

However, EDCs invented during the 20th century such as BPA and other plastic-related endocrine disruptors could not be directly related to the existence of schizophrenia in centuries prior to the invention of plastics. This does not mean such chemicals could not enhance the disease's prevalence or severity in the 21st century, and this possibility should be ruled out before any final policy is made about the safety of endocrine disruptors in the environment. This is especially true now that endocrine disruptors have been shown to cause transgenerational mutations that evolve new disease conditions that perpetuate in future generations.324,325

There are several synthetic and naturally occurring endocrine disruptors that were not examined in detail in this study. Many of these, such as cadmium and genistein, have been in the human environment perhaps for thousands of years. The human exposure to cadmium as an environmental contaminant from coal burning326 and tobacco smoking327 probably increased with urbanization, a risk factor often associated with schizophrenia.328 The higher urban risk of schizophrenia has been attributed to higher urban rates of infectious diseases, risk-prone genetic populations, poor nutrition, and stress.329 Although cadmium has never been mentioned as a risk factor in this context before, perhaps it should be included as it has estrogenic-disrupting potential at low doses.330

More than one pathway may exist for endocrine disruption from infections, genetics, malnutrition, and stress. The influence of maternal influenza on gender-related birth defects has been mentioned previously, and nutritional sources of endocrine disruptors include modern chemicals like BPA and naturally occurring substances like genistein. Fetal injury from maternal influenza could be enhanced in an endocrine-disrupted fetus as perinatal exposure to low doses of the endocrine disruptor, PCB-126, impairs maternal and neonatal immunity in a fashion similar to the immune effects induced by perinatal exposure to DES that acts through estrogenic mechanisms.331

Stress has been shown to alter the changes of sex-related behaviors in mice that are influenced by intrauterine positions.332 Studies have shown that gender-related behaviors of both male and female mice are influenced by intrauterine positions that cause variations in exposure to estradiol and T.332,333 Prenatal stress can eliminate these effects,332 acting as an endocrine disruptor of the intrauterine hormonal state. In an endocrine disruption model of schizophrenia, this would imply that the maternal genetics of responding to stress influences the prenatal risk factors of schizophrenia. The notion of “disentangling” maternal genes from environmental risk factors for chronic diseases is not new334 and should be considered for future genetic studies of schizophrenia. Other assessments of schizophrenia that should be performed based on the proposed model would be measures of exposure to endocrine disruption or disruptors, whether synthetic, endogenous, or natural substances, in utero and in later life. This author is proceeding with review of the literature to identify and describe other endocrine disruptors that cause pathological changes similar to those observed in schizophrenia and other diseases as described above.


The author is self-supported and receives no financial or logistical support for this work.


1. Marx CE, Lieberman JA. Psychoneuroendocrinology of schizophrenia. Psychiatr Clin North Am. 1998;21:413–434. [PubMed]
2. Stevens JR. Schizophrenia: reproductive hormones and the brain. Am J Psychiatry. 2002;159:713–719. [PubMed]
3. Koenig JI, Elmer GI, Shepard PD, et al. Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia. Behav Brain Res. 2005;156:251–261. [PubMed]
4. Goldstein JM. Sex, hormones and affective arousal circuitry dysfunction in schizophrenia. Horm Behav. 2006;50:612–622. [PubMed]
5. Baskin LS, Ebbers MB. Hypospadias: anatomy, etiology, and technique. J Pediatr Surg. 2006;41:463–472. [PubMed]
6. North K, Golding J. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int. 2000;85:107–113. [PubMed]
7. Brown AS, Begg MD, Gravenstein S, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. 2004;61:774–780. [PubMed]
8. Kaneda Y, Ohmori T. Relation between estradiol and negative symptoms in men with schizophrenia. J Neuropsychiatry Clin Neurosci. 2005;17:239–242. [PubMed]
9. Huber TJ, Tettenborn C, Leifke E, Emrich HM. Sex hormones in psychotic men. Psychoneuroendocrinology. 2005;30:111–114. [PubMed]
10. Segal M, Avital A, Berstein S, Derevenski A, Sandbank S, Weizman A. Prolactin and estradiol serum levels in unmedicated male paranoid schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:378–382. [PubMed]
11. Huber TJ, Rollnik J, Wilhelms J, von zur MA, Emrich HM, Schneider U. Estradiol levels in psychotic disorders. Psychoneuroendocrinology. 2001;26:27–35. [PubMed]
12. Hoff AL, Kremen WS, Wieneke MH, et al. Association of estrogen levels with neuropsychological performance in women with schizophrenia. Am J Psychiatry. 2001;158:1134–1139. [PubMed]
13. Ko YH, Joe SH, Cho W, et al. Estrogen, cognitive function and negative symptoms in female schizophrenia. Neuropsychobiology. 2006;53:169–175. [PubMed]
14. Huber TJ, Borsutzky M, Schneider U, Emrich HM. Psychotic disorders and gonadal function: evidence supporting the oestrogen hypothesis. Acta Psychiatr Scand. 2004;109:269–274. [PubMed]
15. Salokangas RK, Honkonen T, Saarinen S. Women have later onset than men in schizophrenia—but only in its paranoid form. Results of the DSP project. Eur Psychiatry. 2003;18:274–281. [PubMed]
16. Hochman KM, Lewine RR. Age of menarche and schizophrenia onset in women. Schizophr Res. 2004;69:183–188. [PubMed]
17. Bergemann N, Parzer P, Runnebaum B, Resch F, Mundt C. Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia. Psychol Med. 2007;37:1427–1436. [PubMed]
18. Bergemann N, Mundt C, Parzer P, et al. Plasma concentrations of estradiol in women suffering from schizophrenia treated with conventional versus atypical antipsychotics. Schizophr Res. 2005;73:357–366. [PubMed]
19. Van den BM, Eikelis N. Estrogen increases prepulse inhibition of acoustic startle in rats. Eur J Pharmacol. 2001;425:33–41. [PubMed]
20. Gogos A, Van den BM. Estrogen and progesterone prevent disruption of prepulse inhibition by the serotonin-1A receptor agonist 8-hydroxy-2-dipropylaminotetralin. J Pharmacol Exp Ther. 2004;309:267–274. [PubMed]
21. Gogos A, Nathan PJ, Guille V, Croft RJ, Van den BM. Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women. Neuropsychopharmacology. 2006;31:885–889. [PubMed]
22. Landry M, Di Paolo T. Effect of chronic estradiol, tamoxifen or raloxifene treatment on serotonin 5-HT1A receptor. Brain Res Mol Brain Res. 2003;112:82–89. [PubMed]
23. Cyr M, Calon F, Morissette M, Di Paolo T. Estrogenic modulation of brain activity: implications for schizophrenia and Parkinson's disease. J Psychiatry Neurosci. 2002;27:12–27. [PMC free article] [PubMed]
24. Osterlund MK, Halldin C, Hurd YL. Effects of chronic 17beta-estradiol treatment on the serotonin 5-HT(1A) receptor mRNA and binding levels in the rat brain. Synapse. 2000;35:39–44. [PubMed]
25. Bertrand PP, Paranavitane UT, Chavez C, Gogos A, Jones M, Van den BM. The effect of low estrogen state on serotonin transporter function in mouse hippocampus: a behavioral and electrochemical study. Brain Res. 2005;1064:10–20. [PubMed]
26. Cyr M, Ghribi O, Di Paolo T. Regional and selective effects of oestradiol and progesterone on NMDA and AMPA receptors in the rat brain. J Neuroendocrinol. 2000;12:445–452. [PubMed]
27. Chua WL, de Izquierdo SA, Kulkarni J, Mortimer A. Estrogen for schizophrenia. Cochrane Database Syst Rev. 2005 CD004719. [PubMed]
28. Louza MR, Marques AP, Elkis H, Bassitt D, Diegoli M, Gattaz WF. Conjugated estrogens as adjuvant therapy in the treatment of acute schizophrenia: a double-blind study. Schizophr Res. 2004;66:97–100. [PubMed]
29. Bergemann N, Mundt C, Parzer P, et al. Estrogen as an adjuvant therapy to antipsychotics does not prevent relapse in women suffering from schizophrenia: results of a placebo-controlled double-blind study. Schizophr Res. 2005;74:125–134. [PubMed]
30. Katz DL, Frankenburg FR, Benowitz LI, Gilbert JM. Psychosis and prenatal exposure to diethylstilbestrol. J Nerv Ment Dis. 1987;175:306–308. [PubMed]
31. Sandner G, Silva RC, Angst MJ, Knobloch J, Danion JM. Prenatal exposure of Long-Evans rats to 17alpha-ethinylestradiol modifies neither latent inhibition nor prepulse inhibition of the startle reflex but elicits minor deficits in exploratory behavior. Brain Res Dev Brain Res. 2004;152:177–187. [PubMed]
32. Patisaul HB, Fortino AE, Polston EK. Differential disruption of nuclear volume and neuronal phenotype in the preoptic area by neonatal exposure to genistein and bisphenol-A. Neurotoxicology. 2007;28:1–12. [PubMed]
33. Kawanishi C, Kono M, Onishi H, Ishii N, Ishii K. A case of Turner syndrome with schizophrenia: genetic relationship between Turner syndrome and psychosis. Psychiatry Clin Neurosci. 1997;51:83–85. [PubMed]
34. Bamrah JS, Mackay ME. Chronic psychosis in Turner's syndrome. Case report and a review. Br J Psychiatry. 1989;155:857–859. [PubMed]
35. Everhart DE, Shucard JL, Quatrin T, Shucard DW. Tone probe event-related potential differences during a face recognition task in prepubertal children and Turner syndrome girls. Psychoneuroendocrinology. 2004;29:1260–1271. [PubMed]
36. Prior TI, Chue PS, Tibbo P. Investigation of Turner syndrome in schizophrenia. Am J Med Genet. 2000;96:373–378. [PubMed]
37. Delisi LE, Maurizio AM, Svetina C, et al. Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet. 2005;135:15–23. [PubMed]
38. Cotter D, Pariante CM. Stress and the progression of the developmental hypothesis of schizophrenia. Br J Psychiatry. 2002;181:363–365. [PubMed]
39. Conrad CD, McLaughlin KJ, Harman JS, et al. Chronic glucocorticoids increase hippocampal vulnerability to neurotoxicity under conditions that produce CA3 dendritic retraction but fail to impair spatial recognition memory. J Neurosci. 2007;27:8278–8285. [PMC free article] [PubMed]
40. Cerqueira JJ, Pego JM, Taipa R, Bessa JM, Almeida OF, Sousa N. Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J Neurosci. 2005;25:7792–7800. [PubMed]
41. Ingram N, Martin S, Wang JH, van der LS, Loiacono R, Van den BM. Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice. Neuropharmacology. 2005;48:80–92. [PubMed]
42. Van den BM, Morris M, Chavez C, Martin S, Wang J. Effect of adrenalectomy and corticosterone replacement on prepulse inhibition and locomotor activity in mice. Br J Pharmacol. 2004;142:543–550. [PMC free article] [PubMed]
43. Albrecht ED, Aberdeen GW, Pepe GJ. Estrogen elicits cortical zone-specific effects on development of the primate fetal adrenal gland. Endocrinology. 2005;146:1737–1744. [PubMed]
44. Pepe GJ, Albrecht ED. Central integrative role of oestrogen in the regulation of placental steroidogenic maturation and the development of the fetal pituitary-adrenocortical axis in the baboon. Hum Reprod Update. 1998;4:406–419. [PubMed]
45. Muneoka KT, Shirayama Y, Minabe Y, Takigawa M. Effects of a neurosteroid, pregnenolone, during the neonatal period on adenosine A1 receptor, dopamine metabolites in the fronto-parietal cortex and behavioral response in the open field. Brain Res. 2002;956:332–338. [PubMed]
46. Marx CE, Stevens RD, Shampine LJ, et al. Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology. 2006;31:1249–1263. [PubMed]
47. Morrow AL. Recent developments in the significance and therapeutic relevance of neuroactive steroids—introduction to the special issue. Pharmacol Ther. 2007;116:1–6. [PMC free article] [PubMed]
48. Hosie AM, Wilkins ME, da Silva HM, Smart TG. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature. 2006;444:486–489. [PubMed]
49. Gizerian SS, Morrow AL, Lieberman JA, Grobin AC. Neonatal neurosteroid administration alters parvalbumin expression and neuron number in medial dorsal thalamus of adult rats. Brain Res. 2004;1012:66–74. [PubMed]
50. Marx CE, VanDoren MJ, Duncan GE, Lieberman JA, Morrow AL. Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology. 2003;28:1–13. [PubMed]
51. Marx CE, Shampine LJ, Khisti RT, et al. Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions. Pharmacol Biochem Behav. 2006;84:609–617. [PubMed]
52. Frye CA, Rhodes ME. Estrogen-priming can enhance progesterone's anti-seizure effects in part by increasing hippocampal levels of allopregnanolone. Pharmacol Biochem Behav. 2005;81:907–916. [PubMed]
53. Andreen L, Sundstrom-Poromaa I, Bixo M, Andersson A, Nyberg S, Backstrom T. Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone. Psychoneuroendocrinology. 2005;30:212–224. [PubMed]
54. Andreen L, Spigset O, Andersson A, Nyberg S, Backstrom T. Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone. Maturitas. 2006;54:238–244. [PubMed]
55. Bernardi F, Pluchino N, Pieri M, et al. Progesterone and medroxyprogesterone acetate effects on central and peripheral allopregnanolone and beta-endorphin levels. Neuroendocrinology. 2006;83:348–359. [PubMed]
56. Agis-Balboa RC, Pinna G, Pibiri F, Kadriu B, Costa E, Guidotti A. Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice. Proc Natl Acad Sci USA. 2007;104:18736–18741. [PubMed]
57. Cabrera RJ, Bregonzio C, Laconi M, Mampel A. Allopregnanolone increase in striatal N-methyl-D-aspartic acid evoked [3H] dopamine release is estrogen and progesterone dependent. Cell Mol Neurobiol. 2002;22:445–454. [PubMed]
58. Laconi MR, Reggiani PC, Penissi A, Yunes R, Cabrera RJ. Allopregnanolone modulates striatal dopamingergic activity of rats under different gonadal hormones conditions. Neurol Res. 2007;29:622–627. [PubMed]
59. Blomquist CH, Lima PH, Hotchkiss JR. Inhibition of 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C(18)-, C(19)- and C(21)-hydroxysteroids and ketosteroids. Steroids. 2005;70:507–514. [PubMed]
60. Hiipakka RA, Zhang HZ, Dai W, Dai Q, Liao S. Structure-activity relationships for inhibition of human 5alpha-reductases by polyphenols. Biochem Pharmacol. 2002;63:1165–1176. [PubMed]
61. Weber KS, Jacobson NA, Setchell KD, Lephart ED. Brain aromatase and 5alpha-reductase, regulatory behaviors and testosterone levels in adult rats on phytoestrogen diets. Proc Soc Exp Biol Med. 1999;221:131–135. [PubMed]
62. Doering DD, Steckelbroeck S, Doering T, Klingmuller D. Effects of butyltins on human 5alpha-reductase type 1 and type 2 activity. Steroids. 2002;67:859–867. [PubMed]
63. Campbell EL, Chebib M, Johnston GA. The dietary flavonoids apigenin and (−)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA(A) receptors. Biochem Pharmacol. 2004;68:1631–1638. [PubMed]
64. Kimura-Kuroda J, Nagata I, Kuroda Y. Disrupting effects of hydroxy-polychlorinated biphenyl (PCB) congeners on neuronal development of cerebellar Purkinje cells: a possible causal factor for developmental brain disorders? Chemosphere. 2007;67:S412–S420. [PubMed]
65. Masuo Y, Morita M, Oka S, Ishido M. Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain. Regul Pept. 2004;123:225–234. [PubMed]
66. National Toxicology Program. Center for the Evaluation of Risks to Human Reproduction. Draft meeting summary. Expert Panel Evaluation of Bisphenol-A. August 6–8, 2007. 2007.
67. Akingbemi BT, Sottas CM, Koulova AI, Klinefelter GR, Hardy MP. Inhibition of testicular steroidogenesis by the xenoestrogen bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells. Endocrinology. 2004;145:592–603. [PubMed]
68. Patisaul HB, Fortino AE, Polston EK. Neonatal genistein or bisphenol-A exposure alters sexual differentiation of the AVPV. Neurotoxicol Teratol. 2006;28:111–118. [PubMed]
69. Kang JH, Kondo F, Katayama Y. Human exposure to bisphenol A. Toxicology. 2006;226:79–89. [PubMed]
70. Vom Saal FS, Akingbemi BT, Belcher SM, et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol. 2007;24:131–138. [PMC free article] [PubMed]
71. Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Hum Reprod. 2002;17:2839–2841. [PubMed]
72. Yamada H, Furuta I, Kato EH, et al. Maternal serum and amniotic fluid bisphenol A concentrations in the early second trimester. Reprod Toxicol. 2002;16:735–739. [PubMed]
73. Lloyd T, Dazzan P, Dean K, et al. Minor physical anomalies in patients with first-episode psychosis: their frequency and diagnostic specificity. Psychol Med. 2008;38:71–77. [PubMed]
74. Gourion D, Goldberger C, Bourdel MC, Jean BF, Loo H, Krebs MO. Minor physical anomalies in patients with schizophrenia and their parents: prevalence and pattern of craniofacial abnormalities. Psychiatry Res. 2004;125:21–28. [PubMed]
75. Baroni T, Bellucci C, Lilli C, et al. Retinoic acid, GABA-ergic, and TGF-beta signaling systems are involved in human cleft palate fibroblast phenotype. Mol Med. 2006;12:237–245. [PMC free article] [PubMed]
76. Nishizawa H, Morita M, Sugimoto M, Imanishi S, Manabe N. Effects of in utero exposure to bisphenol A on mRNA expression of arylhydrocarbon and retinoid receptors in murine embryos. J Reprod Dev. 2005;51:315–324. [PubMed]
77. Fukushima A, Funabashi T, Kawaguchi M, Mitsushima D, Kimura F. Bisphenol A induces transforming growth factor-beta3 mRNA in the preoptic area: a cDNA expression array and Northern blot study. Neurosci Lett. 2007;411:81–85. [PubMed]
78. Walder DJ, Andersson TL, McMillan AL, Breedlove SM, Walker EF. Sex differences in digit ratio (2D:4D) are disrupted in adolescents with schizotypal personality disorder: altered prenatal gonadal hormone levels as a risk factor. Schizophr Res. 2006;86:118–122. [PubMed]
79. Arato M, Frecska E, Beck C, An M, Kiss H. Digit length pattern in schizophrenia suggests disturbed prenatal hemispheric lateralization. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:191–194. [PubMed]
80. Procopio M, Davies RJ, Marriott P. The hormonal environment in utero as a potential aetiological agent for schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2006;256:77–81. [PubMed]
81. Kubo K, Arai O, Omura M, Watanabe R, Ogata R, Aou S. Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats. Neurosci Res. 2003;45:345–356. [PubMed]
82. Monje L, Varayoud J, Luque EH, Ramos JG. Neonatal exposure to bisphenol A modifies the abundance of estrogen receptor {alpha} transcripts with alternative 5′-untranslated regions in the female rat preoptic area. J Endocrinol. 2007;194:201–212. [PubMed]
83. Patisaul HB, Polston EK. Influence of endocrine active compounds on the developing rodent brain. Brain Res Rev. 2007 [PubMed]
84. Khurana S, Ranmal S, Ben Jonathan N. Exposure of newborn male and female rats to environmental estrogens: delayed and sustained hyperprolactinemia and alterations in estrogen receptor expression. Endocrinology. 2000;141:4512–4517. [PubMed]
85. Ceccarelli I, Della SD, Fiorenzani P, Farabollini F, Aloisi AM. Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats. Neurotoxicol Teratol. 2007;29:108–115. [PubMed]
86. Picard H, Amado I, Mouchet-Mages S, Olie JP, Krebs MO. The role of the cerebellum in schizophrenia: an update of clinical, cognitive, and functional evidences. Schizophr Bull. 2008;34:155–172. [PMC free article] [PubMed]
87. Daskalakis ZJ, Christensen BK, Fitzgerald PB, Fountain SI, Chen R. Reduced cerebellar inhibition in schizophrenia: a preliminary study. Am J Psychiatry. 2005;162:1203–1205. [PubMed]
88. Tran KD, Smutzer GS, Doty RL, Arnold SE. Reduced Purkinje cell size in the cerebellar vermis of elderly patients with schizophrenia. Am J Psychiatry. 1998;155:1288–1290. [PubMed]
89. Eastwood SL, Law AJ, Everall IP, Harrison PJ. The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology. Mol Psychiatry. 2003;8:148–155. [PubMed]
90. Zsarnovszky A, Le HH, Wang HS, Belcher SM. Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A. Endocrinology. 2005;146:5388–5396. [PubMed]
91. Shikimi H, Sakamoto H, Mezaki Y, Ukena K, Tsutsui K. Dendritic growth in response to environmental estrogens in the developing Purkinje cell in rats. Neurosci Lett. 2004;364:114–118. [PubMed]
92. Sakamoto H, Mezaki Y, Shikimi H, Ukena K, Tsutsui K. Dendritic growth and spine formation in response to estrogen in the developing Purkinje cell. Endocrinology. 2003;144:4466–4477. [PubMed]
93. Ostlund H, Keller E, Hurd YL. Estrogen receptor gene expression in relation to neuropsychiatric disorders. Ann N Y Acad Sci. 2003;1007:54–63. [PubMed]
94. Craven RM, Priddle TH, Crow TJ, Esiri MM. The locus coeruleus in schizophrenia: a postmortem study of noradrenergic neurones. Neuropathol Appl Neurobiol. 2005;31:115–126. [PubMed]
95. Reif A, Fritzen S, Finger M, et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006;11:514–522. [PubMed]
96. Kim K, Son TG, Kim SJ, et al. Suppressive effects of bisphenol A on the proliferation of neural progenitor cells. J Toxicol Environ Health A. 2007;70:1288–1295. [PubMed]
97. Nakamura K, Itoh K, Yaoi T, Fujiwara Y, Sugimoto T, Fushiki S. Murine neocortical histogenesis is perturbed by prenatal exposure to low doses of bisphenol A. J Neurosci Res. 2006;84:1197–1205. [PubMed]
98. Yamamoto M, Tase N, Okuno T, et al. Monitoring of gene expression in differentiation of embryoid bodies from cynomolgus monkey embryonic stem cells in the presence of bisphenol A. J Toxicol Sci. 2007;32:301–310. [PubMed]
99. Oka T, Adati N, Shinkai T, Sakuma K, Nishimura T, Kurose K. Bisphenol A induces apoptosis in central neural cells during early development of Xenopus laevis. Biochem Biophys Res Commun. 2003;312:877–882. [PubMed]
100. Keilhoff G, Bernstein HG, Becker A, Grecksch G, Wolf G. Increased neurogenesis in a rat ketamine model of schizophrenia. Biol Psychiatry. 2004;56:317–322. [PubMed]
101. Negishi T, Ishii Y, Kyuwa S, Kuroda Y, Yoshikawa Y. Inhibition of staurosporine-induced neuronal cell death by bisphenol A and nonylphenol in primary cultured rat hippocampal and cortical neurons. Neurosci Lett. 2003;353:99–102. [PubMed]
102. Miyatake M, Miyagawa K, Mizuo K, Narita M, Suzuki T. Dynamic changes in dopaminergic neurotransmission induced by a low concentration of bisphenol-A in neurones and astrocytes. J Neuroendocrinol. 2006;18:434–444. [PubMed]
103. Wang CZ, Johnson KM. The role of caspase-3 activation in phencyclidine-induced neuronal death in postnatal rats. Neuropsychopharmacology. 2007;32:1178–1194. [PubMed]
104. Jarskog LF, Gilmore JH, Glantz LA, et al. Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics. Neuropsychopharmacology. 2007;32:95–102. [PubMed]
105. Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH. Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry. 2004;161:109–115. [PubMed]
106. Lin Y, Zhang H, Wang WD, Wu DS, Jiang SH, Qu WD. Effects of perinatal exposure to bisphenol A inducing dopaminergic neuronal cell to apoptosis happening in midbrain of male rat offspring. Sichuan Da Xue Xue Bao Yi Xue Ban. 2006;37:570–573. [PubMed]
107. Humphrey WM, Dong H, Csernansky CA, Csernansky JG. Immediate and delayed hippocampal neuronal loss induced by kainic acid during early postnatal development in the rat. Brain Res Dev Brain Res. 2002;137:1–12. [PubMed]
108. Ishido M, Yonemoto J, Morita M. Mesencephalic neurodegeneration in the orally administered bisphenol A-caused hyperactive rats. Toxicol Lett. 2007;173:66–72. [PubMed]
109. MacLusky NJ, Hajszan T, Leranth C. The environmental estrogen bisphenol A inhibits estradiol-induced hippocampal synaptogenesis. Environ Health Perspect. 2005;113:675–679. [PMC free article] [PubMed]
110. Kyosseva SV, Elbein AD, Griffin WS, Mrak RE, Lyon M, Karson CN. Mitogen-activated protein kinases in schizophrenia. Biol Psychiatry. 1999;46:689–696. [PubMed]
111. Gursoy E, Cardounel A, Kalimi M. The environmental estrogenic compound bisphenol A exerts estrogenic effects on mouse hippocampal (HT-22) cells: neuroprotection against glutamate and amyloid beta protein toxicity. Neurochem Int. 2001;38:181–186. [PubMed]
112. Chana G, Landau S, Beasley C, Everall IP, Cotter D. Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Biol Psychiatry. 2003;53:1086–1098. [PubMed]
113. Nakamura K, Itoh K, Sugimoto T, Fushiki S. Prenatal exposure to bisphenol A affects adult murine neocortical structure. Neurosci Lett. 2007;420:100–105. [PubMed]
114. Hof PR, Haroutunian V, Copland C, Davis KL, Buxbaum JD. Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochem Res. 2002;27:1193–1200. [PubMed]
115. Katsel P, Davis KL, Haroutunian V. Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: a gene ontology study. Schizophr Res. 2005;79:157–173. [PubMed]
116. Haroutunian V, Davis KL. Introduction to the special section: myelin and oligodendrocyte abnormalities in schizophrenia. Int J Neuropsychopharmacol. 2007;10:499–502. [PubMed]
117. Seiwa C, Nakahara J, Komiyama T, Katsu Y, Iguchi T, Asou H. Bisphenol A exerts thyroid-hormone-like effects on mouse oligodendrocyte precursor cells. Neuroendocrinology. 2004;80:21–30. [PubMed]
118. Watanabe Y, Hashimoto S, Kakita A, et al. Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats. Neurosci Res. 2004;48:345–353. [PubMed]
119. Cadman ED, Witte DG, Lee CM. Regulation of the release of interleukin-6 from human astrocytoma cells. J Neurochem. 1994;63:980–987. [PubMed]
120. van Kammen DP, McAllister-Sistilli CG, Kelley ME, Gurklis JA, Yao JK. Elevated interleukin-6 in schizophrenia. Psychiatry Res. 1999;87:129–136. [PubMed]
121. Zhang XY, Zhou DF, Zhang PY, Wu GY, Cao LY, Shen YC. Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res. 2002;57:247–258. [PubMed]
122. Garver DL, Tamas RL, Holcomb JA. Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. Neuropsychopharmacology. 2003;28:1515–1520. [PubMed]
123. Yamaguchi H, Zhu J, Yu T, et al. Serum-free mouse embryo cells generate a self-sustaining feedback loop for an astrocyte marker protein and respond to cytokines and bisphenol A in accordance with the subtle difference in their differentiation state. Cell Biol Int. 2007;31:638–644. [PubMed]
124. Yamaguchi H, Zhu J, Yu T, et al. Low-level bisphenol A increases production of glial fibrillary acidic protein in differentiating astrocyte progenitor cells through excessive STAT3 and Smad1 activation. Toxicology. 2006;226:131–142. [PubMed]
125. Yamamoto T, Matsuda T, Junicho A, Kishi H, Saatcioglu F, Muraguchi A. Cross-talk between signal transducer and activator of transcription 3 and estrogen receptor signaling. FEBS Lett. 2000;486:143–148. [PubMed]
126. Ueberham U, Ueberham E, Gruschka H, Arendt T. Altered subcellular location of phosphorylated Smads in Alzheimer's disease. Eur J Neurosci. 2006;24:2327–2334. [PubMed]
127. Arif M, Chikuma T, Ahmed MM, Yoshida S, Kato T. Suppressive effect of clozapine but not haloperidol on the increases of neuropeptide-degrading enzymes and glial cells in MK-801-treated rat brain regions. Neurosci Res. 2007;57:248–258. [PubMed]
128. Rothermundt M, Ohrmann P, Abel S, et al. Glial cell activation in a subgroup of patients with schizophrenia indicated by increased S100B serum concentrations and elevated myo-inositol. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:361–364. [PubMed]
129. Mrak RE, Griffinbc WS. The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease. Neurobiol Aging. 2001;22:915–922. [PubMed]
130. Yokosuka M, Ohtani-Kaneko R, Yamashita K, Muraoka D, Kuroda Y, Watanabe C. Estrogen and environmental estrogenic chemicals exert developmental effects on rat hypothalamic neurons and glias. Toxicol In Vitro. 2007 [PubMed]
131. Perlman WR, Webster MJ, Kleinman JE, Weickert CS. Reduced glucocorticoid and estrogen receptor alpha messenger ribonucleic acid levels in the amygdala of patients with major mental illness. Biol Psychiatry. 2004;56:844–852. [PubMed]
132. Perlman WR, Tomaskovic-Crook E, Montague DM, et al. Alteration in estrogen receptor alpha mRNA levels in frontal cortex and hippocampus of patients with major mental illness. Biol Psychiatry. 2005;58:812–824. [PubMed]
133. Osterlund MK, Keller E, Hurd YL. The human forebrain has discrete estrogen receptor alpha messenger RNA expression: high levels in the amygdaloid complex. Neuroscience. 2000;95:333–342. [PubMed]
134. Kretz O, Fester L, Wehrenberg U, et al. Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci. 2004;24:5913–5921. [PubMed]
135. Choi JM, Romeo RD, Brake WG, Bethea CL, Rosenwaks Z, McEwen BS. Estradiol increases pre- and post-synaptic proteins in the CA1 region of the hippocampus in female rhesus macaques (Macaca mulatta) Endocrinology. 2003;144:4734–4738. [PubMed]
136. Lustig RH, Sudol M, Pfaff DW, Federoff HJ. Estrogenic regulation and sex dimorphism of growth-associated protein 43 kDa (GAP-43) messenger RNA in the rat. Brain Res Mol Brain Res. 1991;11:125–132. [PubMed]
137. Chambers JS, Thomas D, Saland L, Neve RL, Perrone-Bizzozero NI. Growth-associated protein 43 (GAP-43) and synaptophysin alterations in the dentate gyrus of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:283–290. [PubMed]
138. Webster MJ, Shannon WC, Herman MM, Hyde TM, Kleinman JE. Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia. Schizophr Res. 2001;49:89–98. [PubMed]
139. Ritsner M, Gibel A, Ram E, Maayan R, Weizman A. Alterations in DHEA metabolism in schizophrenia: two-month case-control study. Eur Neuropsychopharmacol. 2006;16:137–146. [PubMed]
140. Shirayama Y, Hashimoto K, Suzuki Y, Higuchi T. Correlation of plasma neurosteroid levels to the severity of negative symptoms in male patients with schizophrenia. Schizophr Res. 2002;58:69–74. [PubMed]
141. Kritzer MF, Adler A, Bethea CL. Ovarian hormone influences on the density of immunoreactivity for tyrosine hydroxylase and serotonin in the primate corpus striatum. Neuroscience. 2003;122:757–772. [PubMed]
142. Benes FM, Todtenkopf MS, Taylor JB. Differential distribution of tyrosine hydroxylase fibers on small and large neurons in layer II of anterior cingulate cortex of schizophrenic brain. Synapse. 1997;25:80–92. [PubMed]
143. Lee D, Wang L, Dong P, Tran T, Copolov D, Lim AT. Progesterone modulation of D5 receptor expression in hypothalamic ANP neurons, the role of estrogen. Mol Psychiatry. 2001;6:112–117. [PubMed]
144. Takagi H, Shibutani M, Lee KY, et al. Impact of maternal dietary exposure to endocrine-acting chemicals on progesterone receptor expression in microdissected hypothalamic medial preoptic areas of rat offspring. Toxicol Appl Pharmacol. 2005;208:127–136. [PubMed]
145. Lewis RW, Brooks N, Milburn GM, et al. The effects of the phytoestrogen genistein on the postnatal development of the rat. Toxicol Sci. 2003;71:74–83. [PubMed]
146. Funabashi T, Sano A, Mitsushima D, Kimura F. Bisphenol A increases progesterone receptor immunoreactivity in the hypothalamus in a dose-dependent manner and affects sexual behaviour in adult ovariectomized rats. J Neuroendocrinol. 2003;15:134–140. [PubMed]
147. Funabashi T, Kawaguchi M, Kimura F. The endocrine disrupters butyl benzyl phthalate and bisphenol A increase the expression of progesterone receptor messenger ribonucleic acid in the preoptic area of adult ovariectomized rats. Neuroendocrinology. 2001;74:77–81. [PubMed]
148. Funabashi T, Nakamura TJ, Kimura F. p-Nonylphenol, 4-tert-octylphenol and bisphenol A increase the expression of progesterone receptor mRNA in the frontal cortex of adult ovariectomized rats. J Neuroendocrinol. 2004;16:99–104. [PubMed]
149. Ferrier IN, Johnstone EC, Crow TJ, Rincon-Rodriguez I. Anterior pituitary hormone secretion in chronic schizophrenics. Arch Gen Psychiatry. 1983;40:755–761. [PubMed]
150. Tripodianakis J, Markianos M, Rouvali O, Istikoglou C. Gonadal axis hormones in psychiatric male patients after a suicide attempt. Eur Arch Psychiatry Clin Neurosci. 2007;257:135–139. [PubMed]
151. Grattan DR, Jasoni CL, Liu X, Anderson GM, Herbison AE. Prolactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice. Endocrinology. 2007;148:4344–4351. [PubMed]
152. Hashimoto T, Arion D, Unger T, et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2007 [PMC free article] [PubMed]
153. Facciolo RM, Madeo M, Alo R, Canonaco M, Dessi-Fulgheri F. Neurobiological effects of bisphenol A may be mediated by somatostatin subtype 3 receptors in some regions of the developing rat brain. Toxicol Sci. 2005;88:477–484. [PubMed]
154. Facciolo RM, Alo R, Madeo M, Canonaco M, Dessi-Fulgheri F. Early cerebral activities of the environmental estrogen bisphenol A appear to act via the somatostatin receptor subtype sst(2) Environ Health Perspect. 2002;110(suppl 3):397–402. [PMC free article] [PubMed]
155. Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI. Prenatal stress generates deficits in rat social behavior: reversal by oxytocin. Brain Res. 2007;1156:152–167. [PMC free article] [PubMed]
156. Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI. Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin. Neuropsychopharmacology. 2005;30:1883–1894. [PubMed]
157. Liu W, Pappas GD, Carter CS. Oxytocin receptors in brain cortical regions are reduced in haploinsufficient (+/−) reeler mice. Neurol Res. 2005;27:339–345. [PubMed]
158. Della SD, Minder I, Dessi-Fulgheri F, Farabollini F. Bisphenol-A exposure during pregnancy and lactation affects maternal behavior in rats. Brain Res Bull. 2005;65:255–260. [PubMed]
159. Risterucci C, Jeanneau K, Schoppenthau S, et al. Functional magnetic resonance imaging reveals similar brain activity changes in two different animal models of schizophrenia. Psychopharmacology (Berl) 2005;180:724–734. [PubMed]
160. Conti LH, Murry JD, Ruiz MA, Printz MP. Effects of corticotropin-releasing factor on prepulse inhibition of the acoustic startle response in two rat strains. Psychopharmacology (Berl) 2002;161:296–303. [PubMed]
161. Dirks A, Groenink L, Schipholt MI, et al. Reduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone. Biol Psychiatry. 2002;51:583–590. [PubMed]
162. Gayle DA, Beloosesky R, Desai M, Amidi F, Nunez SE, Ross MG. Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain. Am J Physiol Regul Integr Comp Physiol. 2004;286:R1024–R1029. [PubMed]
163. Funabashi T, Kawaguchi M, Furuta M, Fukushima A, Kimura F. Exposure to bisphenol A during gestation and lactation causes loss of sex difference in corticotropin-releasing hormone-immunoreactive neurons in the bed nucleus of the stria terminalis of rats. Psychoneuroendocrinology. 2004;29:475–485. [PubMed]
164. Katoh K, Matsuda A, Ishigami A, et al. Suppressing effects of bisphenol A on the secretory function of ovine anterior pituitary cells. Cell Biol Int. 2004;28:463–469. [PubMed]
165. Miyamoto S, Mailman RB, Lieberman JA, Duncan GE. Blunted brain metabolic response to ketamine in mice lacking D(1A) dopamine receptors. Brain Res. 2001;894:167–180. [PubMed]
166. Mateos JJ, Lomena F, Parellada E, et al. Lower striatal dopamine transporter binding in neuroleptic-naive schizophrenic patients is not related to antipsychotic treatment but it suggests an illness trait. Psychopharmacology (Berl) 2007;191:805–811. [PubMed]
167. Parikh V, Apparsundaram S, Kozak R, Richards JB, Sarter M. Reduced expression and capacity of the striatal high-affinity choline transporter in hyperdopaminergic mice. Neuroscience. 2006;141:379–389. [PubMed]
168. Mueller HT, Haroutunian V, Davis KL, Meador-Woodruff JH. Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. Brain Res Mol Brain Res. 2004;121:60–69. [PubMed]
169. Klejbor I, Myers JM, Hausknecht K, et al. Fibroblast growth factor receptor signaling affects development and function of dopamine neurons—inhibition results in a schizophrenia-like syndrome in transgenic mice. J Neurochem. 2006;97:1243–1258. [PubMed]
170. Rubin BS, Lenkowski JR, Schaeberle CM, Vandenberg LN, Ronsheim PM, Soto AM. Evidence of altered brain sexual differentiation in mice exposed perinatally to low, environmentally relevant levels of bisphenol A. Endocrinology. 2006;147:3681–3691. [PubMed]
171. Tando S, Itoh K, Yaoi T, Ikeda J, Fujiwara Y, Fushiki S. Effects of pre- and neonatal exposure to bisphenol A on murine brain development. Brain Dev. 2007;29:352–356. [PubMed]
172. Ishido M, Morita M, Oka S, Masuo Y. Alteration of gene expression of G protein-coupled receptors in endocrine disruptors-caused hyperactive rats. Regul Pept. 2005;126:145–153. [PubMed]
173. Ishido M, Masuo Y, Kunimoto M, Oka S, Morita M. Bisphenol A causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity. J Neurosci Res. 2004;76:423–433. [PubMed]
174. Suzuki T, Mizuo K, Nakazawa H, et al. Prenatal and neonatal exposure to bisphenol-A enhances the central dopamine D1 receptor-mediated action in mice: enhancement of the methamphetamine-induced abuse state. Neuroscience. 2003;117:639–644. [PubMed]
175. Miyagawa K, Narita M, Narita M, et al. Changes in central dopaminergic systems with the expression of Shh or GDNF in mice perinatally exposed to bisphenol-A. Nihon Shinkei Seishin Yakurigaku Zasshi. 2007;27:69–75. [PubMed]
176. Yoneda T, Hiroi T, Osada M, Asada A, Funae Y. Non-genomic modulation of dopamine release by bisphenol-A in PC12 cells. J Neurochem. 2003;87:1499–1508. [PubMed]
177. Mizuo K, Narita M, Yoshida T, Narita M, Suzuki T. Functional changes in dopamine D3 receptors by prenatal and neonatal exposure to an endocrine disruptor bisphenol-A in mice. Addict Biol. 2004;9:19–25. [PubMed]
178. Bruins Slot LA, Palmier C, Tardif S, Cussac D. Action of novel antipsychotics at human dopamine D(3) receptors coupled to G protein and ERK1/2 activation. Neuropharmacology. 2007;53:232–241. [PubMed]
179. Fishburn CS, Bedford M, Lonai P, Fuchs S. Early expression of D3 dopamine receptors in murine embryonic development. FEBS Lett. 1996;381:257–261. [PubMed]
180. Le Foll B, Diaz J, Sokoloff P. Neuroadaptations to hyperdopaminergia in dopamine D3 receptor-deficient mice. Life Sci. 2005;76:1281–1296. [PubMed]
181. Guillin O, Demily C, Thibaut F. Brain-derived neurotrophic factor in schizophrenia and its relation with dopamine. Int Rev Neurobiol. 2007;78:377–395. [PubMed]
182. Bernardo A, Minghetti L. PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr Pharm Des. 2006;12:93–109. [PubMed]
183. Wada K, Nakajima A, Katayama K, et al. Peroxisome proliferator-activated receptor gamma-mediated regulation of neural stem cell proliferation and differentiation. J Biol Chem. 2006;281:12673–12681. [PubMed]
184. Hunter RL, Dragicevic N, Seifert K, et al. Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem. 2007;100:1375–1386. [PubMed]
185. Heneka MT, Feinstein DL, Galea E, Gleichmann M, Wullner U, Klockgether T. Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J Neuroimmunol. 1999;100:156–168. [PubMed]
186. Heneka MT, Klockgether T, Feinstein DL. Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. J Neurosci. 2000;20:6862–6867. [PubMed]
187. Garcia-Bueno B, Caso JR, Perez-Nievas BG, Lorenzo P, Leza JC. Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology. 2007;32:1251–1260. [PubMed]
188. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE. Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci. 2000;20:558–567. [PubMed]
189. Storer PD, Xu J, Chavis J, Drew PD. Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis. J Neuroimmunol. 2005;161:113–122. [PubMed]
190. Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta. 2007;1771:1031–1045. [PubMed]
191. Maeda T, Kiguchi N, Fukazawa Y, Yamamoto A, Ozaki M, Kishioka S. Peroxisome proliferator-activated receptor gamma activation relieves expression of behavioral sensitization to methamphetamine in mice. Neuropsychopharmacology. 2007;32:1133–1140. [PubMed]
192. Koivisto AM, Helisalmi S, Pihlajamaki J, et al. Association analysis of peroxisome proliferator-activated receptor gamma polymorphisms and late onset Alzheimer's disease in the Finnish population. Dement Geriatr Cogn Disord. 2006;22:449–453. [PubMed]
193. Scacchi R, Pinto A, Gambina G, Rosano A, Corbo RM. The peroxisome proliferator-activated receptor gamma (PPAR-gamma2) Pro12Ala polymorphism is associated with higher risk for Alzheimer's disease in octogenarians. Brain Res. 2007;1139:1–5. [PubMed]
194. Hyoung UJ, Yang YJ, Kwon SK, et al. Developmental toxicity by exposure to bisphenol A diglycidyl ether during gestation and lactation period in Sprague-Dawley male rats. J Prev Med Pub Health. 2007;40:155–161. [PubMed]
195. Fehlberg S, Gregel CM, Goke A, Goke R. Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO. Br J Pharmacol. 2003;139:495–500. [PMC free article] [PubMed]
196. Hanaoka T, Kawamura N, Hara K, Tsugane S. Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents. Occup Environ Med. 2002;59:625–628. [PMC free article] [PubMed]
197. Schaefer KL, Takahashi H, Morales VM, et al. PPARgamma inhibitors reduce tubulin protein levels by a PPARgamma, PPARdelta and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells. Int J Cancer. 2007;120:702–713. [PubMed]
198. Raikwar HP, Muthian G, Rajasingh J, Johnson C, Bright JJ. PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol. 2005;167:99–107. [PubMed]
199. Raikwar HP, Muthian G, Rajasingh J, Johnson CN, Bright JJ. PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2. J Neuroimmunol. 2006;178:76–86. [PubMed]
200. Zander T, Kraus JA, Grommes C, et al. Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma. J Neurochem. 2002;81:1052–1060. [PubMed]
201. Park KS, Lee RD, Kang SK, et al. Neuronal differentiation of embryonic midbrain cells by upregulation of peroxisome proliferator-activated receptor-gamma via the JNK-dependent pathway. Exp Cell Res. 2004;297:424–433. [PubMed]
202. Kim CH, Hahn MK, Joung Y, et al. A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder. Proc Natl Acad Sci U S A. 2006;103:19164–19169. [PubMed]
203. Aneja A, Fremont WP, Antshel KM, et al. Manic symptoms and behavioral dysregulation in youth with velocardiofacial syndrome (22q11.2 deletion syndrome) J Child Adolesc Psychopharmacol. 2007;17:105–114. [PubMed]
204. Toyohira Y, Utsunomiya K, Ueno S, et al. Inhibition of the norepinephrine transporter function in cultured bovine adrenal medullary cells by bisphenol A. Biochem Pharmacol. 2003;65:2049–2054. [PubMed]
205. Mancama D, Mata I, Kerwin RW, Arranz MJ. Choline acetyltransferase variants and their influence in schizophrenia and olanzapine response. Am J Med Genet B Neuropsychiatr Genet. 2007;144:849–853. [PubMed]
206. Miyagawa K, Narita M, Narita M, Akama H, Suzuki T. Memory impairment associated with a dysfunction of the hippocampal cholinergic system induced by prenatal and neonatal exposures to bisphenol-A. Neurosci Lett. 2007;418:236–241. [PubMed]
207. Juarez de Ku LM, Sharma-Stokkermans M, Meserve LA. Thyroxine normalizes polychlorinated biphenyl (PCB) dose-related depression of choline acetyltransferase (ChAT) activity in hippocampus and basal forebrain of 15-day-old rats. Toxicology. 1994;94:19–30. [PubMed]
208. Schwabe K, Gavrilovici C, McIntyre DC, Poulter MO. Neurosteroids exhibit differential effects on mIPSCs recorded from normal and seizure prone rats. J Neurophysiol. 2005;94:2171–2181. [PubMed]
209. Kawato S. Endocrine disrupters as disrupters of brain function: a neurosteroid viewpoint. Environ Sci. 2004;11:1–14. [PubMed]
210. Choi IS, Cho JH, Park EJ, et al. Multiple effects of bisphenol A, an endocrine disrupter, on GABA(A) receptors in acutely dissociated rat CA3 pyramidal neurons. Neurosci Res. 2007;59:8–17. [PubMed]
211. Okada M, Corfas G. Neuregulin1 downregulates postsynaptic GABAA receptors at the hippocampal inhibitory synapse. Hippocampus. 2004;14:337–344. [PubMed]
212. Reddy DS. The clinical potentials of endogenous neurosteroids. Drugs Today (Barc) 2002;38:465–485. [PubMed]
213. Arsic D, Beasley SW, Sullivan MJ. Switched-on Sonic hedgehog: a gene whose activity extends beyond fetal development—to oncogenesis. J Paediatr Child Health. 2007;43:421–423. [PubMed]
214. Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J Rare Dis. 2007;2:8. [PMC free article] [PubMed]
215. Ogura H, Aruga J, Mikoshiba K. Behavioral abnormalities of Zic1 and Zic2 mutant mice: implications as models for human neurological disorders. Behav Genet. 2001;31:317–324. [PubMed]
216. Michelato A, Bonvicini C, Ventriglia M, et al. 3′ UTR (AGG)n repeat of glial cell line-derived neurotrophic factor (GDNF) gene polymorphism in schizophrenia. Neurosci Lett. 2004;357:235–237. [PubMed]
217. Boger HA, Middaugh LD, Patrick KS, et al. Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice. J Neurosci. 2007;27:8816–8825. [PMC free article] [PubMed]
218. Kehr J, Yoshitake T, Wang FH, et al. Galanin is a potent in vivo modulator of mesencephalic serotonergic neurotransmission. Neuropsychopharmacology. 2002;27:341–356. [PubMed]
219. Ericson E, Ahlenius S. Suggestive evidence for inhibitory effects of galanin on mesolimbic dopaminergic neurotransmission. Brain Res. 1999;822:200–209. [PubMed]
220. Elliott-Hunt CR, Pope RJ, Vanderplank P, Wynick D. Activation of the galanin receptor 2 (GalR2) protects the hippocampus from neuronal damage. J Neurochem. 2007;100:780–789. [PMC free article] [PubMed]
221. Ding X, MacTavish D, Kar S, Jhamandas JH. Galanin attenuates beta-amyloid (Abeta) toxicity in rat cholinergic basal forebrain neurons. Neurobiol Dis. 2006;21:413–420. [PubMed]
222. Mazarati A, Lundstrom L, Sollenberg U, Shin D, Langel U, Sankar R. Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: the effects of subtype-selective agonists and the role of G-protein-mediated signaling. J Pharmacol Exp Ther. 2006;318:700–708. [PubMed]
223. Bailey KR, Pavlova MN, Rohde AD, Hohmann JG, Crawley JN. Galanin receptor subtype 2 (GalR2) null mutant mice display an anxiogenic-like phenotype specific to the elevated plus-maze. Pharmacol Biochem Behav. 2007;86:8–20. [PMC free article] [PubMed]
224. Becker A, Grecksch G, Schroder H. Pain sensitivity is altered in animals after subchronic ketamine treatment. Psychopharmacology (Berl) 2006;189:237–247. [PubMed]
225. Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol Psychiatry. 2002;7:837–844. [PubMed]
226. Harte MK, Powell SB, Swerdlow NR, Geyer MA, Reynolds GP. Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats. J Neural Transm. 2007;114:893–898. [PubMed]
227. Chance SA, Walker M, Crow TJ. Reduced density of calbindin-immunoreactive interneurons in the planum temporale in schizophrenia. Brain Res. 2005;1046:32–37. [PubMed]
228. Goodman AB. Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci U S A. 1998;95:7240–7244. [PubMed]
229. Levesque D, Rouillard C. Nur77 and retinoid X receptors: crucial factors in dopamine-related neuroadaptation. Trends Neurosci. 2007;30:22–30. [PubMed]
230. Palha JA, Goodman AB. Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia. Brain Res Rev. 2006;51:61–71. [PubMed]
231. Ruano D, Aulchenko YS, Macedo A, et al. Association of the gene encoding neurogranin with schizophrenia in males. J Psychiatr Res. 2008;42:125–133. [PubMed]
232. Broadbelt K, Ramprasaud A, Jones LB. Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. Schizophr Res. 2006;87:6–14. [PubMed]
233. Sandhu HK, Sarkar M, Turner BM, Wassink TH, Philibert RA. Polymorphism analysis of HOPA: a candidate gene for schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2003;123:33–38. [PubMed]
234. Beyer KS, Klauck SM, Benner A, Poustka F, Poustka A. Association studies of the HOPA dodecamer duplication variant in different subtypes of autism. Am J Med Genet. 2002;114:110–115. [PubMed]
235. Philibert RA. A meta-analysis of the association of the HOPA12bp polymorphism and schizophrenia. Psychiatr Genet. 2006;16:73–76. [PubMed]
236. Iwamuro S, Yamada M, Kato M, Kikuyama S. Effects of bisphenol A on thyroid hormone-dependent up-regulation of thyroid hormone receptor alpha and beta and down-regulation of retinoid X receptor gamma in Xenopus tail culture. Life Sci. 2006;79:2165–2171. [PubMed]
237. Zoeller RT, Bansal R, Parris C. Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain. Endocrinology. 2005;146:607–612. [PubMed]
238. Xu X, Liu Y, Sadamatsu M, et al. Perinatal bisphenol A affects the behavior and SRC-1 expression of male pups but does not influence on the thyroid hormone receptors and its responsive gene. Neurosci Res. 2007;58:149–155. [PubMed]
239. Moriyama K, Tagami T, Akamizu T, et al. Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrinol Metab. 2002;87:5185–5190. [PubMed]
240. Inoshita H, Masuyama H, Hiramatsu Y. The different effects of endocrine-disrupting chemicals on estrogen receptor-mediated transcription through interaction with coactivator TRAP220 in uterine tissue. J Mol Endocrinol. 2003;31:551–561. [PubMed]
241. Nakamura T, Lipton SA. Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases. Cell Mol Life Sci. 2007;64:1609–1620. [PubMed]
242. Cummings JL. Dementia with lewy bodies: molecular pathogenesis and implications for classification. J Geriatr Psychiatry Neurol. 2004;17:112–119. [PubMed]
243. Hiroi T, Okada K, Imaoka S, Osada M, Funae Y. Bisphenol A binds to protein disulfide isomerase and inhibits its enzymatic and hormone-binding activities. Endocrinology. 2006;147:2773–2780. [PubMed]
244. Paz RD, Andreasen NC, Daoud SZ, et al. Increased expression of activity-dependent genes in cerebellar glutamatergic neurons of patients with schizophrenia. Am J Psychiatry. 2006;163:1829–1831. [PubMed]
245. Buckley PF, Pillai A, Evans D, Stirewalt E, Mahadik S. Brain derived neurotropic factor in first-episode psychosis. Schizophr Res. 2007;91:1–5. [PMC free article] [PubMed]
246. Imamura L, Kurashina K, Kawahira T, Omoteno M, Tsuda M. Additional repression of activity-dependent c-fos and BDNF mRNA expression by lipophilic compounds accompanying a decrease in Ca2+ influx into neurons. Neurotoxicology. 2005;26:17–25. [PubMed]
247. Southam E, Lloyd A, Jennings CA, et al. Effect of the selective dopamine D3 receptor antagonist SB-277011-A on regional c-Fos-like expression in rat forebrain. Brain Res. 2007;1149:50–57. [PubMed]
248. Turgeon SM, Case LC. The effects of phencyclidine pretreatment on amphetamine-induced behavior and c-Fos expression in the rat. Brain Res. 2001;888:302–305. [PubMed]
249. Uslaner JM, Norton CS, Watson SJ, Akil H, Robinson TE. Amphetamine-induced c-fos mRNA expression in the caudate-putamen and subthalamic nucleus: interactions between dose, environment, and neuronal phenotype. J Neurochem. 2003;85:105–114. [PubMed]
250. Hamamura M, Ozawa H, Kimuro Y, et al. Differential decreases in c-fos and aldolase C mRNA expression in the rat cerebellum after repeated administration of methamphetamine. Brain Res Mol Brain Res. 1999;64:119–131. [PubMed]
251. Kawanishi Y, Harada S, Tachikawa H, Okubo T, Shiraishi H. Novel variants in the promoter region of the CREB gene in schizophrenic patients. J Hum Genet. 1999;44:428–430. [PubMed]
252. Young LT, Bezchlibnyk YB, Chen B, Wang JF, MacQueen GM. Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment. Biol Psychiatry. 2004;55:570–577. [PubMed]
253. Kyosseva SV, Elbein AD, Hutton TL, et al. Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients. Arch Gen Psychiatry. 2000;57:685–691. [PubMed]
254. Quesada I, Fuentes E, Viso-Leon MC, Soria B, Ripoll C, Nadal A. Low doses of the endocrine disruptor bisphenol-A and the native hormone 17beta-estradiol rapidly activate transcription factor CREB. FASEB J. 2002;16:1671–1673. [PubMed]
255. Strack S, Detzel T, Wahl M, Kuch B, Krug HF. Cytotoxicity of TBBPA and effects on proliferation, cell cycle and MAPK pathways in mammalian cells. Chemosphere. 2007;67:S405–S411. [PubMed]
256. Vawter MP, Thatcher L, Usen N, Hyde TM, Kleinman JE, Freed WJ. Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Mol Psychiatry. 2002;7:571–578. [PubMed]
257. Sui L, Anderson WL, Gilbert ME. Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci. 2005;85:647–656. [PubMed]
258. Mizuno M, Malta RS, Jr., Nagano T, Nawa H. Conditioned place preference and locomotor sensitization after repeated administration of cocaine or methamphetamine in rats treated with epidermal growth factor during the neonatal period. Ann N Y Acad Sci. 2004;1025:612–618. [PubMed]
259. Lee KY, Ahn YM, Joo EJ, et al. Partial evidence of an association between epidermal growth factor A61G polymorphism and age at onset in male schizophrenia. Neurosci Res. 2006;56:356–362. [PubMed]
260. Fan X, Warner M, Gustafsson JA. Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. Proc Natl Acad Sci U S A. 2006;103:19338–19343. [PubMed]
261. Dang VH, Choi KC, Hyun SH, Jeung EB. Analysis of gene expression profiles in the offspring of rats following maternal exposure to xenoestrogens. Reprod Toxicol. 2007;23:42–54. [PubMed]
262. Abdolmaleky HM, Smith CL, Faraone SV, et al. Methylomics in psychiatry: modulation of gene-environment interactions may be through DNA methylation. Am J Med Genet B Neuropsychiatr Genet. 2004;127:51–59. [PubMed]
263. Shimabukuro M, Sasaki T, Imamura A, et al. Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia. J Psychiatr Res. 2006;41:1042–1046. [PubMed]
264. Abdolmaleky HM, Cheng KH, Faraone SV, et al. Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet. 2006;15:3132–3145. [PMC free article] [PubMed]
265. Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. 2007;104:13056–13061. [PubMed]
266. Iwamoto K, Bundo M, Yamada K, et al. DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia. J Neurosci. 2005;25:5376–5381. [PubMed]
267. Veldic M, Kadriu B, Maloku E, et al. Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder. Schizophr Res. 2007;91:51–61. [PMC free article] [PubMed]
268. Huang HS, Akbarian S. GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS ONE. 2007;2:e809. [PMC free article] [PubMed]
269. West RL, Lee JM, Maroun LE. Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient. J Mol Neurosci. 1995;6:141–146. [PubMed]
270. Weber B, Collins C, Kowbel D, Riess O, Hayden MR. Identification of multiple CpG islands and associated conserved sequences in a candidate region for the Huntington disease gene. Genomics. 1991;11:1113–1124. [PubMed]
271. Tochigi M, Iwamoto K, Bundo M, et al. Methylation status of the reelin promoter region in the brain of schizophrenic patients. Biol Psychiatry. 2007 [PubMed]
272. Bai J, He F, Novikova SI, et al. Abnormalities in the dopamine system in schizophrenia may lie in altered levels of dopamine receptor-interacting proteins. Biol Psychiatry. 2004;56:427–440. [PubMed]
273. Bergson C, Levenson R, Goldman-Rakic PS, Lidow MS. Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling. Trends Pharmacol Sci. 2003;24:486–492. [PubMed]
274. Ali MK, Bergson C. Elevated intracellular calcium triggers recruitment of the receptor cross-talk accessory protein calcyon to the plasma membrane. J Biol Chem. 2003;278:51654–51663. [PubMed]
275. Bernstein HG, Sahin J, Smalla KH, Gundelfinger ED, Bogerts B, Kreutz MR. A reduced number of cortical neurons show increased caldendrin protein levels in chronic schizophrenia. Schizophr Res. 2007;96:246–256. [PubMed]
276. Mikhaylova M, Sharma Y, Reissner C, et al. Neuronal Ca2+ signaling via caldendrin and calneurons. Biochim Biophys Acta. 2006;1763:1229–1237. [PubMed]
277. Tanabe N, Kimoto T, Kawato S. Rapid Ca(2+) signaling induced by bisphenol A in cultured rat hippocampal neurons. Neuro Endocrinol Lett. 2006;27:97–104. [PubMed]
278. Obata T, Kinemuchi H, Aomine M. Protective effect of diltiazem, a L-type calcium channel antagonist, on bisphenol A-enhanced hydroxyl radical generation by 1-methyl-4-phenylpyridinium ion in rat striatum. Neurosci Lett. 2002;334:211–213. [PubMed]
279. Ogunbayo OA, Michelangeli F. The widely utilized brominated flame retardant, tetrabromobisphenol A (TBBPA) is a potent inhibitor of the SERCA Ca 2+ pump. Biochem J. 2007;408:407–415. [PubMed]
280. Gysin R, Kraftsik R, Sandell J, et al. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A. 2007;104:16621–16626. [PubMed]
281. Yao JK, Leonard S, Reddy R. Altered glutathione redox state in schizophrenia. Dis Markers. 2006;22:83–93. [PubMed]
282. Steullet P, Neijt HC, Cuenod M, Do KQ. Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience. 2006;137:807–819. [PubMed]
283. Cabungcal JH, Preissmann D, Delseth C, Cuenod M, Do KQ, Schenk F. Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. Neurobiol Dis. 2007;26:634–645. [PubMed]
284. Kabuto H, Hasuike S, Minagawa N, Shishibori T. Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues. Environ Res. 2003;93:31–35. [PubMed]
285. Arvindakshan M, Sitasawad S, Debsikdar V, et al. Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients. Biol Psychiatry. 2003;53:56–64. [PubMed]
286. Kabuto H, Amakawa M, Shishibori T. Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci. 2004;74:2931–2940. [PubMed]
287. Maino K, Gruber R, Riedel M, Seitz N, Schwarz M, Muller N. T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment. Psychiatry Res. 2007;152:173–180. [PubMed]
288. Nyffeler M, Meyer U, Yee BK, Feldon J, Knuesel I. Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: implications for schizophrenia. Neuroscience. 2006;143:51–62. [PubMed]
289. Strous RD, Shoenfeld Y. Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun. 2006;27:71–80. [PubMed]
290. Schwarz MJ, Kronig H, Riedel M, et al. IL-2 and IL-4 polymorphisms as candidate genes in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2006;256:72–76. [PubMed]
291. Riedel M, Spellmann I, Schwarz MJ, et al. Decreased T cellular immune response in schizophrenic patients. J Psychiatr Res. 2007;41:3–7. [PubMed]
292. Yamashita U, Kuroda E, Yoshida Y, Sugiura T. Effect of endocrine disrupters on immune responses in vivo. J UOEH. 2003;25:365–374. [PubMed]
293. Yurino H, Ishikawa S, Sato T, et al. Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicol Sci. 2004;81:139–147. [PubMed]
294. Youn JY, Park HY, Lee JW, et al. Evaluation of the immune response following exposure of mice to bisphenol A: induction of Th1 cytokine and prolactin by BPA exposure in the mouse spleen cells. Arch Pharm Res. 2002;25:946–953. [PubMed]
295. Alizadeh M, Ota F, Hosoi K, Kato M, Sakai T, Satter MA. Altered allergic cytokine and antibody response in mice treated with bisphenol A. J Med Invest. 2006;53:70–80. [PubMed]
296. Yoshino S, Yamaki K, Li X, et al. Prenatal exposure to bisphenol A up-regulates immune responses, including T helper 1 and T helper 2 responses, in mice. Immunology. 2004;112:489–495. [PubMed]
297. Yoshino S, Yamaki K, Yanagisawa R, Takano H, Hayashi H, Mori Y. Effects of bisphenol A on antigen-specific antibody production, proliferative responses of lymphoid cells, and TH1 and TH2 immune responses in mice. Br J Pharmacol. 2003;138:1271–1276. [PMC free article] [PubMed]
298. Goto M, Takano-Ishikawa Y, Ono H, Yoshida M, Yamaki K, Shinmoto H. Orally administered bisphenol A disturbed antigen specific immunoresponses in the naive condition. Biosci Biotechnol Biochem. 2007;71:2136–2143. [PubMed]
299. Lee MH, Chung SW, Kang BY, et al. Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor-AT and Ca2+ Immunology. 2003;109:76–86. [PubMed]
300. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27:10695–10702. [PMC free article] [PubMed]
301. Martin JT. Sexual dimorphism in immune function: the role of prenatal exposure to androgens and estrogens. Eur J Pharmacol. 2000;405:251–261. [PubMed]
302. Lamason R, Zhao P, Rawat R, et al. Sexual dimorphism in immune response genes as a function of puberty. BMC Immunol. 2006;7:2. [PMC free article] [PubMed]
303. Marriott I, Huet-Hudson YM. Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res. 2006;34:177–192. [PubMed]
304. Gourdy P, Araujo LM, Zhu R, et al. Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-gamma production by invariant natural killer T cells. Blood. 2005;105:2415–2420. [PubMed]
305. Yamada K, Gerber DJ, Iwayama Y, et al. Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc Natl Acad Sci U S A. 2007;104:2815–2820. [PubMed]
306. Hayashi S, Yamaguchi Y. Estrogen signaling and prediction of endocrine therapy. Cancer Chemother Pharmacol. 2005;56(suppl 1):27–31. [PubMed]
307. Farabollini F, Porrini S, Della SD, Bianchi F, Dessi-Fulgheri F. Effects of perinatal exposure to bisphenol A on sociosexual behavior of female and male rats. Environ Health Perspect. 2002;110(suppl 3):409–414. [PMC free article] [PubMed]
308. Porrini S, Belloni V, Della SD, Farabollini F, Giannelli G, Dessi-Fulgheri F. Early exposure to a low dose of bisphenol A affects socio-sexual behavior of juvenile female rats. Brain Res Bull. 2005;65:261–266. [PubMed]
309. Adriani W, Seta DD, Dessi-Fulgheri F, Farabollini F, Laviola G. Altered profiles of spontaneous novelty seeking, impulsive behavior, and response to D-amphetamine in rats perinatally exposed to bisphenol A. Environ Health Perspect. 2003;111:395–401. [PMC free article] [PubMed]
310. Rubin BS, Murray MK, Damassa DA, King JC, Soto AM. Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environ Health Perspect. 2001;109:675–680. [PMC free article] [PubMed]
311. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
312. Negishi T, Kawasaki K, Suzaki S, et al. Behavioral alterations in response to fear-provoking stimuli and tranylcypromine induced by perinatal exposure to bisphenol A and nonylphenol in male rats. Environ Health Perspect. 2004;112:1159–1164. [PMC free article] [PubMed]
313. Schmauss C, Emrich HM. Dopamine and the action of opiates: a reevaluation of the dopamine hypothesis of schizophrenia. With special consideration of the role of endogenous opioids in the pathogenesis of schizophrenia. Biol Psychiatry. 1985;20:1211–1231. [PubMed]
314. Aloisi AM, Della SD, Rendo C, Ceccarelli I, Scaramuzzino A, Farabollini F. Exposure to the estrogenic pollutant bisphenol A affects pain behavior induced by subcutaneous formalin injection in male and female rats. Brain Res. 2002;937:1–7. [PubMed]
315. Razzoli M, Valsecchi P, Palanza P. Chronic exposure to low doses bisphenol A interferes with pair-bonding and exploration in female Mongolian gerbils. Brain Res Bull. 2005;65:249–254. [PubMed]
316. Gioiosa L, Fissore E, Ghirardelli G, Parmigiani S, Palanza P. Developmental exposure to low-dose estrogenic endocrine disruptors alters sex differences in exploration and emotional responses in mice. Horm Behav. 2007;52:307–316. [PubMed]
317. Kawai K, Nozaki T, Nishikata H, Aou S, Takii M, Kubo C. Aggressive behavior and serum testosterone concentration during the maturation process of male mice: the effects of fetal exposure to bisphenol A. Environ Health Perspect. 2003;111:175–178. [PMC free article] [PubMed]
318. Laviola G, Gioiosa L, Adriani W, Palanza P. D-amphetamine-related reinforcing effects are reduced in mice exposed prenatally to estrogenic endocrine disruptors. Brain Res Bull. 2005;65:235–240. [PubMed]
319. Mizuo K, Narita M, Miyagawa K, Narita M, Okuno E, Suzuki T. Prenatal and neonatal exposure to bisphenol-A affects the morphine-induced rewarding effect and hyperlocomotion in mice. Neurosci Lett. 2004;356:95–98. [PubMed]
320. Le Pen G, Gaudet L, Mortas P, Mory R, Moreau JL. Deficits in reward sensitivity in a neurodevelopmental rat model of schizophrenia. Psychopharmacology (Berl) 2002;161:434–441. [PubMed]
321. Schwabe K, Klein S, Koch M. Behavioural effects of neonatal lesions of the medial prefrontal cortex and subchronic pubertal treatment with phencyclidine of adult rats. Behav Brain Res. 2006;168:150–160. [PubMed]
322. Stevens JR. Schizophrenia and multiple sclerosis. Schizophr Bull. 1988;14:231–241. [PubMed]
323. Torrey EF. Are we overestimating the genetic contribution to schizophrenia? Schizophr Bull. 1992;18:159–170. [PubMed]
324. Anway MD, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors. Endocrinology. 2006;147(suppl 6):S43–S49. [PubMed]
325. Crews D, McLachlan JA. Epigenetics, evolution, endocrine disruption, health, and disease. Endocrinology. 2006;147(suppl 6):S4–S10. [PubMed]
326. Yapici G, Can G, Kiziler AR, Aydemir B, Timur IH, Kaypmaz A. Lead and cadmium exposure in children living around a coal-mining area in Yatagan, Turkey. Toxicol Ind Health. 2006;22:357–362. [PubMed]
327. Pappas RS, Polzin GM, Watson CH, Ashley DL. Cadmium, lead, and thallium in smoke particulate from counterfeit cigarettes compared to authentic US brands. Food Chem Toxicol. 2007;45:202–209. [PubMed]
328. Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry. 2001;58:1039–1046. [PubMed]
329. Torrey EF, Bowler A. Geographical distribution of insanity in America: evidence for an urban factor. Schizophr Bull. 1990;16:591–604. [PubMed]
330. Alonso-Gonzalez C, Gonzalez A, Mazarrasa O, et al. Melatonin prevents the estrogenic effects of sub-chronic administration of cadmium on mice mammary glands and uterus. J Pineal Res. 2007;42:403–410. [PubMed]
331. Lyche JL, Larsen HJ, Skaare JU, Tverdal A, Johansen GM, Ropstad E. Perinatal exposure to low doses of PCB 153 and PCB 126 affects maternal and neonatal immunity in goat kids. J Toxicol Environ Health A. 2006;69:139–158. [PubMed]
332. Vom Saal FS. Variation in infanticide and parental behavior in male mice due to prior intrauterine proximity to female fetuses: elimination by prenatal stress. Physiol Behav. 1983;30:675–681. [PubMed]
333. Vom Saal FS, Bronson FH. Sexual characteristics of adult female mice are correlated with their blood testosterone levels during prenatal development. Science. 1980;208:597–599. [PubMed]
334. Thapar A, Harold G, Rice F, et al. Do intrauterine or genetic influences explain the foetal origins of chronic disease? A novel experimental method for disentangling effects. BMC Med Res Methodol. 2007;7:25. [PMC free article] [PubMed]

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