Altered functional activations of prefrontal brain areas during emotional processing of fear in Inuit adolescents exposed to environmental contaminants.

Exposure to mercury, lead and polychlorinated biphenyls (PCBs) have been associated with emotional dysregulation, but their neuronal correlates have yet to be examined. Inuit from Nunavik (Northern Quebec, Canada) face internalizing problems and are among the most exposed individuals to these environmental contaminants in the world. The aim of this study was to examine the link between pre- and postnatal exposure to these contaminants and brain fear-circuitry in Inuit adolescents. Facial expression stimuli were presented to participants (mean age = 18.3 years) in a magnetic resonance imaging (MRI) scanner. Fear conditioning and extinction tasks included neutral faces as the conditioned threat and safety cues and a fearful face paired with a shrieking scream as the unconditioned stimulus. Functional MRI data were gathered at the conditioning phase (n = 71) and at the extinction phase (n = 62). Mercury, lead and PCB 153 concentrations were measured in blood samples at birth (cord blood) and at the time of the adolescent testing to estimate pre- and postnatal exposure, respectively. For each time point, exposures were categorized in tertiles (low, moderate and high exposed groups). Mixed analyses of variance were conducted for each contaminant of interest controlling for sex, age, socioeconomic status, drug/alcohol use, food insecurity and contaminant co-exposure. Results revealed greater differential activation during the conditioning phase in the right orbitofrontal cortex in participants with moderate and high concentrations of cord blood PCB 153 compared to those in the low exposure group. During the extinction phase, the high prenatal mercury exposed group showed a lower differential activation in the right and left anterior cingulate cortex compared to those in the low-exposed group; whereas there was a higher differential activation in right dorsolateral prefrontal cortex in the high postnatal lead exposed group compared to the moderate- and low-exposed groups. Our study is the first to show alterations in the prefrontal brain areas in fear conditioning and extinction tasks in relation to environmental contaminant exposures. The observed brain correlates may advance our understanding of the emotional problems associated with environmental chemical toxicity.

Neurotoxicity of low-level lead exposure: History, mechanisms of action, and behavioral effects in humans and preclinical models.

Lead is a neurotoxin that produces long-term, perhaps irreversible, effects on health and well-being. This article summarizes clinical and preclinical studies that have employed a variety of research techniques to examine the neurotoxic effects of low levels of lead exposure. A historical perspective is presented, followed by an overview of studies that examined behavioral and cognitive outcomes. In addition, a short summary of potential mechanisms of action is provided with a focus on calcium-dependent processes. The current level of concern, or reference level, set by the CDC is 5 µg/dL of lead in blood and a revision to 3.5 µg/dL has been suggested. However, levels of lead below 3 µg/dL have been shown to produce diminished cognitive function and maladaptive behavior in humans and animal models. Because much of the research has focused on higher concentrations of lead, work on low concentrations is needed to better understand the neurobehavioral effects and mechanisms of action of this neurotoxic metal.

Auditory Training Reverses Lead (Pb)-Toxicity-Induced Changes in Sound-Azimuth Selectivity of Cortical Neurons.

Lead (Pb) causes significant adverse effects on the developing brain, resulting in cognitive and learning disabilities in children. The process by which lead produces these negative changes is largely unknown. The fact that children with these syndromes also show deficits in central auditory processing, however, indicates a speculative but disturbing relationship between lead-exposure, impaired auditory processing, and behavioral dysfunction. Here we studied in rats the changes in cortical spatial tuning impacted by early lead-exposure and their potential restoration to normal by auditory training. We found animals that were exposed to lead early in life displayed significant behavioral impairments compared with naïve controls while conducting the sound-azimuth discrimination task. Lead-exposure also degraded the sound-azimuth selectivity of neurons in the primary auditory cortex. Subsequent sound-azimuth discrimination training, however, restored to nearly normal the lead-degraded cortical azimuth selectivity. This reversal of cortical spatial fidelity was paralleled by changes in cortical expression of certain excitatory and inhibitory neurotransmitter receptor subunits. These results in a rodent model demonstrate the persisting neurotoxic effects of early lead-exposure on behavioral and cortical neuronal processing of spatial information of sound. They also indicate that attention-demanding auditory training may remediate lead-induced cortical neurological deficits even after these deficits have occurred.

The effects of lead on GABAergic interneurons in rodents.

Lead is a heavy metal that affects various systems and organs in the body, especially the nervous system. In this study, the in vivo and in vitro effects of lead on neurons were analyzed. We divided mouse pups into three groups based on the concentration of lead exposure: the control group, the low-dose group, and the high-dose group. Changes in behavior (measured by an open-field test and a tail suspension test), blood lead levels (measured by atomic absorption spectrophotometry), the number of GABAergic interneurons (measured by immunohistochemistry), gene expression (measured by qRT-PCR), and DNA methylation (measured by pyrosequencing) were determined in the three groups. The lead-exposed pups showed significantly higher blood lead levels ( p < 0.001). Lead exposure caused hyperactivity and reduced the body weight of the exposed mice compared with that of the controls. The lead-exposed groups showed significantly lower numbers of parvalbumin and neuropeptide Y interneurons and lower expression levels of distal-less homeobox ( Dlx) 1, 2, 5, and 6 genes in the cerebral cortex. To further clarify the mechanism of Dlx gene downregulation, we selected the GE6 cell line, which can differentiate into various subtypes of GABAergic interneurons, for in vitro experiments. We found that high levels of lead also inhibited the expression of Dlx 1/ 2/ 5/ 6 in vitro, but DNA methylation levels were not changed in the GE6 cell line. Furthermore, lead exposure significantly decreased the expression of Olig1 and Ki67 and increased that of Tubb3 in vitro. The present study revealed that lead exposure can alter behaviors, reduce the number of GABAergic interneurons, and change the expression of some important genes in neuronal cells.

Beneficial effects of garlic on learning and memory deficits and brain tissue damages induced by lead exposure during juvenile rat growth is comparable to the effect of ascorbic acid.

OBJECTIVE: The neuroprotective effects of both garlic and ascorbic acid (AA) have been documented. In this study the effects of garlic and ascorbic acid on memory deficits and brain tissue oxidative damages induced by lead exposure was investigated. METHODS: The juvenile rats were divided and treated: (1) Control, (2) Lead (lead acetate in drinking water, 8 weeks), (3) Lead - Ascorbic Acid (Lead-AA), (4) Lead - Garlic (100 mg/kg, daily, gavage) (Lead-Gar). RESULTS: In Morris water maze (MWM), the escape latency and traveled path in the Lead group were significantly higher while, the time spent in the target quadrant (Q1) was lower than Control. Both Lead-Gar and Lead-AA groups spent more times in Q1than to lead group. There were no significant differences in swimming speed between the groups. In passive avoidance (PA) test, the time latency for entering the dark compartment by Lead group was lower than Control. Treatment of the animals by AA and garlic significantly increased the time latency. In Lead group, the total thiol concentration in brain tissues was significantly lower while, MDA was higher than Control. Treatment by both garlic and AA increased total thiol concentrations and decreased MDA. Both garlic and AA decreased the lead content of brain tissues. CONCLUSION: It is suggested that treatment with garlic attenuates the learning and memory impairments due to lead exposure during juvenile rat growth which is comparable to AA. The possible mechanism may be due to its protective effects against brain tissues oxidative damage as well the lowering effects of brain lead content.

Olfactory recognition memory is disrupted in young mice with chronic low-level lead exposure.

Chronic developmental lead exposure yielding very low blood lead burden is an unresolved child public health problem. Few studies have attempted to model neurobehavioral changes in young animals following very low level exposure, and studies are needed to identify tests that are sensitive to the neurobehavioral changes that may occur. Mechanisms of action are not yet known however results have suggested that hippocampus/dentate gyrus may be uniquely vulnerable to early chronic low-level lead exposure. This study examined the sensitivity of a novel odor recognition task to differences in pre-adolescent C57BL/6J mice chronically exposed from birth to PND 28, to 0 ppm (control), 30 ppm (low-dose), or 330 ppm (higher-dose) lead acetate (N=33). Blood lead levels (BLLs) determined by ICP-MS ranged from 0.02 to 20.31 µg/dL. Generalized linear mixed model analyses with litter as a random effect showed a significant interaction of BLL×sex. As BLLs increased olfactory recognition memory decreased in males. Among females, non-linear effects were observed at lower but not higher levels of lead exposure. The novel odor detection task is sensitive to effects associated with early chronic low-level lead exposure in young C57BL/6J mice.

Effects of lead exposure on D-serine metabolism in the hippocampus of mice at the early developmental stages.

The aim of this study was to explore the mechanisms of lead neurotoxicity by focusing on the alteration of D-serine metabolism in the hippocampus of mice at the early life. Mother mice and their offspring were exposed to 0, 0.5, 1.0 and 2.0 g/L lead in lead acetate via drinking water from the first day of gestation until the postnatal day (PND) 40. Morris water maze was used to measure the spatial learning and memory ability of PND 40 mice. Expressions of serine racemase (SR), D-amino acid oxidase (DAAO), alanine-serine- cysteine transporter-1 (asc-1) and subunits of N-methyl-D-aspartate receptor (NMDAR) in the hippocampus of PND 10, 20 and 40 mice were examined by western blot and real time RT-PCR. Findings from this study disclosed that the spatial learning ability of mice tested by place trial could be significantly impaired by 0.5 g/L lead exposure, and the spatial memory ability tested by probe trail could be impaired by 1.0 g/L lead exposure. Exposure to 2.0 g/L lead in the water could significantly inhibit the protein and mRNA expression of SR; conversely enhance the expression of DAAO protein and mRNA in the hippocampus during the early developmental stages. However, the protein expressions of DAAO and asc-1 in the hippocampus were significantly enhanced by 0.5 g/L lead exposure at different developmental stages. On the other hand, the protein and mRNA expressions of both NR1 and NR2A were inhibited significantly by 1.0 g/L lead exposure since PND 10, and by 0.5 g/L lead exposure since PND 20. Noteworthy, the protein expression of NR2B was inhibited significantly by 0.5 g/L lead exposure in PND 10 mice, and by 1.0 g/L lead exposure in PND 20 mice, but there was no significant group difference in PND 40 mice. Meanwhile, expressions of asc-1 and NR2B mRNA were not affected obviously by lead exposure. In conclusion, chronic lead exposure during brain development might affect D-serine metabolism by enhancing its degradation, which might be related to the inhibited expression of NMDAR subunits, and furthermore contribute to deficits in learning and memory ability in mice.

Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats.

Lead (Pb) exposure was commonly considered as a high environmental risk factor for the development of attention-deficit/hyperactivity disorder (ADHD). However, the molecular basis of this pathological process still remains elusive. In light of the role of epigenetics in modulating the neurological disease and the causative environment, the alterations of histone modifications in the hippocampus of rats exposed by various doses of lead, along with concomitant behavioral deficits, were investigated in this study. According to the free and forced open field test, there showed that in a dosage-dependent manner, lead exposure could result in the increased locomotor activity of rats, that is, hyperactivity: a subtype of ADHD. Western blotting assays revealed that the levels of histone acetylation increased significantly in the hippocampus by chronic lead exposure, while no dramatic changes were detected in terms of expression yields of ADHD-related dopaminergic proteins, indicating that histone acetylation plays essential roles in this toxicant-involved pathogenesis. In addition, the increased level of histone acetylation might be attributed to the enzymatic activity of p300, a typical histone acetyltransferase, as the transcriptional level of p300 was significantly increased upon higher-dose Pb exposure. In summary, this study first discovered the epigenetic mechanism bridging the environmental influence (Pb) and the disease itself (ADHD) in the histone modification level, paving the way for the comprehensive understanding of ADHD's etiology and in further steps, establishing the therapy strategy of this widespread neurological disorder.

Prenatal lead and cadmium co-exposure and infant neurodevelopment at 6 months of age: the Mothers and Children's Environmental Health (MOCEH) study.

BACKGROUND: This study aimed to explore the developmental effects of prenatal exposure to Pb and Cd on infant cognitive development at 6 months of age. METHODS: Between 2006 and 2010, the blood levels of Pb and Cd were measured in 884 mothers during their early and late pregnancy. The mental (MDI) and psychomotor (PDI) development index scores of the infants were assessed using the Bayley Scales of Infant Development. The development index scores were adjusted for birth weight, maternal age, maternal education level, family income, breastfeeding status, and residential area. RESULTS: The geometric mean of the maternal blood concentration was 1.36µg/dL (10th percentile=0.83; 90th percentile=2.13; range=0.26-9.10) for Pb and 1.42µg/L (10th percentile=1.01; 90th percentile=2.16; range=0.03-9.87) for Cd during the early pregnancy period and 1.27µg/dL (10th percentile=0.77; 90th percentile=2.10; range=0.12-4.28) for Pb and 1.52µg/L for Cd (10 percentile=1.07; 90th percentile=2.10; range=0.43-3.73) during the late pregnancy period. The prenatal Pb and Cd concentrations during the early pregnancy period showed no association with the adjusted MDI or PDI scores. The antagonistic interaction between the prenatal Pb and Cd levels during the early pregnancy period had a significant effect on the MDI score (B=-4.64, 95% CI=-8.17 to -1.12, p=0.01), but the effect of this interaction did not reach statistical significance for the PDI score (B=-3.69, 95% CI=-7.94 to 0.56, p=0.09). The Pb levels during the late pregnancy period were inversely associated with the MDI score (B=-1.94, 95% CI=-3.60 to -0.29, p=0.02) but not with the PDI score (B=-1.69, 95% CI=-3.65 to 0.27, p=0.09). The prenatal Cd levels during the late pregnancy period showed no association with the MDI or PDI score. However, the MDI score (B=-3.20, 95% CI=-5.35 to -1.06, p<0.01) and the PDI score (B=-2.86, 95% CI=-5.55 to -0.16, p=0.04) of infants with Cd levels >1.51µg/L were significantly associated with the Pb level, whereas there were no such associations for infants with Cd levels <1.51µg/L. These results suggest that there is a synergistic effect modification between Pb and Cd during the late pregnancy period. CONCLUSIONS: These findings suggest that there is dose-dependent interaction between prenatal exposure to Pb and prenatal exposure to Cd. The results further demonstrate the biological complexities of examining the neurodevelopmental effects of co-exposure to multiple toxicants.

Effects of chronic lead exposure on functions of nervous system in Chinese children and developmental rats.

Lead pollution is a very serious problem in China with the rapid economic development. A large amount of lead has been released into the environment due to mineral processing activities and has impacted water resources, soils, vegetables, and crops. The gasoline with lead has been banned in China since July 1, 2000. Though a noticeable decrease of lead poisoning rates has been evidenced, the children's blood lead levels are still significantly higher than those in developed countries. Therefore, lowering the lead exposure in childhood continues to be an important public health objective in China. There is also a lot that remains to be done to reduce children's exposure to lead. In this section, five scientists from China presented latest research results regarding the current situation of lead poisoning in China, the mechanisms involved in lead-induced neurotoxicity, and the new advances related to the potential therapy methods. Their researches may pave new way not only for the prevention of lead poisoning but also for the treatment of affected children in China and other countries.

Blood lead levels and cumulative blood lead index (CBLI) as predictors of late neurodevelopment in lead poisoned children.

OBJECTIVE: To find the best lead exposure assessment marker for children. METHODS: We recruited 11 children, calculated a cumulative blood lead index (CBLI) for the children, measured their concurrent BLL, assessed their development, and measured their bone lead level. RESULTS: Nine of 11 children had clinically significant neurodevelopment problems. CBLI and current blood lead level, but not the peak lead level, were significantly or marginally negatively associated with the full-scale IQ score. CONCLUSION: Lead exposure at younger age significantly impacts a child's later neurodevelopment. CBLI may be a better predictor of neurodevelopment than are current or peak blood lead levels.

Environmental lead exposure and otoacoustic emissions in Andean children.

Studies relating sensory hearing impairment to lead (Pb) exposure in children have presented inconsistent results. The objective of this study was to measure distortion product otoacoustic emissions (DPOAE), sounds emanating from the outer hair cells of the inner ear, in Pb-exposed children to determine the effects of Pb poisoning on the inner ear. DPOAE were recorded for 9 f(2) frequencies from 1187 to 7625 Hz on 102 ears of 53 Pb-exposed children (aged 6-16 yr) residing in Pb-contaminated environments in the Andes Mountains of Ecuador where Pb glazing of ceramics is the primary livelihood. Blood lead (PbB) levels ranged from 4.2 to 94.3 µg/dl (mean: 37.7; SD: 25.7; median: 36.4). The median PbB level was markedly higher than the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) 10-µg/dl action level. Spearman rho correlation analyses of the relation between PbB level and DPOAE amplitude and between PbB level and DPOAE signal-to-noise ratio revealed no significant associations at any of the f(2) frequencies tested. In addition, no significant correlation (Spearman rho) between PbB level and hearing sensitivity for 6 pure-tone test frequencies from 1000 to 8000 Hz was found. Although the study group was found to have abnormally elevated PbB levels, in contrast to some earlier reports, the results of the current study showed no consistent Pb-induced sensory effects on the cochlea of Pb-intoxicated children.

Children's blood lead and standardized test performance response as indicators of neurotoxicity in metropolitan New Orleans elementary schools.

This study analyzes pre-Katrina variation in aggregate student performance and children's blood lead (BPb) in 117 elementary school districts in metropolitan New Orleans. Fourth grade student achievement on Louisiana Educational Assessment Program (LEAP) tests were analyzed as a function of BPb for children 1-6 years old within school districts, controlling for student-teacher ratios, percent of students eligible for a free or discounted lunch, and school racial demography. Measures of performance across subject areas (English Language Arts, Science, Mathematics, and Social Studies) include school Achievement Test Scores (ATS) and indices of agreement and variation in student achievement. ATS are measured on a 5-point scale, corresponding to achievement categories of advanced=5 to unsatisfactory=1. Regression results show that median BPb (microg/dL) and percent of children with BPb > or =10 microg/dL are significantly associated with reductions in test scores across all subjects and depress variation in student performance across achievement categories. These data suggest that assisting children with improved school performance requires alleviation of pre-school Pb exposure and its associated neurotoxic damage. Cost-benefit calculations suggest that it is more cost effective to pay for onetime primary prevention instead of paying continuous expenses focused on reversing neurotoxic damage.

The relation of lead neurotoxicity to the event-related potential P3b component in Inuit children from arctic Québec.

The event-related potential (ERP) P3b, a cognitive electrophysiological measure that has been linked to working memory processing in many experimental paradigms, was measured in Inuit children from Nunavik (Arctic Québec, Canada) to assess lead (Pb) neurotoxicity. Visual and auditory oddball paradigms were administered at 5 (N=27) and 11 (N=110) years of age, respectively, to elicit this ERP component. Pearson correlations and multiple regression analyses were performed to examine the associations between Pb levels and P3b parameters (peak latency and amplitude). Greater prenatal Pb exposure was related to a decrease in P3b amplitude at 5 years of age, and early childhood Pb exposure was associated with delayed P3b latency at 5 years. No significant association was observed at 11 years. These results, in line with those from previous neurobehavioral studies, suggest that Pb exposure affects cognitive processing in children even though the Pb levels measured in a large majority of our sample were below the threshold value for public health intervention used by federal agencies. This study strengthens the arguments for reducing sources of Pb exposure in Nunavik and for lowering the blood Pb concentrations considered "acceptable" in governmental policies.

Cognitive development and low-level lead exposure in poly-drug exposed children.

The impact of early postnatal lead exposure measured at age 4 on children's IQ and academic achievement at and 11 years of age was examined. The sample consisted of 278 inner-city, primarily African American children who were polydrug exposed prenatally. Regression analyses indicated a linear effect of lead exposure on outcomes and no moderating effects of polydrug exposure. An IQ loss of about 4.1-5.4 Full Scale IQ points was estimated for each 10 microg/dL increase in blood lead level at ages 4, 9, and 11 years as a function of blood lead level at age 4. Decrements in scores on tests of non-verbal reasoning were consistently associated with higher lead levels at age 4, while verbal decrements became apparent only at age 11. Lower reading summary scores at 9 and 11 years were consistently associated with higher lead exposure, while decrements in mathematics were not apparent until 11 years. Subgroup analyses on children with blood lead levels <10 microg/dL showed detrimental lead effects even at the 5 microg/dL level, providing additional evidence of adverse effects occurring at blood lead levels below the current 10 microg/dL public health blood lead action level.

Supranormal electroretinogram in a 10-year-old girl with lead toxicity.

PURPOSE: To report a case of lead exposure in a 10-year-old girl which resulted in a supranormal ERG and clinical findings of decreased visual acuity, color vision, and stereopsis. METHOD: Case report. RESULTS: A 10-year-old girl was exposed to unknown levels of lead, with peak recorded blood levels of 19 mcg/dl 5 years prior to presentation. Lead levels had since normalized. Uncorrected visual acuity was 20/200-OU, improving to 20/80-OU with a refractive correction of +1.50 + 0.75 x 90 degrees OD, +2.50 sphere OS. Color vision was tested with Ishihara plates, and appeared markedly impaired. Stereopsis was grossly impaired, as the patient could not perceive stereoscopic depth with the Titmus "fly" target. Her cognitive function appeared to be slowed and her reaction time also delayed. ERG waveforms were supranormal under photopic and scotopic conditions. Implicit times were normal. CONCLUSION: Lead toxicity with significant visual and cognitive dysfunction, and supranormal ERG, can persist at lead levels below those recognized for lead poisoning.

Zinc protoporphyrin levels, blood lead levels and neurocognitive deficits in Andean children with chronic lead exposure.

OBJECTIVES: To investigate the relationship between blood lead (PbB), zinc protoporphyrin (ZPP) levels and performance on a test of auditory memory in Andean children and adolescents with chronic lead (Pb) exposure. DESIGN AND METHODS: PbB and ZPP levels were measured in blood samples from 166 participants (aged 6-16 yrs.) exposed to Pb in a local ceramic glazing cottage industry in Ecuadorian villages. PbB levels and ZPP/heme ratios were analyzed in relation to performance on the Digit Span subtest of the Wechsler IV intelligence scale, a test of auditory memory. RESULTS: Mean PbB level for the study group was 18.0 microg/dL (S.D.: 15.1; range: 3.0-86.0), and the mean ZPP/heme ratio was 105.7 mumol/mol (S.D.: 100.9; range: 36.0-592.0). There was no significant difference in PbB and ZPP levels between the 84 females and the 82 males. The mean Digit Span scale score (DS SS) for the study group was 6.81 (S.D.: 2.95; range: 1.0-17.0), which is below the average score of 10 for the test, with the females performing significantly better than males (t=2.435; p=0.01). Regression analyses revealed statistically significant inverse associations between DS SS and PbB level (r=0.251, p=0.001), and between DS SS and ZPP/heme ratio (r=0.246, p=0.001). CONCLUSION: Elevated PbB levels, representing acute exposure, and ZPP levels, reflecting chronic Pb exposure in this cohort of Andean inhabitants were associated with poor performance on a test of auditory memory, suggesting that the children and adolescents in the study area have neurocognitive deficits that may affect learning.

Effect of living in lead mining area on growth.

OBJECTIVE: Blood lead level BLL and growth parameters including weight and height, in children, living in lead mining area was surveyed. METHODS: Two groups of 7-11 yr old children, including 45 from a lead mining area (Angooran-Zanjan Province-Iran) and 36 from control area (similar area to the study area, but not lead mining: Ijrood--the same province), were selected to assess BLL (by atomic absorption spectrometry) and growth parameters. RESULTS: In the children of the study and control areas, mean BLLs were 36.97+/-24.67 (microg/dL; mean +/- SD) and 15.57 +/- 13.35 (microg/dL; mean+/-SD), respectively (P=0.0005). No significant correlation was found between BLL in children and their fathers' occupation. In addition, there was no significant difference in growth parameters, including weight and height, in the children of two groups. CONCLUSION: Regarding the results of this study, environmental exposure due to living in lead mining area can lead to increased BLL in children. In addition, our results suggest there is no significant effect of BLL on growth parameters in children in lead mining area. Since some clinical and sub clinical problems are strongly probable when BLL is increased, special attention of the relevant organizations and more research about the problem and its outcome, is recommended.