Search tips
Search criteria

Results 1-25 (1296022)

Clipboard (0)

Related Articles

1.  Animal Models of Human Disease: Severe and Mild Lead Encephalopathy in the Neonatal Rat* 
Inorganic lead produces cerebral dysfunction and clinically definable encephalopathies in man. To date there have been few studies on the biochemical changes in brain following exposure to inorganic lead. Studies correlating toxicity with behavioral and brain neurochemical changes following lead exposure have been hindered because adult laboratory animals are resistant to the central nervous system effects of lead poisoning. Such studies have been impeded by lack of suitable experimental models until Pentschew and Garro showed that brain lesions develop in neonatal rats when a pregnant rat newly delivered of her litter is placed on a 4% lead carbonate containing diet. Lead passes into the developing sucklings via maternal milk. Lead-poisoned new-borns have pronounced retardation of growth and during the fourth week of ilfe develop the severe signs of lead encephalopathy, namely, extensive histological lesions of the cerebellum, brain edema, and paraplegia. There is an approximate 85-fold increase in the lead concentration of both the cerebellum and cerebral cortex relative to controls, but edema and gross vascular changes are confined to the cerebellum. Ingested lead had little effect on RNA, DNA, and protein concentrations of developing rat cerebellum and cerebral cortex. However, there was a reduction of between 10 and 20% in the DNA content of the cerebellum around 3 weeks of age in the lead-exposed sucklings. This suggests a failure of cell multiplication in this part of the brain.
A critical evaluation of this experimental approach indicated that under similar dietary conditions experimental lactating rats eat 30% less food than controls resulting in: (a) sustained loss in body weight of nursing mothers and that (b) offsprings who develop paraplegia and cerebellar damage do so after gaining access to lead containing diet.
We have studied mothers' food consumption and body weight changes and blood, milk, and brain lead content; and newborns' body and brain weight changes, blood and brain lead content, and brain serotonin (5HT), norepinephrine (NE), dopamine (DA), and γ-aminobutyric acid (GABA). We have found that a lactating mother rat eating 5% lead acetate (2.73% Pb) produced milk containing 25 ppm lead. When the mothers' diet is changed at day 16 from 5% PbAc to one containing 25 ppm Pb, and neonates allowed free access to the solid diet, the sucklings still have retarded body growth but do not develop paraplegia or grossly apparent vascular damage of the cerebellum. However, during the fourth week these animals exhibit a less severe form of “encephalopathy” consisting of hyperactivity, tremors, and stereotype behavior. Pair-fed controls coetaneous to experimental groups do not display such activities. There was no change in brain 5HT, GABA, or NE, but a 15–20% decrease in brain DA. Change in DA relative to other monoamines suggests a relationship between CNS dysfunction due to lead and DA metabolism in the brain.
The experimental design as discribed provides a model of CNS dysfunction due to lead exposure without debilitating histopathologies. It is possible that our findings on increased motor activity and changes in brain dopamine may correspond to early responses to lead exposure before recognized overt signs of toxicity.
PMCID: PMC1475133  PMID: 4831141
2.  Monoamine neurotransmitters and fibroblast growth factor-2 in the brains of rats with post-stroke depression 
The aim of the present study was to investigate the changes in the levels of serotonin (5-HT), dopamine (DA), norepinephrine (NE) and fibroblast growth factor-2 (FGF-2) in the brains of rats with post-stroke depression (PSD). A rat model of stroke was established by middle cerebral artery occlusion and the rats were randomly divided into two groups: Control and modification groups. The rats in the modification group had PSD, while the rats in the control group had experienced a stroke only. The PSD model was established by applying chronic mild stress to the individually housed rats. High-performance liquid chromatography was used to detect the levels of 5-HT, DA and NE, while western blotting was used to detect the FGF-2 protein expression levels in the frontal lobe and hippocampus. Quantitative polymerase chain reaction was also used to determine the mRNA expression levels of FGF-2 in the frontal lobes of the two groups. The levels of 5-HT, DA and NE in the frontal lobe and hippocampus of the rats in the PSD group were significantly lower than the levels observed in the rats in the stroke group (P<0.01). In addition, protein expression levels of FGF-2 in the frontal lobe of the rats in the PSD group were significantly lower when compared with the control group rats (P<0.01), however, the protein expression levels of FGF-2 in the hippocampus did not exhibit a statistically significant difference (P>0.05). The mRNA expression levels of FGF-2 in the frontal lobe of the rats in the modification group were significantly lower than the levels in the control group rats (P<0.01). Therefore, reduced levels of monoamine neurotransmitters and FGF-2 expression in the brains of rats with PSD are associated with the incidence of PSD.
PMCID: PMC4061212  PMID: 24944615
post-stroke depression rat; serotonin; dopamine; norepinepherine; fibroblast growth factor-2
3.  Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats 
Higher aluminum (Al) content in infant formula and its effects on neonatal brain development are a cause for concern. This study aimed to evaluate the distribution and concentration of Al in neonatal rat brain following Al treatment, and oxidative stress in brain tissues induced by Al overload.
Postnatal day 3 (PND 3) rat pups (n =46) received intraperitoneal injection of aluminum chloride (AlCl3), at dosages of 0, 7, and 35 mg/kg body wt (control, low Al (LA), and high Al (HA), respectively), over 14 d.
Aluminum concentrations were significantly higher in the hippocampus (751.0 ± 225.8 ng/g v.s. 294.9 ± 180.8 ng/g; p < 0.05), diencephalon (79.6 ± 20.7 ng/g v.s. 20.4 ± 9.6 ng/g; p < 0.05), and cerebellum (144.8 ± 36.2 ng/g v.s. 83.1 ± 15.2 ng/g; p < 0.05) in the HA group compared to the control. The hippocampus, diencephalon, cerebellum, and brain stem of HA animals displayed significantly higher levels of lipid peroxidative products (TBARS) than the same regions in the controls. However, the average superoxide dismutase (SOD) activities in the cerebral cortex, hippocampus, cerebellum, and brain stem were lower in the HA group compared to the control. The HA animals demonstrated increased catalase activity in the diencephalon, and increased glutathione peroxidase (GPx) activity in the cerebral cortex, hippocampus, cerebellum, and brain stem, compared to controls.
Aluminum overload increases oxidative stress (H2O2) in the hippocampus, diencephalon, cerebellum, and brain stem in neonatal rats.
PMCID: PMC3404950  PMID: 22613782
Aluminum; Neonatal rats; Functional brain tissues; Intraperitoneal injection
4.  Effects of sex and chronic neonatal nicotine treatment on NKCC1, KCC2, BDNF, NR2A and NR2B mRNA expression in the postnatal rat hippocampus 
Neuroscience  2012;225:105-117.
Chronic exposure to nicotine during the first postnatal week in rats, a developmental period that corresponds to the third trimester of human gestation, results in sexually dimorphic long-term functional defects in the adult hippocampus. One potential cause could be the sex-specific differences in the maturation of GABAA receptor-mediated responses from excitatory to inhibitory, which depends on the expression of the Na2+/K+/Cl−-co-transporter NKCC1 and the K+/Cl− co-transporter KCC2. In the rat hippocampus, this switch occurs during the first and second postnatal week in females and males, respectively, and is regulated by nicotinic receptor activation. Excitatory GABAergic signaling can increase BDNF expression, which might exacerbate sex differences by impacting synaptogenesis. We hypothesized that chronic neonatal nicotine (CNN) exposure differentially regulates the expression of these co-transporters and BDNF in males and females. We use quantitative isotopic in situ hybridization to examine the expression of mRNAs for NKCC1, KCC2, BDNF, and NMDA receptor subunits NR2A and NR2B in the postnatal day (P) 5 and 8 rat hippocampus in both sexes that were either control-treated or with 6 mg/kg/day nicotine in milk formula (CNN) via gastric intubation starting at P1. In line with prolonged GABAergic excitation, we found that at P5 males had significantly higher mRNA expression of NKCC1 and BDNF than females. CNN treatment resulted in a significant increase in KCC2 and BDNF mRNA expression in male but not female hippocampus (p<0.05). Males also had higher expression of NR2A and lower expression of NR2B at P5 compared to females (p<0.05). At P8, there were neither sex nor treatment effects on mRNA expression, indicating the end of a critical period for sensitivity to nicotine. These results suggest that differential maturation of GABAAR-mediated responses result in sex-specific sensitivity to nicotine during early postnatal development, potentially explaining the differential long-term effects of CNN on hippocampal function.
PMCID: PMC3485076  PMID: 22982626
nicotinic; nAChR; GABAergic; NMDA; development; in situ hybridization
5.  Chronic nicotine treatment induces rat CYP2D in the brain but not in the liver: an investigation of induction and time course 
CYP2D6 levels are higher in many brain regions of human smokers in comparison with nonsmokers. We have shown that CYP2D is expressed in rat brain regions and that enzyme activities correlate with protein and messenger ribonucleic acid (mRNA) levels. The aims of this study were to investigate whether nicotine can induce rat brain CYP2D, to determine the recovery time course of the induction and to investigate the mechanism of induction through measuring mRNA levels over time.
Rats were either treated once with either saline or nicotine (1 mg base/kg, subcutaneous and sacrificed 8 hours after the treatment or treated daily for 7 days and sacrificed 0.5–24 hours after the last injection. The CYP2D protein and mRNA levels were assessed by immunoblotting, immunocytochemistry and slot blotting.
There were no changes in brain CYP2D levels after a single nicotine injection. Following chronic nicotine treatment, levels were maximal at 8 hours and returned to control levels by 12 hours after nicotine treatment in all 3 regions assessed. At 8 hours after nicotine treatment, CYP2D levels were significantly (p < 0.05) higher than levels in saline-treated control animals in the cerebellum (1.4-fold), hippocampus (1.3-fold) and striatum (3.2-fold); they tended to be higher in the frontal cortex, brainstem and thalamus. Induction was specific to brain region and cell, for example, in some striatal neurons and in neurons in the cerebellar granular layer and white matter. At no time was there any increase in brain CYP2D mRNA levels. Hepatic CYP2D levels were unchanged at all times tested.
Chronic nicotine treatment induced CYP2D enzymes in rat brain but not rat liver. The induction was maximal 8 hours after the last injection and did not involve alterations in mRNA, indicating a posttranscriptional mechanism. These findings suggest that, in humans exposed to nicotine, response to centrally acting drugs metabolized by CYP2D, susceptibility to neurotoxins either activated or inactivated by CYP2D and the general homeostasis of endogenous neurochemicals metabolized by CYP2D may be affected, owing to increased CYP2D in the brain.
PMCID: PMC2186369  PMID: 18197273
animals; cytochrome P450 enzyme system; nicotine; brain; central nervous system; metabolism; smoking; Parkinson disease
6.  Long-term, low-dose lead exposure alters the gonadotropin-releasing hormone system in the male rat. 
Environmental Health Perspectives  2002;110(9):871-874.
Lead is a male reproductive toxicant. Data suggest that rats dosed with relatively high levels of lead acetate for short periods of time induced changes in the hypothalamic gonadotropin-releasing hormone (GnRH) at the molecular level, but these changes were attenuated with increased concentration of exposure. The current study evaluated whether exposure to low levels of lead acetate over longer periods of time would produce a similar pattern of adaptation to toxicity at the molecular and biologic levels. Adult 100-day-old Sprague-Dawley male rats were dosed with 0, 0.025, 0.05, 0.1, and 0.3% lead acetate in water. Animals were killed after 1, 4, 8, and 16 weeks of treatment. Luteinzing hormone (LH) and GnRH levels were measured in serum, and lead levels were quantified in whole blood. Hypothalamic GnRH mRNA levels were also quantified. We found no significant differences in serum LH and GnRH among the groups of animals treated within each time period. A significant dose-related increase of GnRH mRNA concentrations with lead dosing occurred in animals treated for 1 week. Animals treated for more than 1 week also exhibited a significant increase in GnRH mRNA, but with an attenuation of the increase at the higher concentrations of lead with increased duration of exposure. We conclude that the signals within and between the hypothalamus and pituitary gland appear to be disrupted by long-term, low-dose lead exposure.
PMCID: PMC1240985  PMID: 12204820
7.  Effects of chronic neonatal nicotine exposure on nAChR binding, cell death and morphology in hippocampus and cerebellum 
Neuroscience  2007;146(4):1854-1868.
Nicotine, the major psychoactive ingredient in tobacco interacting with nicotinic acetylcholine receptors (nAChR), is believed to have neuroprotective and neurotoxic effects on the developing brain. Neurotoxicity has been attributed to activation of homomeric α7 nAChRs, neuroprotection to heteromeric α4β2 nAChRs. Thus, developmental nicotine could have opposite effects in different brain regions, depending on nAChR subtype expression. Here, we determined if chronic neonatal nicotine exposure (CNN), during a period of brain growth corresponding to the third human trimester, differentially regulates nAChR expression, cell death, and morphological properties in hippocampus and cerebellum, two structures maturing postnatally. Rat pups were orally treated with 6 mg/kg/day nicotine from postnatal day (P)1 to P7. On P8, expression for α4, α7 and β2 mRNA was determined by in situ hybridization; nAChR binding sites in by receptor autoradiography, dying neurons by TUNEL and Fluoro-Jade staining and morphological properties by analysis of Cresyl-Violet stained sections. In control cerebellum, strong expression of α4, β2 mRNA and heteromeric nAChRs labeled with [125I]-Epibatidine were found in granule cells, and α7 mRNA and homomeric nAChRs labeled with [125I]-αBungarotoxin in the external germinal layer. In control hippocampus, low expression of α4 mRNA and heteromeric nAChRs and high expression of α7 mRNA and homomeric nAChRs were detected. CNN increased heteromeric nAChR binding in hippocampus but not cerebellum and significantly decreased neuronal soma size and increased packing density in hippocampal principal cells but not in cerebellum. CNN did not increase the number of dying cells in any area, but significantly fewer TUNEL-labeled cells were found in CA3 strata oriens and radiatum and cerebellar granule layer. Thus, the hippocampus seems to be more sensitive than the cerebellum to CNN which could result from different nAChR subtype expression and might explain long-lasting altered cognitive functions correlated with gestational nicotine exposure due to changes in hippocampal cell morphology.
PMCID: PMC2001269  PMID: 17434679
apoptosis; development; nicotinic; receptor; neuronal density
8.  Peanut sprouts extract (Arachis hypogaea L.) has anti-obesity effects by controlling the protein expressions of PPARγ and adiponectin of adipose tissue in rats fed high-fat diet 
Nutrition Research and Practice  2014;8(2):158-164.
This study aims to find out the effects of peanut sprout extracts on weight controls and protein expressions of transcription factors related to adipocyte differentiation and adipocytokine in rats under high-fat diets.
Four week-old Sparague-Dawley (SD) were assigned to 4 groups; normal-fat (NF) diets (7% fat diet), high-fat (HF) diets (20% fat diet), high fat diets with low peanut sprout extract (HF + PSEL) diet (20% fat and 0.025% peanut sprout extract), and high fat diets with high peanut sprout extract (HF + PSEH) diet (20% fat and 0.05% peanut sprout extract). Body weight changes, lipid profiles in adipose tissue, and the mRNA protein expressions, such as peroxisome proliferator-activated receptor γ (PPARγ), CCAAT element binding protein α (C/EBP α), leptin, and adiponectin, were determined.
After 9 weeks of feeding, the HF + PSEH group had significantly less weight gains than the HF group (P < 0.05). However, the total dietary intakes or food efficiency ratios among groups were not significantly different. The weight of epididymal fat in HF + PSEH group, 3.61 ± 0.5 g, or HF + PSEL group, 3.80 ± 0.7 g, was significantly lower than the HF group, 4.39 ± 0.4g, (P < 0.05). Total lipids and total cholesterol in adipose tissue were significantly decreased in HF + PSEH group compared to those in the HF group, respectively (P < 0.05). PSEH supplementation caused AST and ALT levels to decrease when it compared to HF group, but it was not statistically significant. The protein expression of PPARγ in HF + PSEH group was significantly lower than the HF group (P < 0.05). Comparing with the HF group, the protein expression of adiponectin in HF + PSEH group was significantly increased (P < 0.05). The protein expressions of C/EBP α and leptin in HF + PSEH group were lower than the HF group, but it was not statistical significant.
In conclusion, peanut sprout extract has anti-obesity effect by lowering the expressions of PPARγ which regulates the expression of adiponectin.
PMCID: PMC3988504  PMID: 24741399
Peanut sprout extract; obesity; PPARγ; adiponectin; high fat diet
9.  Evidence for oxidative stress in the developing cerebellum of the rat after chronic mild carbon monoxide exposure (0.0025% in air) 
BMC Neuroscience  2009;10:53.
The present study was designed to test the hypothesis that chronic very mild prenatal carbon monoxide (CO) exposure (25 parts per million) subverts the normal development of the rat cerebellar cortex. Studies at this chronic low CO exposure over the earliest periods of mammalian development have not been performed to date. Pregnant rats were exposed chronically to CO from gestational day E5 to E20. In the postnatal period, rat pups were grouped as follows: Group A: prenatal exposure to CO only; group B: prenatal exposure to CO then exposed to CO from postnatal day 5 (P5) to P20; group C: postnatal exposure only, from P5 to P20, and group D, controls (air without CO). At P20, immunocytochemical analyses of oxidative stress markers, and structural and functional proteins were assessed in the cerebellar cortex of the four groups. Quantitative real time PCR assays were performed for inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) nitric oxide synthases.
Superoxide dismutase-1 (SOD1), SOD2, and hemeoxygenase-1 (HO-1) immunoreactivity increased in cells of the cerebellar cortex of CO-exposed pups. INOS and nitrotyrosine immunoreactivity also increased in blood vessels and Purkinje cells (PCs) of pups from group-A, B and C. By contrast, nNOS immunoreactivity decreased in PCs from group-B. Endothelial NOS immunoreactivity showed no changes in any CO-exposed group. The mRNA levels for iNOS were significantly up-regulated in the cerebellum of rats from group B; however, mRNA levels for nNOS and eNOS remained relatively unchanged in groups A, B and C. Ferritin-H immunoreactivity increased in group-B. Immunocytochemistry for neurofilaments (structural protein), synapsin-1 (functional protein), and glutamic acid decarboxylase (the enzyme responsible for the synthesis of the inhibitory neurotransmitter GABA), were decreased in groups A and B. Immunoreactivity for two calcium binding proteins, parvalbumin and calbindin, remained unchanged. The immunoreactivity of the astrocytic marker GFAP increased after prenatal exposure.
We conclude that exogenously supplied CO during the prenatal period promotes oxidative stress as indicated by the up-regulation of SOD-1, SOD-2, HO-1, Ferritin-H, and iNOS with increased nitrotyrosine in the rat cerebella suggesting that deleterious and protective mechanisms were activated. These changes correlate with reductions of proteins important to cerebellar function: pre-synaptic terminals proteins (synapsin-1), proteins for the maintenance of neuronal size, shape and axonal quality (neurofilaments) and protein involved in GABAergic neurotransmission (GAD). Increased GFAP immunoreactivity after prenatal CO-exposure suggests a glial mediated response to the constant presence of CO. There were differential responses to prenatal vs. postnatal CO exposure: Prenatal exposure seems to be more damaging; a feature exemplified by the persistence of markers indicating oxidative stress in pups at P20, following prenatal only CO-exposure. The continuation of this cellular environment up to day 20 after CO exposure suggests the condition is chronic. Postnatal exposure without prenatal exposure shows the least impact, whereas prenatal followed by postnatal exposure exhibits the most pronounced outcome among the groups.
PMCID: PMC2700113  PMID: 19580685
10.  Fluoride and Arsenic Exposure Impairs Learning and Memory and Decreases mGluR5 Expression in the Hippocampus and Cortex in Rats 
PLoS ONE  2014;9(4):e96041.
Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague-Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and mGluR5 expression in cortex and hippocampus.
PMCID: PMC3997496  PMID: 24759735
11.  Prenatal Exposure to Benzo(a)pyrene Impairs Later-Life Cortical Neuronal Function 
Neurotoxicology  2008;29(5):846-854.
Prenatal exposure to environmental contaminants, such as Benzo(a)pyrene [B(a)P] has been shown to impair brain development. The overarching hypothesis of our work is that glutamate receptor subunit expression is crucial for cortical evoked responses and that prenatal B(a)P exposure modulates the temporal developmental expression of glutamatergic receptor subunits in the somatosensory cortex. To characterize prenatal B(a)P exposure on the development of cortical function, pregnant Long Evans rats were exposed to low-level B(a)P (300μg/kg BW) by oral gavage on gestational days 14 to 17. At this exposure dose, there was no significant effect of B(a)P on 1) the number of pups born per litter, 2) the pre-weaning growth curves and 3) initial and final brain to body weight ratios. Control and B(a)P-exposed offspring were profiled for B(a)P metabolites in plasma and whole brain during the pre-weaning period. No detectable levels of metabolites were found in the control offspring. However, a time-dependent decrease in total metabolite concentration was observed in B(a)P-exposed offspring. On PND100-120, cerebrocortical mRNA expression was determined for the glutamatergic NMDA receptor subunit (NR2B) in control and B(a)P-exposed offspring. Neural activity was also recorded from neurons in primary somatic sensory (barrel) cortex. Semiquantitative PCR from B(a)P-exposed offspring revealed a significant 50% reduction in NR2B mRNA expression in B(a)P-exposed offspring relative to controls. Recordings from B(a)P-exposed offspring revealed that N-methyl-D-aspartate (NMDA) receptor -dependent neuronal activity in barrel cortex evoked by whisker stimulation was also significantly reduced (70%) as compared to controls. Analysis showed that the greatest deficit in cortical neuronal responses occurred in the shorter latency epochs from 5-20ms post-stimulus. The results suggest that in utero exposure to benzo(a)pyrene results in diminished mRNA expression of the NMDA NR2B receptor subunit to result in late life deficits in cortical neuronal activity in the offspring. The findings from this study lead to a strong prediction that in utero exposure to benzo(a)pyrene at a time when synapses are first formed and adjusted in strength by activity in the sensory pathways will produce a strong negative effect on brain function in offspring progeny.
PMCID: PMC2752856  PMID: 18761371
polycyclic aromatic hydrocarbon-(PAH); benzo(a)pyrene-B(a)P; World Trade Center (WTC); small for gestational age (SGA); intrauterine growth restriction (IUGR); Bailey Scales of Infant Development (BSID-II); susceptibility-exposure paradigm; somatosensory cortex-S1 cortex; cortical neuronal activity and behavior; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA); N-methyl-D-aspartate (NMDA); environmental aryl hydrocarbon receptor agonists-eAhR agonist; developmental neurotoxicity
12.  Effect of hyperbaric oxygen on neurological recovery of neonatal rats following hypoxic-ischemic brain damage and its underlying mechanism 
Objective: To investigate the mechanism underlying the effect of hyperbaric oxygen (HBO) on hypoxic/ischemic brain damage (HIBD) in a neonatal rat model. Methods: A total of 30 neonatal SD rats aged 7 days were randomly assigned into control group, HIBD group and HBO group (n=10 per group). Following HIBD modeling in neonatal rats, HBO treatment was performed for consecutive 7 days. Immunohistochemistry was done to measure the expression of bone morphogenetic protein-4 (BMP-4) and nestin in the hippocampus. In situ hybridization was employed to detect the mRNA expression of BMP-4 and nestin in the hippocampus. TUNEL staining was done to detect the apoptosis of nerve cells. Results: HIBD was successfully established in the present study. Among three groups, the protein expression of BMP-4 in the hippocampus was the highest in the HBO group, and the smallest in the HIBD group. The BMP-4 expression in the HIBD group was significantly lower than that in the control group. The protein expression of nestin in the hippocampus was the highest in the HBO group, and the smallest in the HIBD group. The nestin protein expression in the hippocampus of HIBD group was significantly lower than that in the control group. The mRNA expression of BMP-4 in the hippocampus was the highest in the HBO group, and the smallest in the HIBD group. The mRNA expression of nestin in the hippocampus was the highest in the HBO group, and the smallest in the HIBD group. The number of apoptotic cells was the largest in the HIBD group, and the number of apoptotic cells in the HBO group was still larger than that in the control group (P<0.01). Conclusion: HBO may promote the neurological recovery in neonatal rats with HIBD, which may be attributed to the increased protein and mRNA expression of BMP-4 and nestin in the hippocampus and the inhibition of neural apoptosis.
PMCID: PMC3515988  PMID: 23236544
Neonatal rat; ischemic/hypoxic brain damage; hyperbaric oxygen; bone morphogenetic protein – 4; nestin
13.  Methamphetamine Regulation of Sulfotransferase 1A1 and 2A1 Expression in Rat Brain Sections 
Neurotoxicology  2012;34:212-218.
Sulfotransferase catalyzed sulfation regulates the biological activities of various neurotransmitters/hormones and detoxifies xenobiotics. Rat sulfotransferase rSULT1A1 catalyzes the sulfation of neurotransmitters and xenobiotic phenolic compounds. rSULT2A1 catalyzes the sulfation of hydroxysteroids and xenobiotic alcoholic compounds. In this work, Western blot and real-time RT-PCR were used to investigate the effect of methamphetamine on rSULT1A1 and rSULT2A1 protein and mRNA expression in rat cerebellum, frontal cortex, hippocampus, and striatum. After 1-day treatment, significant induction of rSULT1A1 was observed only in the cerebellum; rSULT2A1 was induced significantly in the cerebellum, frontal cortex, and hippocampus. After 7-days of exposure, rSULT1A1 was induced in the cerebellum, frontal cortex, and hippocampus, while rSULT2A1 was induced significantly in all four regions. Western blot results agreed with the real-time RT-PCR results, suggesting that the induction occurred at the gene transcriptional level. Results indicate that rSULT1A1 and rSULT2A1 are expressed in rat frontal cortex, cerebellum, striatum, and hippocampus. rSULT1A1 and rSULT2A1are inducible by methamphetamine in rat brain sections in a time dependable manner. rSULT2A1 is more inducible than rSULT1A1 by methamphetamine in rat brain sections. Induction activity of methamphetamine is in the order of cerebellum > frontal cortex, hippocampus > striatum. These results suggest that the physiological functions of rSULT1A1 and rSULT2A1 in different brain regions can be affected by methamphetamine.
PMCID: PMC3557703  PMID: 23026138
sulfotransferase; methamphetamine; gene regulation; rat brain sections; rSULT1A1; rSULT2A1
14.  Effect of silencing of high mobility group A2 gene on gastric cancer MKN-45 cells 
AIM: To investigate the effect of high mobility group A2 (HMGA2) gene silencing on gastric cancer MKN-45 cells in vitro.
METHODS: HMGA2 short hairpin RNA (shRNA) expression plasmids were constructed, including a pair of random scrambled sequences. Human gastric cancer cell line MKN-45 cells were divided into three groups: blank control group (non-transfected cells), transfected group (cells transfected with HMGA2 shRNA recombinant plasmid) and scrambled sequence group (transfected with random scrambled plasmid). Cells were transfected with HMGA2 shRNA recombinant plasmids and scrambled plasmid in vitro, and the cells transfection efficiency was assayed by fluorescence microscopy. The HMGA2 messenger RNA (mRNA) expression was detected by reverse transcription polymerase chain reaction, gastric cancer cells apoptosis was detected by flow cytometry, cell proliferation was detected by methyl thiazol tetrazolium, and the protein expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), P27, caspase-9 and B-cell leukemia/lymphoma-2 (Bcl-2) were analyzed by Western blotting.
RESULTS: Compared with the blank control group and the scrambled sequence group, the levels of HMGA2 mRNA and protein expression in the transfected group were significantly reduced (P < 0.05). The relative HMGA2 mRNA expression levels of the blank control group, transfected group and scrambled sequence group were 0.674 ± 0.129, 0.374 ± 0.048 and 0.689 ± 0.124, respectively. The relative HMGA2 protein expression levels of the blank control group, transfected group and scrambled sequence group were 0.554 ± 0.082, 0.113 ± 0.032 and 0.484 ± 0.123, respectively. Moreover, transfection with the scrambled sequence had no effect on the expression of HMGA2. After being transfected with shRNA for 24, 48 and 72 h, the cell apoptotic rates of the transfected group were 21.65% ± 0.28%, 39.98% ± 1.82% and 24.51% ± 0.93%, respectively, which significantly higher than those of blank control group (4.72% ± 1.34%, 5.83% ± 0.13% and 5.22% ± 1.07%) and scrambled sequence group (4.28% ± 1.33%, 7.87% ± 1.43% and 6.71% ± 0.92%). After 24, 48 and 72 h, the cell proliferation inhibition rates in the transfected group were 31.57% ± 1.17%, 39.45% ± 2.07% and 37.56% ± 2.32%, respectively; the most obvious cell proliferation inhibition appeared at 48 h after transfection. Compared with the blank control group and scrambled sequence group, after transfection of shRNA for 72 h, the protein expression levels of PI3K (0.042 ± 0.005 vs 0.069 ± 0.003, 0.067 ± 0.05), Akt (0.248 ± 0.004 vs 0.489 ± 0.006, 0.496 ± 0.104) and Bcl-2 (0.295 ± 0.084 vs 0.592 ± 0.072, 0.594 ± 0.109) were significantly reduced. The protein expression levels of P27 (0.151 ± 0.010 vs 0.068 ± 0.014, 0.060 ± 0.013) and caspase-9 (0.136 ± 0.042 vs 0.075 ± 0.010, 0.073 ± 0.072) were significantly upregulated.
CONCLUSION: HMGA2 shRNA gene silencing induces apoptosis and suppresses proliferation of MKN-45 cells.
PMCID: PMC3587480  PMID: 23482887
Gastric cancer cells; RNA interference; High mobility group A2; Proliferation; Apoptosis
15.  Opposite effects of acute ethanol exposure on GAP-43 and BDNF expression in the hippocampus versus the cerebellum of juvenile rats 
Alcohol (Fayetteville, N.Y.)  2011;45(5):461-471.
The adolescent brain is particularly vulnerable to the effects of alcohol, with intoxications at this developmental age often producing long-lasting effects. The present study addresses the effects of a single acute ethanol exposure on GAP-43 and BDNF gene expression in neurons in the cerebellum and hippocampus of adolescent rats. Male postnatal day 23 (P23) Sprague-Dawley rats were exposed to ethanol vapors for two hours and after a recovery period of two hours, the cerebellum and hippocampus were harvested and samples were taken for blood alcohol concentration (BAC) determinations. We found that this exposure resulted in a mean BAC of 174 mg/dl, which resembles levels in human adolescents after binge drinking. Analyses of total RNA and protein by qRT-PCR and western blotting, respectively, revealed that this single ethanol exposure significantly decreased the levels of GAP-43 mRNA and protein in the cerebellum but increased the levels of mRNA and protein in the hippocampus. BDNF mRNA and protein levels were also increased in the hippocampus but not in the cerebellum of these animals. In situ hybridizations revealed that GAP-43 and BDNF mRNA levels were primarily increased by alcohol exposure in hippocampal dentate granule cells and CA3 neurons. Overall, the reported alterations in the expression of the plasticity-associated genes GAP-43 and BDNF in juvenile rats are consistent with the known deleterious effects of binge drinking on motor coordination and cognitive function.
PMCID: PMC3119774  PMID: 21367572
GAP-43; BDNF; ethanol; hippocampus; cerebellum; juvenile rats
16.  Effects of trypan blue on corneal endothelium and anterior lens capsule in albino wistar rats: An investigator-masked, controlled, two-period, experimental study 
The development of continuous curvilinear capsulorrhexis (CCC) has contributed significantly to the tolerability and effectiveness of cataract extraction and intraocular lens implantation. Staining of the anterior capsule has become a popular method of increasing visibility when performing CCC.
The aim of this study was to determine, using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), the highest concentrations of trypan blue dye that would not cause long-term toxicity after injection into the anterior chamber of rat eyes.
The eyes of healthy female albino Wistar rats were used in this investigator-masked, controlled, 2-period, experimental study conducted over 12 weeks at the Dicle University Experimental Animal Laboratory, Diyarbakir, Turkey. The rats were randomly divided into 5 groups of 4 using a random-number table. Each rat was administered a 0.05-mL injection of trypan blue into the right eye in 1 of the following concentrations: 0.4%, 0.2%, 0.1%, 0.05%, or 0.025%. A 0.05-mL pH-balanced saline solution was injected into the left eye of each rat to act as a control. At 1 day after injection and 4 weeks after injection (early period), 1 rat from each concentration group was euthanized and their eyes were enucleated. At 12 weeks after injection (late period) the remaining 2 rats from each group were euthanized and their eyes were enucleated. Corneal endothelial cells and the anterior lens capsule of the enucleated eyes were analyzed using SEM and TEM, and the results were compared with those of the control group. In the TEM analysis, the primary end point was the histopathologic changes in the cellular organelles when compared with those in the control group. In the SEM analysis, the primary end point was changes in cell shape, intracellular junctions, and density of the microvilli when compared with those in the control group.
Forty eyes from 20 albino Wistar rats (mean [SD] age, 8.2 [1.6] weeks; mean [SD] weight, 175.6 [16.5] g) were used in the study. Each group of rats received a different concentration of trypan blue in the right eye. In the early period, both the 0.4% and 0.2% concentrations were associated with the impairment of the hexagonal structure of corneal endothelial cells and intercellular junctions. Those concentrations were also associated with an increased occurrence of cellular vacuolation, cytoplasmic edema, extensive granulation of the endoplasmic reticulum, pyknotic nuclei, and mitochondrial degeneration. In the late period, these changes were observed as persisting in a decreasing manner. With the 0.1% and 0.05% concentrations, the density of microvilli decreased, nuclei appeared normal, granulation of the endoplasmic reticulum and Golgi apparatus was active, and minimal levels of mitochondrial degeneration were observed.
In this small experimental study in rat eyes, trypan blue at concentrations >0.025% was associated with impaired morphology and structure of corneal endothelial cells after short-term exposure. This effect continued in a decreasing fashion after long-term exposure. No significant changes were noted in the control group or the group administered the 0.025% concentration.
PMCID: PMC3966004  PMID: 24678109
trypan blue; corneal endothelium; lens epithelium; capsulorrhexis
17.  Effectiveness of Saccharomyces boulardii in a rat model of colitis 
AIM: To investigate the effects of Saccharomyces boulardii (S. boulardii) in an experimental rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis.
METHODS: Thirty-two Wistar albino female rats were categorized into five groups. On the first day of the study, 50 mg TNBS was administered via a rectal catheter in order to induce colitis in all rats, except those in the control group. For 14 d, the rats were fed a standard diet, without the administration of any additional supplements to either the control or TNBS groups, in addition to 1 mg/kg per day S. boulardii to the S. boulardii group, 1 mg/kg per day methyl prednisolone (MP) to the MP group. The animals in the S. boulardii + MP group were coadministered these doses of S. boulardii and MP. During the study, weight loss, stool consistency, and the presence of obvious blood in the stool were evaluated, and the disease activity index (DAI) for colitis was recorded. The intestines were examined and colitis was macro- and microscopically scored. The serum and tissue levels of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) were determined, and fungemia was evaluated in the blood samples.
RESULTS: The mean DAI scores for the MP and S. boulardii + MP groups was significantly lower than the TNBS group (3.69 ± 0.61 vs 4.46 ± 0.34, P = 0.018 and 3.77 ± 0.73 vs 4.46 ± 0.34, P = 0.025, respectively). While no significant differences between the TNBS and the S. boulardii or MP groups could be determined in terms of serum NO levels, the level of serum NO in the S. boulardii + MP group was significantly higher than in the TNBS and S. boulardii groups (8.12 ± 4.25 μmol/L vs 3.18 ± 1.19 μmol/L, P = 0.013; 8.12 ± 4.25 μmol/L vs 3.47 ± 1.66 μmol/L, P = 0.012, respectively). The tissue NO levels in the S. boulardii, MP and S. boulardii + MP groups were significantly lower than the TNBS group (16.62 ± 2.27 μmol/L vs 29.72 ± 6.10 μmol/L, P = 0.002; 14.66 ± 5.18 μmol/L vs 29.72 ± 6.10 μmol/L, P = 0.003; 11.95 ± 2.34 μmol/L vs 29.72 ± 6.10 μmol/L, P = 0.002, respectively). The tissue NO levels in the S. boulardii, MP and S. boulardii + MP groups were similar. The mean serum and tissue TNF-α levels were determined to be 12.97 ± 18.90 pg/mL and 21.75 ± 15.04 pg/mL in the control group, 18.25 ± 15.44 pg/mL and 25.27 ± 11.95 pg/mL in the TNBS group, 20.59 ± 16.15 pg/mL and 24.39 ± 13.06 pg/mL in the S. boulardii group, 9.05 ± 5.13 pg/mL and 24.46 ± 10.85 pg/mL in the MP group, and 13.95 ± 10.17 pg/mL and 24.26 ± 10.37 pg/mL in the S. boulardii + MP group. Significant differences in terms of the levels of serum and tissue TNF-α and the macroscopic and microscopic scores were not found between the groups. S. boulardii fungemia was not observed in any of the rats. However, Candida fungemia was detected in one rat (14%) in the TNBS group, two rats (28%) in the S. boulardii group, three rats (50%) in the MP group, and three rats (42%) in S. boulardii + MP group.
CONCLUSION: S. boulardii does not demonstrate considerable effects on the DAI, pathological scores, or cytokine levels but does decrease the tissue NO levels.
PMCID: PMC3508640  PMID: 23197891
Saccharomyces boulardii; Rat; Trinitrobenzene sulfonic acid; Tumor necrosis factor-α; Nitric oxide; Fungemia
18.  Effect of Tangweian Jianji on upper gastrointestinal remodeling in streptozotocin-induced diabetic rats 
AIM: To investigate the effect of Tangweian Jianji (TWAJJ) on the biomechanical and morphometrical remodeling of the upper gastrointestinal tract in diabetic rats.
METHODS: Diabetes was induced in 27 rats by injecting streptozotocin (40 mg/kg body weight), the animals were then divided into three groups (n = 9 in each group), i.e., diabetic control (DM); high dose (10 g/kg, T1) and low dose (5 g/kg, T2). Another 10 rats acted as normal controls (Control). TWAJJ was administered by gavage once daily. Blood glucose and serum insulin levels were measured. Circumferential length, wall thickness and opening angle were measured from esophageal, duodenal, jejunal and ileal ring segments. The residual strain was calculated from the morphometric data. Step-wise distension was carried out on esophageal and jejunal segments. The obtained data on the length, diameter and pressure changes were then used to calculate the circumferential and longitudinal stresses and strains. Real-time reverse transcription polymerase chain reaction was used to detect the receptor of advanced glycation end-products (RAGE) mRNA level in jejunal tissues.
RESULTS: At the end of the experiment, the blood glucose level was significantly higher and the serum insulin level was significantly lower in DM, T1 and T2 groups than in the control group (Glucose: 30.23 ± 0.41 mmol/L, 27.48 ± 0.27 mmol/L and 27.84 ± 0.29 mmol/L vs 5.05 ± 0.04 mmol/L, P = 1.65 × 10-16, P = 5.89 × 10-19 and P = 1.63 × 10-18, respectively; Insulin: 1.47 ± 0.32 μg/L, 2.66 ± 0.44 μg/L, 2.03 ± 0.29 μg/L and 4.17 ± 0.54 μg/L, P = 0.0001, P = 0.029 and P = 0.025, respectively). However, these levels did not differ among the DM, T1 and T2 groups. The wet weight per unit length, wall thickness and opening angle of esophageal and intestinal segments in the DM group were significantly higher than those in the control group (from P = 0.009 to P = 0.004). These parameters in the T1 group were significantly lower than those in the DM group (wet weight, duodenum: 0.147 ± 0.003 g/cm vs 0.158 ± 0.001 g/cm, P = 0.047; jejunum, 0.127 ± 0.003 g/cm vs 0.151 ± 0.002 g/cm, P = 0.017; ileum, 0.127 ± 0.004 g/cm vs 0.139 ± 0.003 g/cm, P = 0.046; wall thickness, esophagus: 0.84 ± 0.03 mm vs 0.94 ± 0.02 mm, P = 0.014; duodenum: 1.27 ± 0.06 mm vs 1.39 ± 0.05 mm, P = 0.031; jejunum: 1.19 ± 0.07 mm vs 1.34 ± 0.04 mm, P = 0.047; ileum: 1.09 ± 0.04 mm vs 1.15 ± 0.03 mm, P = 0.049; opening angle, esophagus: 112.2 ± 13.2˚ vs 134.7 ± 14.7˚, P = 0.027; duodenum: 105.9 ± 12.3˚ vs 123.1 ± 13.1˚, P = 0.046; jejunum: 90.1 ± 15.4˚ vs 115.5 ± 13.3˚, P = 0.044; ileum: 112.9 ± 13.4˚ vs 136.1 ± 17.1˚, P = 0.035). In the esophageal and jejunal segments, the inner residual stain was significantly smaller and the outer residual strain was larger in the DM group than in the control group (P = 0.022 and P = 0.035). T1 treatment significantly restored this biomechanical alteration (P = 0.011 and P = 0.019), but T2 treatment did not. Furthermore, the circumferential and longitudinal stiffness of the esophageal and jejunal wall increased in the DM group compared with those in the control group. T1, but not T2 treatment, significantly decreased the circumferential wall stiffness in the jejunal segment (P = 0.012) and longitudinal wall stiffness in the esophageal segment (P = 0.023). The mRNA level of RAGE was significantly decreased in the T1 group compared to that in the DM group (P = 0.0069).
CONCLUSION: TWAJJ (high dose) treatment partly restored the morphometric and biomechanical remodeling of the upper gastrointestinal tract in diabetic rats.
PMCID: PMC3447269  PMID: 23002359
Biomechanics and morphometric remodeling; Diabetes rats; Gastrointestinal tract; Mechanism; Tangweian Jianji
19.  Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors 
BMC Neuroscience  2011;12:109.
Cigarette smoking enhances the risk of stroke. However, the underlying molecular mechanisms are largely unknown. The present study established an in vivo rat secondhand cigarette smoking (SHS) model and examined the hypothesis that SHS upregulates endothelin receptors with increased cerebrovascular contraction via the Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway.
Rats were exposed to SHS for up to 8 weeks. The cerebral artery vasoconstriction was recorded by a sensitive myograph. The mRNA and protein expressions for endothelin receptors in cerebral arteries were studied by real-time PCR and Western blot. Compared to fresh air exposed rats, cerebral arteries from SHS rats exhibited stronger contractile responses (P < 0.05) mediated by endothelin type A (ETA) receptors. The expressions of mRNA and protein for ETA receptors in the cerebral arteries from SHS rats were higher (P < 0.05) than that in control. SHS did not affect endothelin type B (ETB) receptor-mediated contractions, mRNA or protein levels. The results suggest that SHS upregulates ETA, but not ETB receptors in vivo. After SHS exposure, the mRNA levels of Raf-1 and ERK1/2, the protein expression of phosphorylated (p)-Raf-1 and p-ERK1/2 were increased (P < 0.05). Raf-1 inhibitor, GW5074 suppressed the enhanced ETA receptor-mediated contraction, mRNA and protein levels induced by SHS. In addition, GW5074 inhibited the SHS-caused increased mRNA and phosphorylated protein levels of Raf-1 and ERK1/2, suggesting that SHS induces activation of the Raf/ERK/MAPK pathway.
SHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.
PMCID: PMC3219602  PMID: 22044770
20.  Temporal profiles of age-dependent changes in cytokine mRNA expression and glial cell activation after status epilepticus in postnatal rat hippocampus 
Status epilepticus (SE) is proposed to lead to an age-dependent acute activation of a repertoire of inflammatory processes, which may contribute to neuronal damage in the hippocampus. The extent and temporal profiles of activation of these processes are well known in the adult brain, but less so in the developing brain. We have now further elucidated to what extent inflammation is activated by SE by investigating the acute expression of several cytokines and subacute glial reactivity in the postnatal rat hippocampus.
SE was induced by an intraperitoneal (i.p.) injection of kainic acid (KA) in 9- and 21-day-old (P9 and P21) rats. The mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), glial-derived neurotrophic factor (GDNF), interferon gamma (IFN-γ), and transforming growth factor-beta 1 (TGF-β1) were measured from 4 h up to 3 days after KA injection with real-time quantitative PCR (qPCR). IL-1β protein expression was studied with ELISA, GFAP expression with western blotting, and microglial and astrocyte morphology with immunohistochemistry 3 days after SE.
SE increased mRNA expression of IL-1β, TNF-α and IL-10 mRNA in hippocampus of both P9 and P21 rats, their induction being more rapid and pronounced in P21 than in P9 rats. MMP-9 expression was augmented similarly in both age groups and GDNF expression augmented only in P21 rats, whereas neither IFN-γ nor TGF-β1 expression was induced in either age group. Microglia and astrocytes exhibited activated morphology in the hippocampus of P21 rats, but not in P9 rats 3 d after SE. Microglial activation was most pronounced in the CA1 region and also detected in the basomedial amygdala.
Our results suggest that SE provokes an age-specific cytokine expression in the acute phase, and age-specific glial cell activation in the subacute phase as verified now in the postnatal rat hippocampus. In the juvenile hippocampus, transient increases in cytokine mRNA expression after SE, in contrast to prolonged glial reactivity and region-specific microglial activity after SE, suggest that the inflammatory response is changed from a fulminant and general initial phase to a more moderate and specific subacute response.
PMCID: PMC3084156  PMID: 21477276
21.  Association of Prenatal and Childhood Blood Lead Concentrations with Criminal Arrests in Early Adulthood 
PLoS Medicine  2008;5(5):e101.
Childhood lead exposure is a purported risk factor for antisocial behavior, but prior studies either relied on indirect measures of exposure or did not follow participants into adulthood to examine the relationship between lead exposure and criminal activity in young adults. The objective of this study was to determine if prenatal and childhood blood lead concentrations are associated with arrests for criminal offenses.
Methods and Findings
Pregnant women were recruited from four prenatal clinics in Cincinnati, Ohio if they resided in areas of the city with a high concentration of older, lead-contaminated housing. We studied 250 individuals, 19 to 24 y of age, out of 376 children who were recruited at birth between 1979 and 1984. Prenatal maternal blood lead concentrations were measured during the first or early second trimester of pregnancy. Childhood blood lead concentrations were measured on a quarterly and biannual basis through 6.5 y. Study participants were examined at an inner-city pediatric clinic and the Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio. Total arrests and arrests for offenses involving violence were collected from official Hamilton County, Ohio criminal justice records. Main outcomes were the covariate-adjusted rate ratios (RR) for total arrests and arrests for violent crimes associated with each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration. Adjusted total arrest rates were greater for each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration: RR = 1.40 (95% confidence interval [CI] 1.07–1.85) for prenatal blood lead, 1.07 (95% CI 0.88–1.29) for average childhood blood lead, and 1.27 (95% CI 1.03–1.57) for 6-year blood lead. Adjusted arrest rates for violent crimes were also greater for each 5 μg/dl increase in blood lead: RR = 1.34 (95% CI 0.88–2.03) for prenatal blood lead, 1.30 (95% CI 1.03–1.64) for average childhood blood lead, and 1.48 (95% CI 1.15–1.89) for 6-year blood lead.
Prenatal and postnatal blood lead concentrations are associated with higher rates of total arrests and/or arrests for offenses involving violence. This is the first prospective study to demonstrate an association between developmental exposure to lead and adult criminal behavior.
Kim Dietrich and colleagues find an association between developmental exposure to lead and adult criminal behavior.
Editors' Summary
Violent crime is an increasing problem in many countries, but why are some people more aggressive than others? Being male has been identified as a risk factor for violent criminal behavior in several studies, as have exposure to tobacco smoke before birth, having antisocial parents, and belonging to a poor family. Another potential risk factor for antisocial behavior as an adult is exposure to lead during childhood, although few studies have looked directly at whether childhood lead exposure is linked with criminal behavior in adulthood. Lead is a toxic metal that damages the nervous system when ingested or inhaled. It is present throughout the environment because of its widespread use in the past in paint, solder for water pipes, and gasoline. In 1978, 13.5 million US children had a blood lead level above 10 μg/dl, the current US Centers for Disease Control and Prevention blood lead level of concern (the average US blood lead level is 2 μg/dl). Lead paint and solder were banned in 1978 and 1986, respectively, by the US federal government; leaded gasoline was finally phased out in 1996. By 2002, only 310,000 US children had a blood lead level above 10 μg/dl. However, children exposed to lower levels of lead than this—through ingesting flakes or dust residues of old lead paint, for example—can have poor intellectual development and behavioral problems including aggression.
Why Was This Study Done?
Although some studies have suggested that childhood lead exposure is associated with later criminal behavior, these studies have often relied on indirect measurements of childhood lead exposure such as bone lead levels in young adults or a history of lead poisoning. Other studies that have measured childhood lead exposure directly have not followed their participants into adulthood. In this new study, the researchers investigate the association between actual measurements of prenatal and childhood blood lead concentrations and criminal arrests in early adulthood to get a clearer idea about whether early lead exposure is associated with subsequent violent behavior.
What Did the Researchers Do and Find?
Between 1979 and 1984, the researchers recruited pregnant women living in poor areas of Cincinnati, which had a high concentration of older, lead-contaminated housing, into the Cincinnati Lead Study. They measured the women's blood lead concentrations during pregnancy as an indication of their offspring's prenatal lead exposure and the children's blood lead levels regularly until they were six and half years old. They then obtained information from the local criminal justice records on how many times each of the 250 offspring had been arrested between becoming 18 years old and the end of October 2005. The researchers found that increased blood lead levels before birth and during early childhood were associated with higher rates of arrest for any reason and for violent crimes. For example, for every 5 μg/dl increase in blood lead levels at six years of age, the risk of being arrested for a violent crime as a young adult increased by almost 50% (the “relative risk” was 1.48).
What Do These Findings Mean?
These findings provide strong evidence that early lead exposure is a risk factor for criminal behavior, including violent crime, in adulthood. One possibility, which the authors were unable to assess in this study, is that lead exposure impairs intelligence, which in turn makes it more likely that a criminal offender will be caught (i.e., arrested). The authors discuss a number of limitations in their study—for example, they probably did not capture all criminal behavior (since most criminal behavior does not lead to arrest). Although both environmental lead levels and crime rates have dropped over the last 30 years in the US, the overall reduction was not uniform—inner-city children remain particularly vulnerable to lead exposure. The findings therefore suggest that a further reduction in childhood lead exposure might be an important and achievable way to reduce violent crime.
Additional Information.
Please access these Web sites via the online version of this summary at
A PLoS Medicine Perspective article by David Bellinger further discusses this study and a related paper on childhood lead exposure and brain volume reduction in adulthood
Study researcher Kim Dietrich can be heard talking about “The Lethal Legacy of Lead”, a brief MP3 about lead exposure and violent crime
Toxtown, an interactive site from the US National Library of Medicine, provides information on environmental health concerns including exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead in paint, dust, and soil and on protecting children from lead poisoning (in English and Spanish)
MedlinePlus provides a list of links to information on lead poisoning (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about its Childhood Lead Poisoning Prevention Program
The UK Health Protection Agency also provides information about lead and its health hazards
PMCID: PMC2689664  PMID: 18507497
22.  Phencyclidine (PCP)-Induced Disruption in Cognitive Performance is Gender-Specific and Associated with a Reduction in Brain-Derived Neurotrophic Factor (BDNF) in Specific Regions of the Female Rat Brain 
Journal of Molecular Neuroscience  2010;43(3):337-345.
Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n = 8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p < 0.05), motor cortex (p < 0.01), orbital cortex (p < 0.01), olfactory bulb (p < 0.05), retrosplenial cortex (p < 0.001), frontal cortex (p < 0.01), parietal cortex (p < 0.01), CA1 (p < 0.05) and polymorphic layer of dentate gyrus (p < 0.05) of the hippocampus and the central (p < 0.01), lateral (p < 0.05) and basolateral (p < 0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p < 0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.
PMCID: PMC3041899  PMID: 20852970
PCP; BDNF; Gender; Set-shifting; Rats
23.  Lactuside B decreases aquaporin-4 and caspase-3 mRNA expression in the hippocampus and striatum following cerebral ischaemia-reperfusion injury in rats 
This study aimed to investigate the effects of lactuside B (LB) on aquaporin-4 (AQP4) and caspase-3 mRNA expression in the hippocampus and the striatum following cerebral ischaemia-reperfusion (I/R) injury in rats. Cerebral I/R injury was established in Sprague-Dawley rats by occluding the middle cerebral artery for 2 h and then inducing reperfusion. Rats in the I/R + LB groups were treated with various doses of LB following reperfusion. Neurological deficit scores and brain water content were obtained to determine the pharmacodynamics of LB. Reverse transcription polymerase chain reaction was performed to determine the expression levels of AQP4 and caspase-3 mRNA in the hippocampus and the striatum. The results of the present study indicate that LB decreased the neurological deficit scores and the brain water content. In the hippocampus, AQP4 and caspase-3 mRNA expression levels were significantly downregulated in the I/R + LB groups at 24 and 72 h following drug administration, compared with those in the I/R group (P<0.05). In the striatum, LB was also shown to significantly reduce AQP4 and caspase-3 mRNA expression levels at 24 and 72 h following drug administration, compared with those in the I/R group (P<0.05). The effects became stronger as the LB dose was increased. The most significant reductions in AQP4 and caspase-3 mRNA expression were noted in the I/R + LB 25 mg/kg and I/R + LB 50 mg/kg groups at 72 h following drug administration. The results of the present study show that LB is capable of significantly downregulating AQP4 and caspase-3 mRNA expression in the hippocampus and striatum following cerebral I/R injury in rats. The mechanism by which LB improved ischaemic brain injury may be associated with changes in AQP4 and caspase-3 mRNA expression in the hippocampus and the striatum.
PMCID: PMC3919888  PMID: 24520266
lactuside B; cerebral I/R injury; brain edema; AQP4; caspase-3; apoptosis; hippocampus; striatum
24.  Influence of Pre-Training Predator Stress on the Expression of c-fos mRNA in the Hippocampus, Amygdala, and Striatum Following Long-Term Spatial Memory Retrieval 
We have studied the influence of pre-training psychological stress on the expression of c-fos mRNA following long-term spatial memory retrieval. Rats were trained to learn the location of a hidden escape platform in the radial-arm water maze, and then their memory for the platform location was assessed 24 h later. Rat brains were extracted 30 min after the 24-h memory test trial for analysis of c-fos mRNA. Four groups were tested: (1) Rats given standard training (Standard); (2) Rats given cat exposure (Predator Stress) 30 min prior to training (Pre-Training Stress); (3) Rats given water exposure only (Water Yoked); and (4) Rats given no water exposure (Home Cage). The Standard trained group exhibited excellent 24 h memory which was accompanied by increased c-fos mRNA in the dorsal hippocampus and basolateral amygdala (BLA). The Water Yoked group exhibited no increase in c-fos mRNA in any brain region. Rats in the Pre-Training Stress group were classified into two subgroups: good and bad memory performers. Neither of the two Pre-Training Stress subgroups exhibited a significant change in c-fos mRNA expression in the dorsal hippocampus or BLA. Instead, stressed rats with good memory exhibited significantly greater c-fos mRNA expression in the dorsolateral striatum (DLS) compared to stressed rats with bad memory. This finding suggests that stressed rats with good memory used their DLS to generate a non-spatial (cue-based) strategy to learn and subsequently retrieve the memory of the platform location. Collectively, these findings provide evidence at a molecular level for the involvement of the hippocampus and BLA in the retrieval of spatial memory and contribute novel observations on the influence of pre-training stress in activating the DLS in response to long-term memory retrieval.
PMCID: PMC3125520  PMID: 21738501
rat; c-fos; hippocampus; striatum; amygdala; spatial memory
25.  Evaluation of Bcl-2 Family Gene Expression and Caspase-3 Activity in Hippocampus STZ-Induced Diabetic Rats 
Experimental Diabetes Research  2008;2008:638467.
We assessed the expression of Bcl-2 family members at both mRNA and protein levels as well as the Caspase-3 activity, in order to investigate the occurrence of apoptosis in hippocampus of STZ-induced diabetic rats. We selected twenty-four Wistar rats; half of them were made diabetic by intraperitoneal injection of a single 60 mg/kg dose of streptozotocin (STZ, IP), while the others received normal saline and served as controls. The expressions of Bcl-2, Bcl-xL, and Bax mRNA and proteins were measured using RT-PCR and western blotting, respectively. Caspases-3 activity was determined by using the Caspase-3/CPP32 Fluorometric Assay Kit. The result showed that mRNA and protein levels of Bcl-2 and Bcl-xL were lower in hippocampus of diabetic group than that of the control group, whereas expressions of Bax in hippocampus of diabetic rats were higher than that of controls at both mRNA and protein levels (P < .01). Hyperglycemia was found to raise 6.9-fold hippocampal caspase-3 activity in diabetic group compared with control group (P < .001). Therefore, the induction of diabetes is associated with increased ratios of Bax/Bcl-2, Bax/Bcl-xL, and increased caspase-3 activity in hippocampus which shows that apoptosis is favored in hippocampal region.
PMCID: PMC2566751  PMID: 18923682

Results 1-25 (1296022)