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Logo of itxAboutfor AuthorsVersitaInterdisciplinary Toxicology
Interdiscip Toxicol. 2010 June; 3(2): 59–67.
Published online 2010 June. doi:  10.2478/v10102-010-0012-4
PMCID: PMC2984125

Neurobehavioral manifestations of developmental impairment of the brain


Individual characteristics of human nature (e.g. introversion, extroversion, mood, activity, adaptability, aggressiveness, social ability, anxiety) do not need to be primarily innate. They can be determined by the action of various influences and their interactions on functional development of the brain. There is ample epidemiological and experimental evidence that chemical and/or physical factors acting during sensitive time windows of the brain development can cause mental, behavioral, emotional and/or cognitive disorders. Environmental pollutants, addictive substances, drugs, malnutrition, excessive stress and/or hypoxia-ischemia were reported to induce functional maldevelopment of the brain with consequent neurobehavioral disorders. The article provides review on most significant neurobehavioral manifestations of developmental impairment of the brain during prenatal, perinatal and early postnatal period. The most known adverse factors causing developmental neurobehavioral dysfunctions in humans as well as in experimental animals are discussed.

Keywords: neurobehavioral dysfunctions, brain development, cognitive disorder, mental disorder, emotional disorder, behavioral disorder, developmental neurotoxicity, environmental factors


Introversion, extroversion, mood, activity, adaptability, distractibility, persistence and attention span, as well as aggressiveness, social ability, tendency to depression and/or anxiety do not need to be primarily innate. Individual characteristics of human nature and behavior could be determined by the action of various influences and their interactions on functional brain development.

There is ample epidemiological and experimental evidence that chemical and/or physical factors acting during sensitive time windows of the brain development can cause behavioral, emotional and/or cognitive dysfunctions. Environmental pollutants, addictive substances, drugs, malnutrition, excessive stress and/or hypoxia-ischemia were reported to induce functional maldevelopment of the brain with consequent neurobehavioral disorders.

The range of neurobehavioral alterations, however, depends on the intensity/dosage and duration of the factor in question as well as on the developmental stage of the brain. Chronic alcohol consumption during pregnancy results in fetal alcohol related abnormalities (FARA). Most serious manifestation of FARA is fetal alcohol syndrome (FAS). FAS is characterized by triads of pathological signs: prenatal and postnatal growth retardation, impairment of the CNS and facial deformities. On the other hand, mild social drinking in pregnancy causes mostly functional alterations of the brain, called alcohol related neurodevelopmental disorders (ARND) or fetal alcohol effect (FAE). FAE is characterized by verbal, cognitive and attention deficit (McGough et al., 2009; McGee et al., 2009).

Fetal and neonatal brain development is characterized by developmental time windows during which certain brain regions or neuron types are specifically sensitive to environmental influences. The immature brain is much more sensitive to abnormal experience, particularly sleep deprivation, drug exposure, and maternal separation. The critical time period, during which features in brain susceptibility to such experience change, however, has not yet been fully determined. Basal forebrain cholinergic neurons were found to be sensitive to nerve growth factor (NGF) deprivation during the first postnatal week not later (Molnar et al., 1997). The study of Feng et al. (2001) is an excellent example of sensitive developmental periods from the neurotoxicity point of view. Male rats neonatally treated with the tricyclic antidepressant clomipramine (CLI) during various treatment windows, i.e. postnatal days (PD) 12–17, 14–20, 16–22, and 12–15, were in adulthood tested for sexual behavior. The rats treated with CLI showed significant sexual impairment in treatment windows PD12–17 and PD14–20 and slight sexual deficiency in the short window PD12–15. No significant sexual impairment was found in window PD16–22. The results indicate that PD14–20 is the latest window during which CLI treatment can produce adult sexual deficiency and that 6 days might be the shortest treatment window to produce significant behavior abnormalities.

Moreover, genetic disposition of the fetus, gender and racial differences may affect the action of individual factors and/or their interferences. Experimental neonatal stress and/or monosodium glutamate (MSG) treatment can be an example referring to gender issue. MSG and combined stressful stimuli represented by 10% NaCl administration and mild handling on PD 2, 4, 6, 8 and 10 were found to increase locomotor activity and slow down habituation in an open field test in adult male but not female rats (Dubovický et al., 1997; 1999).

Activity of enzyme alcohol-dehydrogenase metabolizing ethanol is different in Whites compared to Chinese, Native Americans and Japanese (Agarwal and Goedde, 1986). In this respect it is possible that fetal susceptibility to alcohol may also be dependent upon maternal racial and genetic dispositions interacting with consumption patterns. The basis of these differences remains however to be elucidated. Among Blacks, slower metabolism of nicotine was found in comparison with Whites (Benowitz et al., 1999). Perera et al. (2004) found higher umbilical cord serum of the nicotine metabolite cotinine in Blacks versus Hispanic newborns. Racial differences in nicotine metabolism could reflect differences in low-level prenatal smoking on infant behavior. While among White infants, increased cotinine levels were associated with increased arousal and excitability and decreased self-regulation (ability to calm dawn), on the contrary, in Black infants increased cotinine levels were associated with decreased arousal and excitability and increased ability to self-regulate (Yolton et al., 2009).

The present article provides review on the most significant neurobehavioral manifestations of developmental impairment of the brain during the prenatal, perinatal and early postnatal/neonatal period. The best known adverse factors causing neurodevelopmental behavioral dysfunctions in humans as well as in experimental animals with possible mechanisms of action are discussed. The classification of neurobehavioral disorders is not unequivocal. Individual manifestations of the disorders can overlap. Attention deficit-hyperactivity disorder (ADHD) generally belongs to the group of behavioral disorders. However, attention deficit as its part can be classified as a cognitive dysfunction and ADHD may be accompanied also by mood changes. To facilitate orientation in the broad spectrum of neurobehavioral disorders, the review is divided into four most important groups of disorders: serious neurodevelopmental disorders, cognitive disorders, mental disorders and emotional and behavioral disorders.

Serious neurodevelopmental disorders

The majority of signs of serious neurodevelopmental disorders do not belong to the spectrum of neurobehavioral dysfunctions. Although some of these disorders can be associated with neurobehavioral deficit or with an increased risk for behavioral alterations in later postnatal development. However, if cerebral palsy, neurological disorders, epilepsy and severe mental retardation were not mentioned, the survey of significant neurodevelopmental pathologies would be incomplete.

Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitations attributed to nonprogressive disturbances occurring in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behavior, or by epilepsy and secondary musculoskeletal problems (Horsman et al., 2010). While in certain cases there is no identifiable cause, other etiologies include problems in intrauterine development (e.g. exposure to radiation, infection), hypoxia of the brain and birth trauma during labor and delivery, and complications in the perinatal period or during childhood (Brucknerová et al., 2008). After birth, other causes include toxins, severe jaundice, lead poisoning, physical brain injury, incidents involving hypoxia to the brain and encephalitis or meningitis (Mendola et al. 2002; Gilbertson, 2004).

A neurological disorder is a disorder of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain or spinal cord or in the nerves leading to or from them, can result in manifestations such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain and altered levels of consciousness. A unique example of neurological complications due to developmental effects of chemicals is the Minamata disease. The first well-documented outbreak of acute developmental methyl mercury poisoning by consumption of contaminated fish occurred in Minamata, Japan, in 1953. Typical features of the disease are as follows: sensory disturbances, ataxia, seizures, constriction of the visual field, auditory disturbances and tremor (Harada, 1995, Ekino et al., 2007). Fetal neurodevelopment depends on cell programs, developmental trajectories, synaptic plasticity, and oligodendrocyte maturation, which are variously modifiable by factors such as stress and endocrine disruption, exposure to pesticides such as chlorpyrifos and to drugs such as terbutaline, and by premature birth (Mendola et al., 2002; Connors et al., 2008). Prenatal nicotine was reported to cause abnormal reflexes and hypertony/hypotony in neonates and infants (Yolton et al., 2009).

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. Epilepsy is more likely to occur in young children or people over the age of 65 years, however it can occur at any time (Fisher et al., 2005). During the neonatal period and early infancy the most common causes of epilepsy include hypoxic-ischemic encephalopathies, CNS infections, toxins, trauma, congenital CNS abnormalities and metabolic disorders (Scher, 2003; Vestergaard et al., 2005).

Mental retardation is a generalized disorder, characterized by significantly impaired cognitive functioning and deficits in adaptive behavior with onset before the age of 18. It has historically been defined by an intelligence quotient score under 70. Once focused almost entirely on cognition, the definition now includes both a component relating to mental functioning and one relating to the individual's functional skills in the environment (Van der Aa et al., 2010). Down syndrome, fetal alcohol syndrome and fragile X syndrome are the three most common inborn causes of mental retardation. A woman who drinks alcohol or gets an infection like rubella during pregnancy may also have a baby with mental disability (Batshaw, 1993; Devenny et al., 2000; Merrick et al., 2006). If a baby has problems during labor and birth, as e.g. not getting enough oxygen, he or she may have developmental disability due to brain damage (Kaindl et al., 2009).

Cognitive disorders

Cognitive disorders are disorders in which the central feature is impairment of memory, attention, perception, thinking, problem solving and language.

Drinking of alcohol during pregnancy seriously affects neurobehavioral development of children. Even social drinking in pregnancy was found to result in cognitive dysfunctions accompanied by deficit in language ability in infants both in reception and expression of the language (McGee et al., 2009). Attention problems were found in children of mothers drinking in pregnancy and/or using psychotropic drugs (Dalen et al., 2009).

Polybrominated diphenyl eters (PBDEs) are synthetic flame retardants added to polymers for the manufacture of electrical appliances, carpets and polyurethane foam. They have similar effects as polychlorinated biphenyls. They bind to androgen and estrogen receptors and can injure the activity of thyroidal hormones, which play a significant role in neurodevelopmental processes such as timing of neural and glial proliferation, migration and differentiation, myelination, synaptic connectivity, development of dopaminergic and cholinergic system (Figueredo et al., 1993; Sawin et al., 1998; Auso et al., 2004;). The functional maldevelopment due to PBDs can lead to neurocognitive dysfunctions. A mixture of PBDs in the neonatal period was reported to result in cognitive deficit with disorders of attention and inhibitory control in rats (Driscoll et al., 2009). Rats exposed prenatally to polychlorinated biphenyls and/or methyl mercury had a deficit in cognitive and behavioral tests (Sable et al., 2009).

About 12% of women do not quit smoking during pregnancy. Nicotine causes intrauterine growth retardation, increases the risk for miscarriage and cognitive and behavioral disorders. Nicotine mimics the action of acetylcholine which plays an important role in the development of auditory neural circuitry. During development, excessive stimulation of nicotine receptors can lead to their injury. This in turn can result in injury of sensory encoding of auditory information associated with disorder of auditory habituation in neonates, delayed vocalization, disorders of language perception and reading abilities in infants (Kable et al., 2009).

The Environment Protection Agency (USA) considers the blood level of 10 µg/dL lead to be a risk for health. Recent studies, however, showed that levels under 5 µg/dL can injure cognitive functions, lower the score of reading abilities and mathematics. Moreover, prenatal alcohol and/or drugs can increase sensitivity to lead toxicity in neonates and infants (Min et al., 2009).

Prenatal cocaine acts adversely during development by two basic mechanisms: it decreases uterine blood flow resulting in fetal hypoxia, and it affects development of the brain monoamines leading to functional maldevelopment of the brain mostly in the prefrontal cortex, which is responsible for executive functions, attention and neurocognitive functions. Prenatal cocaine causes attention deficit and has negative effects on reaction of the organism to new stimuli (Hurt et al., 2009; Eiden et al., 2009).

It is important to note that functional development of the brain does not end in infancy. Functional maturation of the brain continues to adolescence, e.g. processes of sprouting and pruning. Alcohol and addictive substances in adolescents can therefore have more deleterious effects than in adults. Binge drinking in adolescents was reported to cause macrostructural and microstructural changes of the white matter (e.g. volume, density of fibers, etc.) (Jacobus et al., 2009). These alterations in turn can lead to neurocognitive dysfunctions in later development or could potentate unfavorable effects of other environmental factors.

Organophosphate pesticides damage replication of neurons, differentiation, axogenesis, synaptogenesis and development of neuronal circuitry. They affect ACh and 5-HT systems, what in turn may lead to cognitive dysfunction as well as the emotional and behavioral disorders (Slotkin et al., 2009).

Prenatal and/or perinatal hypoxia-ischemia is a major factor for the development of cognitive dysfunctions in later life (Gitto et al., 2009; Brucknerová et al., 2008; Mach et al., 2009). Memory and learning deficits are very frequent consequences of lack of oxygen and nutrition during brain development. The hippocampus is one brain region that can be damaged and this site of damage has been implicated in two different long-term outcomes, cognitive memory impairment and the psychiatric disorder schizophrenia (de Haan et al., 2006). The risk of cognitive deficits is related to the severity of neonatal encephalopathy and the pattern of brain injury on neuroimaging, particularly the watershed pattern of injury (Gonzales & Miller, 2006). Cognitive deficit is one of the manifestations of fetal hydantoin syndrome due to teratogenicity of phenytoin (PHT), an anticonvulsant drug used in treatment of epilepsy. PHT is considered to induce teratogenicity by affecting the hemodynamic status of the pregnant mother as well as of the embryo/fetus, eventually leading to embryo-fetal hypoxia (Adams et al., 1990; Wells and Winn, 1996; Navarová et al., 2005; Ujházy et al., 2008). PHT causes serious structural and functional changes including memory deficiency (Okruhlicová et al., 2003; Ujházy et al., 2004; Mach et al., 2005). Xenoestrogens were reported to negatively affect spatial learning of male rats in water maze (Ceccarelli et al., 2009).

Mental disorders

A mental disorder is a psychological or behavioral pattern associated with distress or disability that occurs in an individual and is not a part of normal development or culture. The recognition and understanding of mental health conditions has changed over time and across cultures, and there are still variations in the definition, assessment, and classification of mental disorders, although standard guideline criteria have been widely accepted (American Psychiatric Association, 2000). Mental disorders can arise from a combination of sources. In many cases there is no single accepted or consistent cause currently established. A common belief even to this day is that disorders result from genetic vulnerabilities exposed to environmental stressors.

Schizophrenia is a mental disorder characterized by abnormalities in the perception or expression of reality. It is most commonly manifested as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking with significant social or occupational dysfunction. Onset of symptoms typically occurs in young adulthood, with around 0.4–0.6% of the population affected (Castle et al., 1991).

There is much evidence of neurodevelopmental origin of schizophrenia. Epidemiological studies found a seasonally-related increase in schizophrenia for people born in winter months when infections are more frequent (Battle et al., 1999). Reelin, a protein that regulates processes of neuronal migration and positioning in the developing brain, showed significantly reduced gene expression in the brain of schizophrenic patients as well as in animals used as amodel of this disease (Erbel-Sieler et al., 2004). In schizophrenia, dopaminergic hyperfunction in certain brain regions is considered the key element of the disease. The developmental model of schizophrenia has been proposed based on the dopamine hypothesis. It has been shown that neonatal exposure to the dopamine D2/3 receptor agonist quinpirole leads to supersensitivity or priming of D2/3 receptors (Kostrzewa, 1995; Kostrzewa et al., 2005). This supersensitivity was accompanied by spatial learning deficit and alterations in motor activity (Vorhees et al., 2009).

Anxiety disorders are blanket terms covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders: generalized anxiety disorder, panic disorder, phobias, social anxiety disorder, obsessive–compulsive disorder, post-traumatic stress disorder, separation anxiety, childhood anxiety disorder. The amygdala is central to the processing of fear and anxiety, and its function may be disrupted in anxiety disorders.

There are many experimental studies confirming the relationship between prenatal/perinatal insults and adult anxiety disorders. Whereas in humans, more studies would be needed to ascertain long-term behavioral effects of adverse stimuli on pregnant women and their offspring. Emerging data from human and animal perinatal exposure studies demonstrate a subtle effect of cannabis upon later brain functioning including specific cognitive deficits, especially in visuospatial function, impulsivity, inattention and hyperactivity, depressive/anxiety signs and symptoms (Sundram, 2006). Maternal exposure to caffeine was found to induce long-term consequences on sleep, locomotion, learning abilities, emotivity, and anxiety in rat offspring (Nehlig & Debry, 1994).

Hypoxia-ischemia represents a risk factor for functional alterations of the brain structures and functions related to anxiety/fear. Asphyxiated animals in the perinatal period were found to exhibit a significantly decreased social aggressiveness and an increased social contact behavior, as well as increased anxiety levels in adulthood (Weitzdoerfer et al., 2004). Antenatal intermittent hypoxia caused a decrease of motor activity as well as an enhanced anxiety level in rats of both sexes, while males appeared to be more sensitive to hypoxic influence (Trofinmova et al., 2010). Other studies have also shown that neurobehavioral changes due to mild perinatal hypoxia were mainly related to emotional/anxious responses (Hoeger et al., 2000; Venerosi et al., 2006).

The neuroendocrine system, especially the hypothalamus-pituitary-adrenal (HPA) axis, is very sensitive to excessive stressful stimuli during development. Prenatal stress can interfere with functional development of the brain acan cause neurobehavioral dysfunctions in later postnatal period. Epidemiological studies provided knowledge on long-term effects of prenatal stress on neurobehavioral development (Graignic-Phillipe & Tordjman, 2009), cognitive ability and fearfulness in infancy (Bergman et al., 2007). Experimental studies showed that increased levels of stress hormones could affect development of hippocampus and other brain regions and cause long-term changes in HPA axis reactivity (Sapolsky et al., 1984; Uno et al., 1990). Behavioral alterations were correlated with an increase of corticostreone level in reaction to a stressful stimulus, as well as its prolonged secretion, and adecreased density of hippocampus glucocorticoid receptors (Henry et al., 1994; Maccari et al., 1995; Vallée et al., 1996; Maccari & Morley-Fletcher, 2007). Prenatal stress is associated with an increased anxiety/fear-like behavior in adult rats and an increased sensitivity of to stressful stimuli (Valleé et al., 1997). Repeated stress in late pregnancy in monkeys was found to induce depressive behavior in infant monkeys and cognitive deficit (Schneider, 1992). Prenatal social stress can program anxiety behavior and HPA axis responses to stress in offspring. Attenuated glucocorticoid feedback mechanisms in the limbic system may underlie HPA axis hyper-reactivity to stress in offspring (Brunton & Russel, 2010). Prenatal stress has been found to affect brain development and behavior of male and female rats differentially (Weinstock, 2007). On the other hand, early postnatal stress in the form of manipulation (handling) resulted in decreased anxiety and corticosterone secretion in reaction to stressful stimuli (Valée et al., 1997). Altered behavior observed in adulthood is likely the result of neurodevelopmental perturbations elicited by early life stress. It can be assumed that there is "a critical period" for neural circuits involved in emotional expression that contribute to lifelong susceptibility to stress (Matsumoto et al., 2009). Moreover, developmental administration of some drugs can affect HPA axis functioning in adulthood. Exposure to phenytoin in utero was found to increase catecholamine and corticosterone concentrations in response to a mild stressor in adult offspring (Makatsori et al., 2005).

Mood/affective disorders are characterized by a consistent, pervasive alteration in mood, and affecting thoughts, emotions, and behaviors. There are two basic types of mood disorders, i.e. depressive and bipolar disorder. In affective disorders, we also need to rely on experimental studies.

It was shown that prenatal exposure to the inhibitor of serotonin (5-HT) synthesis para-chlorophenylalanine (PCPA) caused fetal 5-HT depletion and change both in open field activity and in depression-related behavior in the adult rat offspring (Vataeva et al., 2008). Prescription of selective serotonin reuptake inhibitors and/or serotonin-noradrenalin reuptake inhibitors (SSRI/SNRI) in pregnancy and lactation may represent arisk for the unborn child. Prenatal administration of fluoxetine in mice resulted in dose-dependent development of affective disorders (Noorlander et al., 2008). Prenatal exposure to fluoxetine caused adecrease in a number of neurons in the frontal cortex (Swerts et al., 2009) and decrease in 5-HT receptor density in the frontal cortex in pre-pubescent rats and in the middle brain in adult rats (Cabrera-Vera et al., 1997). Generally, administration of SSRI and/or SNRI drugs during sensitive developmental periods of the brain increases the risk for neuronal circuitry alterations and maladaptive behavior persisting up to adulthood in the form of enhanced depression and/or anxiety, and even aggressive behavior (Borue et al., 2007).

Emotional and behavioral disorders

Emotional and behavioral disorders form a broad category, which is used commonly in educational settings, to group a range of more specific perceived difficulties of children and adolescents. Both general definitions as well as actual diagnosis of these disorders may be controversial as the observed behavior may depend on many factors.

Emotions and behavior are controlled by a complex of central executive and regulatory functions. Executive functions are a complex of cognitive and behavioral competences inevitable in solving demanding, non-routine and aim-oriented tasks and/or situations. (organizational and information processing, oriented attention, working memory, inhibition). The emotional and behavioral regulatory system has two basic components. The first is the latency and intensity of reactions to environmental stimuli (reactivity), the second is represented by behavioral responses and strategy/coping modulated by the reactions (regulatory components) involving self-calming, communicative behavior, behavioral strategy to disperse attention from the incentive stimulus and/or approach/withdrawal behavior. Emotional arousal regulation provides excitatory/inhibitory balance, which protects central executive functions against excessive stimulation and helps to coordinate cortical systems. The dorsal and lateral prefrontal lobe, amygdala and other brain regions are responsible for these functions (Drevets and Raichle, 1998; Avants et al., 2007). Prenatal cocaine inhibits re-uptake of DA, NA and 5-HT on the presynaptic membrane and causes vasoconstriction followed by hypoxia. This can lead to long-term cognitive and neurodevelopmental consequences manifested in middle infancy, puberty or adolescence when there are increased demands, challenges and more complex cognitive processes are needed for educational, behavioral, social and executive functions. It has been shown that prenatal cocaine affects executive functions manifested by lowered inhibitory control of excessive verbal responses in children (Rose-Jacobs et al., 2009). Moreover, prenatal cocaine damages the prefrontal cortex and amygdale, which leads to cognitive and emotional dysfunctions manifested by memory and attention alterations (Li et al., 2009). Prenatal cocaine can affect these regulatory systems and results in attention disorder, frustration, impulsivity, disruptive behavior, low motor inhibition. In experimental animals prenatal cocaine resulted in stress-related freezing and aggressive behavior (Eiden et al., 2009).

Autism spectrum disorders (ASD) are a spectrum of psychological conditions characterized by widespread abnormalities of social interactions and communication, as well as severely restricted interests and highly repetitive behavior. Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering nerve cell and synaptic connection and organization. The other two disorders are Asperger syndrome, where there are delays in cognitive development and language, and Pervasive developmental disorder. Childhood disintegrative disorder, also known as Heller's syndrome and Rett syndrome are very close to autistic spectrum disorders as to certain signs, such as impaired social interaction.

ASD has a strong genetic basis, although the genetics of autism are complex and it is unclear whether it is explained more by rare mutations with major effects, or by rare multigene interactions of common genetic variants. The arising complexity is due to interactions among multiple genes, the environment, and epigenetic factors which do not change DNA but are heritable and influence gene expression (Abrahams & Geschwind, 2008; Buxbaum, 2009). Several lines of evidence point to synaptic dysfunction as a cause of autism. All known teratogens related to the risk of autism appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, there is strong evidence that autism arises very early in development (Arndt et al., 2005).

An association between autism and prenatal thalidomide was found in Sweden study of autistic poeple (Strömland et al., 1994; Strömland et al., 2002). Compared to therate of autistic children in Sweden (approximately 1/1000), there was a highly significant increase in thalidomide victims, about 5%. Animal studies showed that maternal administration of thalidomide or valproic acid caused disruption of early serotonegic neuronal development and neurobehavioral alterations in amanner that is, in part, consistent with human autism (Miyazaki et al., 2005; Narita et al., 2010). Other factors that have been claimed to contribute to or exacerbate autism, include infectious disease, heavy metals, organophosphates, solvents, diesel exhaust, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, illicit drugs, vaccines, and prenatal stress (Newschaffer et al., 2007; Kinney et al., 2008). Moreover, a hyperserotonemia in pregnancy du to SSRI treatment might be one of the reasons of the increasing frequency of autism in the human population (Hadjikhani, 2009). Today children are surrounded by thousands of synthetic chemicals. Two hundred of them are neurotoxic in adult humans, and 1000 more in laboratory models. Yet fewer than 20% of chemicals have been tested for neurodevelopmental toxicity. Prevalence, genetic, exposure, and pathophysiological evidence all suggest a role for environmental factors in the inception and lifelong modulation of ASD. Expanded research into environmental causation of autism is however needed (Herbert, 2010; Landrigan, 2010).

Attention-Deficit Hyperactivity Disorder (ADHD) is a neurobehavioral developmental disorder. It is primarily characterized by “the co-existence of attention problems and hyperactivity, with each behavior occurring infrequently alone” and symptoms starting before seven years of age. ADHD is the most commonly studied and diagnosed psychiatric disorder in children, affecting about 3% to 5% of children globally and diagnosed in about 2% to 16% of school aged children. It is a chronic disorder with 30% to 50% of individuals diagnosed in childhood continuing to have symptoms into adulthood. Adolescents and adults with ADHD tend to develop coping mechanisms to compensate for some or all of their impairments. A specific cause of ADHD is not known. There are, however, a number of factors that may contribute to ADHD. They include genetics, diet and social and physical environments.

Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in humans (Bass et al., 2004). An experimental study on rats showed that perinatal asphyxia (non-sophisticated caesarian section model used) on day 20 of gestation in duration of 20 min resulted in hyperactivity in repeated open field test. However, the hyperactivity manifested gradually during the experiment. In the first session, the rats exhibited lower activity compared to controls, indicating their neophobia in anew environment. This behavioral pattern resembled hyperactive profile in ADHD children. They are behaviorally inhibited in an unknown environment and highly active in familiar surroundings (Dubovicky et al., 2007; 2008). Global brain injury produced by neonatal hypoxia also produced hyperactivity, as did hippocampal injury produced by ontogenetic exposure to X-rays, and cerebellar injury produced by the developmental treatments with the antimitotic agent methylazoxymethanol or with polychlorinated biphenyls (Sable et al., 2009). More recently, developmental exposure to nicotine has been implicated in childhood hyperactivity (Kostrzewa et al., 2008; Kable et al., 2009).


Maintenance of the optimal fetal environment is the key factor of the future quality of life. Conditions like inadequate nutrition and oxygen supply, infection, hypertension, gestational diabetes or drug abuse by the mother, expose the fetus to a non-physiological environment. In conditions of severe intrauterine deprivation, there is a potential loss of structural units within the developing organ systems affecting their functionality and efficiency. Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility (Bezek et al., 2008). There is epidemiological and experimental evidence that environmental factors influence a diverse array of molecular mechanisms and consequently alter disease risk not only for metabolic syndrome and cardiovascular diseases, insulin resistance and diabetes mellitus, osteoporosis, asthma and immune system diseases but also for psychiatric and neurobehavioral disorders (Rinaudo & Lamb, 2008; Bezek et al., 2008).

Fetal and early childhood exposures to industrial chemicals in the environment can damage the developing brain and can lead to neurodevelopmental disorders, such as autism, ADHD and mental retardation. We can speak of "a silent pandemic". As it was mentioned in the editorial in the Nature (2010), the beginning of the 21st century is becoming a decade for psychiatric disorders. Mental disorders affect more than 27% of adult Europeans every year. They are the main cause of suicides in European Union. Economic issue of mental and behavioral disorders is also inconsiderable, treatment of these disorders can cost up to 4% of GDP (Krištofiɩová, 2008). Researchers have found that about 200 industrial chemicals have the capacity to damage the human brain, and they conclude that chemical pollution may have harmed the brains of millions of children worldwide (Labie, 2007). Nevertheless, the toxic effects of industrial chemicals on children have generally been overlooked.

Further knowledge on possible unfavorable effects of chemical compounds as well as other harmful factors on the developing brain is needed. Serious epidemiological studies along with experiments by using appropriate animal models can help to elucidate possible risks for the developing organism and may decrease the frequency of mental and neurobehavioral disorders in the human population.


Supported by the grants VEGA 2/0083/08 and VEGA 2/0066/09.


This review article is dedicated to the memory of Prof. Helena Rašková, MD., DSc.


  • Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341–355. [PMC free article] [PubMed]
  • Adams J, Vorhees CV, Middaugh LD. Developmental neurotoxicity of anticonvulsants: human and animal evidence on phenytoin. Neurotoxicol Teratol. 1990;12:203–214. [PubMed]
  • Agarwal DP, Goedde HW. Ethanol Oxidation: Ethnic Variations in Metabolism and Response. Ethnic Differences in Reactions to Drugs and Xenobiotics. Alan R Liss Inc. 1986:99–112.
  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV. Washington, DC: American Psychiatric Publishing, Inc.; 2000. Schizophrenia.
  • Arndt TL, Stodgell CJ, Rodier PM. The teratology of autism. Int J Dev Neurosci. 2005;23:189–199. [PubMed]
  • Auso E, Lavado-Autric E, Cuevas FE, del Rey GM, de Escobar P, Berbel P. A moderate and transient deficiency in maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migrations. Endocrinolgy. 2004;145:4037–4047. [PubMed]
  • Avants B, Hurt H, Gianneta J, Epstein C, Shera D, Rao H, Wang J, Gee J. Effects of heavy in utero cocaine exposure on adolescent caudate morphology. Pediatr Neurol. 2007;37:275–279. [PubMed]
  • Bass JL, Corwin M, Gozal D, Moore C, Nishida H, Parker S, Schonwald A, Wilker RE, Stehle S, Kinane TB. The effect of chronic or intermittent hypoxia on cogntion in childhood: a review of the evidence. Pediatrics. 2004;114:805–816. [PubMed]
  • Batshaw ML. Mental retardation. Pediatr Clin North Am. 1993;40:507–521. [PubMed]
  • Battle YI, Martin BC, Dofma JH, Miller LS. Seasonalilty and infectious disease on schizophrenia: the birth hypothesis revisited. J Psychiatr Res. 1999;33:501–509. [PubMed]
  • Benowitz NL, Perez-Stable EJ, Fong I, Modin G, Herrera B, Jacob P., 3rd Erthnic differences in n-glucoronidation of nicotine and cotinine. J Pharmacol Exp Ther. 1999;291:1196–1203. [PubMed]
  • Bergman K, Sarkar P, O'Connor TG, Modi N, Glover V. Matrenal stress during pregnancy predicts cognitive ability an fearfulness in infancy. J Am Acad Child Adolesc Psychiatry. 2007;46:1454–1463. [PubMed]
  • Bezek Š, Ujházy E, Dubovický M, Mach M. Nongenomic memory of foetal history in chronic diseases development. Neuro Endocrinol Lett. 2008;29:620–626. [PubMed]
  • Bezek Š, Ujházy E, Mach M, Navarová J, Dubovický M. Developmental origin of chronic diseases: Toxicological implication. Interdisc Toxicol. 2008;1:29–31. [PMC free article] [PubMed]
  • Borue X, Chen J, Condron BG. Developmental effects of SSRIs: lessons learned from animal studies. Int J Dev Neurosci. 2007;25:341–347. [PMC free article] [PubMed]
  • Brucknerova I, Bzduch V, Behulova D, Ferianec V, Dubovicky M, Ujhazy E, Mach M. Reversible asphyxial status in a newborn due to neonatal form of carnitine palmitoyltransferase II deficiency. Neuro Endocrinol Lett. 2008;29:627–630. [PubMed]
  • Brucknerová I, Ujházy E, Dubovický M, Mach M. Early assessment of the severity of asphyxia in term newborns using parameters of blood count. Interdisc Toxicol. 2008;1:211–213. [PMC free article] [PubMed]
  • Brunton PJ, Russell JA. Prenatal social stress in the rat programmes neuroendocrine and behavioural responses to stress in the adult offspring: sex-specific effects. J Neuroendocronol. 2010;22:258–271. [PubMed]
  • Buxbaum JD. Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin Neurosci. 2009;11:35–43. [PMC free article] [PubMed]
  • Cabrera-Vera TM, Garcia F, Pinto W, Battaglia G. Effects of prenatal fluoxetine (Prozac) exposure on brain serotonin neurons in prebubescent and adult male rats offspring. J Pharmacol Exp Therapeut. 1997;280:138–145. [PubMed]
  • Castle D, Wessely S, Der G, Murray RM. The incidence of operationally defined schizophrenia in Camberwell, 1965–84. The British Journal of Psychiatry. 1991 Dec;159:790–794. [PubMed]
  • Ceccarelli I, Fiorenzani P, Della Seta D, Massafra C, Cinci G, Bocci A, Aloisi AM. Perinatal exposure to xenoestrogens affects pian in adult female rats. Neurotoxicol Teratol. 2009;31:203–209. [PubMed]
  • Connors Sl, Levitt P, Matthew SG, Slotkin TA, Johnston MV, Kinney HC, Johnson WG, Dailey RM, Zimmerman AW. Fetal mechanisms in neurodevelopmenatal disorders. Pediatr Neurol. 2008;38:163–176. [PubMed]
  • Dalen K, Bruarǿy S, Wentzel-Larsen T, Laegreid LM. Cognitive functioning in children prenatally exposed to alcohol and psychotropic drugs. Neuropediatrics. 2009;40:162–167. [PubMed]
  • de Haan M, Wyatt JS, Vargha-Khadem F, Gadian D, Mishkin M. Brain and cognitive-behavioural development after asphyxia at term birth. Dev Sci. 2006;9:350–358. [PubMed]
  • Devenny DA, Krinsky-McHale SJ, Sersen G, Silverman WP. Sequence of cognitive decline in dementia in adult with Down's syndrome. J Intellect Disabil Res. 2000;44:654–665. [PubMed]
  • Drevets WC, Raichle M. Reciprocal suppression of regional cerebral blood flow during emotional versus higher cognitive processes: implications for interactions between emotion and cognition. Cogn Emot. 1998;12:353–385.
  • Driscoll LL, Gibson AM, Hieb A. Chronic postnatal DE-71 exposure: Effects on learning, attention and thyroxine levels. Neurotoxicol Teratol. 2009;31:76–84. [PubMed]
  • Dubovický M, Mach M, Brucknerová I, Ujházy E. Effect of perinatal anoxia on exploratory behaviour of rat offspring. Acta Physiologica. 2007;191(Suppl. 658):57.
  • Dubovický M, Škultétyová I, Ježová D. Neonatal stress alters habituation of exploratory behavior in adult male but not female rats. Pharmacol Biochem Behav. 1999;64:681–686. [PubMed]
  • Dubovický M, Tokarev D, Škultétyová I, Ježová D. Changes of exploratory behaviour and its habituation in rats neonatally treated with monosodium glutamate. Pharmacol Biochem Behav. 1997;56:565–569. [PubMed]
  • Dubovický M, Kovačovský P, Ujházy E, Navarová J, Brucknerová I, Mach M. Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development. Interdisc Toxicol. 2008;1:206–210. [PMC free article] [PubMed]
  • Editorial. Adecade for psychiatric disorders. Nature. 2010;463 (7277)
  • Eiden RD, McAuliffe Kachadourian L, Coles C, Colder C, Schuetze P. Effects of prenatal cocaine exposure on infant reactivity and regulation. Neurotoxicol Teratol. 2009;31:60–68. [PMC free article] [PubMed]
  • Ekino S, Susa M, Ninomiya T, Imamura K, Kitamura T. Minamata disease revisited: an uptade on the acute and chronic manifestations of the methyl mercury poisoning. J Neurol Sci. 2007;262:131–144. [PubMed]
  • Erbel-Sieler C, Dudley C, Zhou Y, Wu X, Estill SJ, Han T, Diaz-Arrastia R, Brunskill EW, Potter SS, McKnight SI. Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcriptiojn factors. Proc Natl Acad Sci USA. 2004;101:13648–13653. [PubMed]
  • Feng P, ma Y, Vogel GW. The critical window of the development from susceptive to insuscpetive. Effects of clomipramine neonatal treatment on sexual behavior. Brain Res Dev. 2001;23:107–110. [PubMed]
  • Figueiredo BC, Otten S, Strauss B, Volk D, Maysinger D. Effects of perinatal hypo- and hyperthyroidism on the level of nerve growth factor and its low-affinity receptor in cerebellum. Brain Res Dev Brain Res. 1993;72:237–244. [PubMed]
  • Fisher R, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) Epilepsia. 2005;46:470–472. [PubMed]
  • Gilbertson M. Male cerebral palsy hospitalization as apotential indicator of neurological effects of methylmercury exposure in Great Lakes communities. Environ Res. 2004;95:375–384. [PubMed]
  • Gitto E, Pellegrino S, Gitto P, Barberi I, Reiter RJ. Oxidative stress of the newborn on the pre- and postnatal period and the clinical utility of melatonin. J Pineal Res. 2009;46:128–139. [PubMed]
  • Gonzales FF, Miller SP. Does perinatal asphyxia impair cognitive function without cerebral palsy? Arch Dis Child fetal Neonatol Ed. 2006;91:454–459. [PMC free article] [PubMed]
  • Graignic-Phillipe R, Tordjman S. Effects of stress during pregnancy on infant and child development. Arch Pediatr. 2009;16:1355–1363. [PubMed]
  • Hadjikhani N. Serotonin, pregnancy and increased autism prevelence: Is there a link? Med Hypothesis. 2009 doi: 10.1016/j.mehy.2009.11.015. [PubMed] [Cross Ref]
  • Harada M. Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol. 1995;25:1–24. [PubMed]
  • Henry C, Kabbaj M, Simon H, Le Moal M, Maccari S. Prenatal stress increases the hypothalamus-pituitary-adrenal axis response in young and adult rats. J Neuroendocrinol. 1994;6:341–345. [PubMed]
  • Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorder. Curr Opin Neurol. 2010;23:103–110. [PubMed]
  • Hoeger H, Engelmann M, Bernert G, Seidl R, Bubna-Littitz H, Mosgoeller W, Lubec B, Lubec G. Long term neurological and behavioral effects of graded perinatal asphyxia in the rat. Life Sci. 2000;66:947–962. [PubMed]
  • Horsman M, Suto M, Dudgeon B, Harris SR. Ageing with cerebral palsy: psychosocial assues. Age Ageing. 2010;39:294–299. [PubMed]
  • Hurt H, Betancourt LM, Malmud EK, Shera DM, Giannetta JM, Brodsky NL, Farah MJ. Children with and without gestational cocaine exposure: Aneurocognitive system analysis. Neurotoxicol Teratol. 2009;31:334–341. [PMC free article] [PubMed]
  • Jacobus J, McQueeny T, Schweinsburg BC, Frank LR, Yang TT, Tapert SF. White matter integrity in adolescents with hisories of marijuana use and binge drinking. Neurotoxicol Teratol. 2009;31:349–355. [PMC free article] [PubMed]
  • Kable JA, Coles CD, Lynch ME, Caroll J. Th eimpact of matrenal smoking on fast auditory brainstem responses. Neutoxicol Teratol. 2009;31:216–224. [PMC free article] [PubMed]
  • Kaindl AM, Favrais G, Gressens P. Molecular mechanisms involved in injury to the preterm brain. J Child Neurol. 2009;24:1112–1118. [PubMed]
  • Kinney DK, Munir KM, Crowley DJ, Miller AM. Prenatal stress and risk for autism. Neurosci Biobehav Rev. 2008;32:1519–1532. [PMC free article] [PubMed]
  • Kostrzewa RM, Kostrzewa JP, Kostrzewa RA, Nowak P, Brus R. Pharmacological models of ADHD. J Neural Trans. 2008;115:287–298. [PubMed]
  • Kostrzewa RM. Dopamine receptor supersenzitivity. Neurosci Biobehav Rev. 1995;19:1–17. [PubMed]
  • Krištofiɩová D. How the drug is born. SAFS Bratislava. 2008 in Slovak.
  • Labie D. Developmental neurotoxicity of industrial chemicals. Med Sci (Paris) 2007;23:868–872. [PubMed]
  • Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr. 2010;22:219–225. [PubMed]
  • Li Z, Coles CD, Lynch ME, Hamann S, Peltier S, LaConte S, Hu X. Prenatal cocaine exposure alters emotional arousal regulation and its effects on working memory. Neurotoxicol Teratol. 2009;31:342–348. [PMC free article] [PubMed]
  • Maccari S, Morley-Fletcher S. Effects of prenatal restraint on the hypothalamus-pituitary-adrenal axis and related behavioural and neurobiological alterations. Psychoneuroendocrinology. 2007;(Suppl 1):10–15. [PubMed]
  • Maccari S, Piazza PV, Kabbaj M, Barbazanges A, Simon H, Le Moal M. Adoption reverses the long-term impairment in glucocorticoid feedback induced prenatal stress. J Neurosci. 1995;15:110–116. [PubMed]
  • Mach M, Dubovický M, Navarová J, Brucknerová I, Ujházy E. Experimental modelling of hypoxia in pregnancy and early postnatal life. Interdisc Toxicol. 2009;2:28–32. [PMC free article] [PubMed]
  • Mach M, Dubovický M, Navarová J, Kovacovský P, Ujházy E. Vitamin E supplementation in phenytoin induced developmental toxicity in rats: postnatal study. Neuro Endocrinol Lett. 2006;(Suppl 2):69–73. [PubMed]
  • Makatsori A, Dubovický M, Ujházy E, Bakoš J, Ježová D. Neuroendocrine changes in adult female rats prenatally exposed to phenytoin. Neurotoxicol Teratol. 2005;27:509–514. [PubMed]
  • Matsumoto M, Yoshioka M, Togashi H. Early postnatal stress and neural circuits underlying emotional regulation. Int Rev Neurobiol. 2009;85:95–107. [PubMed]
  • McGee CL, Bjorkquist OA, Riley EP, Mattson SN. Impaired language performance in young children with heavy prenatal alcohol exposure. Neurotoxicol Teratol. 2009;31:71–75. [PMC free article] [PubMed]
  • McGough NNH, Thomas JD, Dominguez HD, Riley EP. Insulin-like growth factor-I mitigates motor coordination deficits associated with neonatal alcohol exposure in rats. Neurotoxicol Teratol. 2009;31:40–48. [PMC free article] [PubMed]
  • Mendola P, Selevan SG, Gutter S, Rice D. Environmental factor associated with a spectrum of neurodevelopment deficits. Ment Retard Dev Disabil Res Rev. 2002;8:188–197. [PubMed]
  • Merrick J, Merrick E, Morad M, Kandel I. Fetal alcohol syndrome and its long-term effects. Minerva Pediatr. 2006;58:211–218. [PubMed]
  • Min MO, Singer LT, Kirchner HL, Minnes S, Short E, Hussain Z, Nelson S. Cognitive development and low-level lead exposure in poly-drug exposed children. Neurotoxicol Teratol. 2009;31:225–231. [PMC free article] [PubMed]
  • Miyazaki K, Narita N, narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotoneregic neurons in the offspring: implications for pathogenesis of autism. Int J Dev Neurosci. 2005;23:287–297. [PubMed]
  • Molnar M, Ruberti F, Cozzari C, Domenici L, Cattaneo A. Acritical period in the sensitivity of basal cholinergic neurones to NGF deprivation. Neuroreport. 1997;8:575–579. [PubMed]
  • Narita M, Oyabu A, Imura Y, Kamada N, Yokoyama T, Tano K, Uchida A, Narita N. Nonexploratory movement and behavioral alterations in a thalidomide or valproic acid-induced autism model rat. Neurosci Res. 2010;66:2–6. [PubMed]
  • Navarová J, Ujházy E, Dubovický M, Mach M. Phenytoin induced oxidative stress in pre- and postnatal rat development – effect of vitamin E on selective biochemical variables. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005;149:325–328. [PubMed]
  • Nehlig A, Debry G. Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data. Neurotoxicol Teratol. 1994;16:531–543. [PubMed]
  • Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, Mandell DS, Miller LA, Pinto-Martin J, Reaven J, Reynolds AM, Rice CE, Schendel D, Windham GC. The epidemiology of autism spectrum disorders. Annu Rev Public Health. 2007;28:235–258. [PubMed]
  • Noorlander CW, Ververs FF, Nikkels PG, van Echteld CJ, Visser GH, Smidt MP. Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities. PloS ONE. 2008;23:e2782. [PMC free article] [PubMed]
  • Okruhlicová L, Ujházy E, Mach M, Sotníková R, Tribulová N, Guller L, Dubovický M. Effect of prenatal phenytoin administration on the fine structure of rat myocardium and aorta. Pathol Res Pract. 2003;199:677–685. [PubMed]
  • Perera FP, Tang D, Tu YH, Cruz LA, Borjas M, Bernert T, Whyatt RM. Biomarkers in maternal and newborn blood indicate heightened fetal susceptibility to procarcinogenic DNA damage. Environ Health Pespect. 2004;112:1133–1136. [PMC free article] [PubMed]
  • Rinaudo PF, Lamb J. Fetal origins of perinatal morbidity and/or adult diseases. Semin Reprod Med. 2008;26:436–445. [PubMed]
  • Rose-Jacobs R, Waber D, Beeghly M, Cabral H, Appugleise D, Heeren T, Marani J, Frank DA. Intrauterine cocaine exposure and executive functioning in a middle childhood. Neurotoxicol Teratol. 2009;31:159–168. [PMC free article] [PubMed]
  • Sable HJK, Eubig PA, Powers PA, Wang VC, Schantz SL. Developmental exposure to PCBs and/or MeHg: Effects on a differential reinforcement of low rates (DRL) operant task before and after amphetamine drug challenge. Neurotoxicol Teratol. 2009;31:149–158. [PMC free article] [PubMed]
  • Sapolsky RM, Krey LC, McEwen BS. Stress down-regulates corticosterone receptors in asite-specific manner in the brain. Endocrinology. 1984;114:287–292. [PubMed]
  • Sawin S, Brodish P, Carter CS, Stanton ME, Lau C. Development of cholinergic neurons in the rat brain regions: dose-dependent effects of propylthiouracil-induced hypothyroidism. Neurotoxicol Teratol. 1998;20:627–635. [PubMed]
  • Scher MS. Prenatal contribution to epilepsy: lesson from the bedside. Epileptic Disord. 2003;5:77–91. [PubMed]
  • Schneider LM. Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge on rhesus monkey infants. Dev Psychobiol. 1992;25:529–540. [PubMed]
  • Slotkin TA, Ryde IT, Wrench E, Card JA, Seidler FJ. Nonenzymatic role of acetylcholinesterase in neuritic sprouting: Regional changes in acetycholinesterase and choline acetyltransferase after neonatal 6-hydroxydopamine lessions. Neurotoxicol Teratol. 2009;31:183–186. [PMC free article] [PubMed]
  • Strömland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol. 1994;36:351–356. [PubMed]
  • Strömland K, Philipson E, Andresson Grönlund M. Offspring of male and female parents with thalidomide embryopathy: birth defects and functional anomalies. Teratology. 2002;66:115–121. [PubMed]
  • Sundram S. Cannabis and neurodevelopment: implications for psychiatric disorders. Hum Psychopharmacol. 2006;21:245–254. [PubMed]
  • Swerts CA, Costa AM, Estevens A, Borato CE, Swerts MS. Effects of fluoxetine and imipramine in rat fetuses treated during acrirtical gestational period: amacro and microscopic study. Rev Bras Psiquitr. 2009;15S1516-44462009005000015 [PubMed]
  • Trofinmova LK, Graf AV, Maslova MV, Dunaeva TU, Maklakova AS, Sokolova NA. Postnatal behavioural consequences of antenatal intermittent hypoxia experienced during early organogenesis in mature rats. Izv Akad Nauk Ser Biol. 2010;1:54–59. in Russian. [PubMed]
  • Ujházy E, Navarová J, Dubovický M, Bezek Š, Mach M. Important issues in developmental toxicity testing. Interdisc Toxicol. 2008;1:27–28. [PMC free article] [PubMed]
  • Ujházy E, Mach M, Dubovický M, Navarová J, Soltés L, Juránek I, Brucknerová I, Zeman M. Effect of melatonin and stobadine on maternal and embryofoetal toxicity in rats due to intrauterine hypoxia induced by phenytoin administration. Cent Eur J Public Health. 2004;12:83–86. [PubMed]
  • Uno H, Lohmiller L, Thieme C, Kemnitz JW, Engle MJ, Roecker EB, Farrel PM. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. 1. Hippocampus. Dev Brain Res. 1990;53:157–167. [PubMed]
  • Valée M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S. Prenatal stress induces high anxiety and postnatal handling inuces low anxiety in adult offspring. Correlation with stress-induced corticosterone secretion. J Neurosci. 1997;17:2626–2636. [PubMed]
  • Valée M, Mayo W, Maccari S, Le Moal M, Simon H. Long-term effects of prenatal stress and handling on metabolic parameters: relationship to corticosterone secretion response. Brain Res. 1996;712:287–292. [PubMed]
  • Van de Aa N, Vandeweyer G, Kooy RF. Aboy with menatal retardation, obesity and hypertrichosis caused by a microdeletion of 19p13.12. Eur J Med Genet. 2010 in press. [PubMed]
  • Vataeva LA, Kudrin VS, Vershinina EA, Mosin VM, Tiulkova EI, Otellin VA. Maternal para-chlophenylalanine exposure modifies central monoamines and behaviors in the adult offspring. Brain Res. 2008;1234:1–7. [PubMed]
  • Venerosi A, Cutuli D, Chiaroti F, Calamandrei G. C-section birth per se or followed by acute global asphyxia altered emotional behaviour in neonate and adult rats. Behav Brain Res. 2006;168:56–63. [PubMed]
  • Vestergaard M, Wisborg K, Henriksen TB, Secher NJ, Ostergaard JR, Plsen J. Prenatal exposure to cigarettes, alcohol, and coffee and the risk for febrile seizures. Pediatrics. 2005;116:1089–1094. [PubMed]
  • Vorhees CV, Johnson HL, Burns Nl, Williams MT. Developmental treatment with dopamine D2/3 agonist quinpirole selectively impairs spatial learning in the Morris water maze. Neurotoxicol Teratol. 2009;31:1–10. [PubMed]
  • Weinstock M. Gender differences in the effects of prenatal stress on brain development and behaviour. Neurochem Res. 2007;32:1730–1740. [PubMed]
  • Weitzdoerfer R, Gerstl N, Pollak D, Hoeger H, Dreher W, Lubec G. Long-term influence of perinatal asphyxia on the social behaviour in aging rats. Gerontology. 2004;50:200–205. [PubMed]
  • Wells PG, Winn LM. Biochemical toxicology of chemical teratogenesis. Crit Rev Biochem Mol Biol. 1996;1:1–40. [PubMed]
  • Yolton K, Khoury J, Xu Y, Succop P, Lanphear B, Bernert JT, Lester B. Low-level exposure to nicotine and infant behavior. Neurotoxicol Teratol. 2009;31:356–363. [PMC free article] [PubMed]

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