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Objective: Perchlorate inhibits the uptake of iodide in the thyroid. Iodide is required to synthesize hormones critical to fetal and neonatal development. Many water supplies and foods are contaminated with perchlorate. Exposure standards are needed but controversial. Here we summarize the basis of the Massachusetts (MA) perchlorate reference dose (RfD) and drinking water standard (DWS), which are considerably lower and more health protective than related values derived by several other agencies. We also review information regarding perchlorate risk assessment and policy.
Data sources: MA Department of Environmental Protection (DEP) scientists, with input from a science advisory committee, assessed a wide range of perchlorate risk and exposure information. Health outcomes associated with iodine insufficiency were considered, as were data on perchlorate in drinking water disinfectants.
Data synthesis: We used a weight-of-the-evidence approach to evaluate perchlorate risks, paying particular attention to sensitive life stages. A health protective RfD (0.07 μg/kg/day) was derived using an uncertainty factor approach with perchlorate-induced iodide uptake inhibition as the point of departure. The MA DWS (2 μg/L) was based on risk management decisions weighing information on perchlorate health risks and its presence in certain disinfectant solutions used to treat drinking water for pathogens.
Conclusions: Current data indicate that perchlorate exposures attributable to drinking water in individuals at sensitive life stages should be minimized and support the MA DEP perchlorate RfD and DWS. Widespread exposure to perchlorate and other thyroid toxicants in drinking water and foods suggests that more comprehensive policies to reduce overall exposures and enhance iodine nutrition are needed.
Background: Adverse health effects of cadmium in adults are well documented, but little is known about the neuropsychological effects of cadmium in children, and no studies of cadmium and blood pressure in children have been conducted.
Objective: We examined the potential effects of low-level cadmium exposure on intelligence quotient, neuropsychological functions, behavior, and blood pressure among children, using blood cadmium as a measure of exposure.
Methods: We used the data from a multicenter randomized clinical trial of lead-exposed children and analyzed blood cadmium concentrations using the whole blood samples collected when children were 2 years of age. We compared neuropsychological and behavioral scores at 2, 5, and 7 years of age by cadmium level and analyzed the relationship between blood cadmium levels at 2 years of age and systolic and diastolic blood pressure at 2, 5, and 7 years of age.
Results: The average cadmium concentration of these children was 0.21 μg/L, lower than for adults in the National Health and Nutrition Examination Survey (NHANES), but comparable to concentrations in children < 3 years of age in NHANES. Except for the California Verbal Learning Test for Children, there were no differences in test scores among children in different cadmium categories. For children with detectable pretreatment blood cadmium, after adjusting for a variety of covariates, general linear model analyses showed that at none of the three age points was the coefficient of cadmium on Mental Development Index or IQ statistically significant. Spline regression analysis suggested that behavioral problem scores at 5 and 7 years of age tended to increase with increasing blood cadmium, but the trend was not significant. We found no significant associations between blood cadmium levels and blood pressure.
Conclusion: We found no significant associations between background blood cadmium levels at 2 years of age and neurodevelopmental end points and blood pressure at 2, 5, and 7 years of age. The neuropsychological or hypertensive effects from longer background exposures to cadmium need further study.
Background: Prenatal exposure to bisphenol A (BPA) increases offspring aggression and diminishes differences in sexually dimorphic behaviors in rodents.
Objective: We examined the association between prenatal BPA exposure and behavior in 2-year-old children.
Methods: We used data from 249 mothers and their children in Cincinnati, Ohio (USA). Maternal urine was collected around 16 and 26 weeks of gestation and at birth. BPA concentrations were quantified using high-performance liquid chromatography–isotope-dilution tandem mass spectrometry. Child behavior was assessed at 2 years of age using the second edition of the Behavioral Assessment System for Children (BASC-2). The association between prenatal BPA concentrations and BASC-2 scores was analyzed using linear regression.
Results: Median BPA concentrations were 1.8 (16 weeks), 1.7 (26 weeks), and 1.3 (birth) ng/mL. Mean (± SD) BASC-2 externalizing and internalizing scores were 47.6 ± 7.8 and 44.8 ± 7.0, respectively. After adjustment for confounders, log10-transformed mean prenatal BPA concentrations were associated with externalizing scores, but only among females [β = 6.0; 95% confidence interval (CI), 0.1–12.0]. Compared with 26-week and birth concentrations, BPA concentrations collected around 16 weeks were more strongly associated with externalizing scores among all children (β = 2.9; 95% CI, 0.2–5.7), and this association was stronger in females than in males. Among all children, measurements collected at ≤ 16 weeks showed a stronger association (β = 5.1; 95% CI, 1.5–8.6) with externalizing scores than did measurements taken at 17–21 weeks (β = 0.6; 95% CI, −2.9 to 4.1).
Conclusions: These results suggest that prenatal BPA exposure may be associated with externalizing behaviors in 2-year-old children, especially among female children.
Background: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardant compounds that are persistent and bioaccumulative and therefore have become ubiquitous environment contaminants. Animal studies suggest that prenatal PBDE exposure may result in adverse neurodevelopmental effects.
Objective: In a longitudinal cohort initiated after 11 September 2001, including 329 mothers who delivered in one of three hospitals in lower Manhattan, New York, we examined prenatal PBDE exposure and neurodevelopment when their children were 12–48 and 72 months of age.
Methods: We analyzed 210 cord blood specimens for selected PBDE congeners and assessed neurodevelopmental effects in the children at 12–48 and 72 months of age; 118, 117, 114, 104, and 96 children with available cord PBDE measurements were assessed at 12, 24, 36, 48, and 72 months, respectively. We used multivariate regression analyses to evaluate the associations between concentrations of individual PBDE congeners and neurodevelopmental indices.
Results: Median cord blood concentrations of PBDE congeners 47, 99, and 100 were 11.2, 3.2, and 1.4 ng/g lipid, respectively. After adjustment for potential confounders, children with higher concentrations of BDEs 47, 99, or 100 scored lower on tests of mental and physical development at 12–48 and 72 months. Associations were significant for 12-month Psychomotor Development Index (BDE-47), 24-month Mental Development Index (MDI) (BDE-47, 99, and 100), 36-month MDI (BDE-100), 48-month full-scale and verbal IQ (BDE-47, 99, and 100) and performance IQ (BDE-100), and 72-month performance IQ (BDE-100).
Conclusions: This epidemiologic study demonstrates neurodevelopmental effects in relation to cord blood PBDE concentrations. Confirmation is needed in other longitudinal studies.
Background: Epidemiologic weight-of-evidence reviews to support regulatory decision making regarding the association between environmental chemical exposures and neurodevelopmental outcomes in children are often complicated by lack of consistency across studies.
Objective: We examined prospective cohort studies evaluating the relation between prenatal and neonatal exposure to polychlorinated biphenyls (PCBs) and neurodevelopment in children to assess the feasibility of conducting a meta-analysis to support decision making.
Data extraction/synthesis: We described studies in terms of exposure and end point categorization, statistical analysis, and reporting of results. We used this evaluation to assess the feasibility of grouping studies into reasonably uniform categories.
Results: The current literature includes 11 cohorts of children for whom effects from prenatal or neonatal PCB exposures were assessed. The most consistently used tests included Brazelton’s Neonatal Behavioral Assessment Scale, the neurologic optimality score in the neonatal period, the Bayley Scales of Infant Development at 5–8 months of age, and the McCarthy Scales of Children’s Abilities in 5-year-olds. Despite administering the same tests at similar ages, the studies were too dissimilar to allow a meaningful quantitative examination of outcomes across cohorts.
Conclusions: These analyses indicate that our ability to conduct weight-of-evidence assessments of the epidemiologic literature on neurotoxicants may be limited, even in the presence of multiple studies, if the available study methods, data analysis, and reporting lack comparability. Our findings add support to previous calls for establishing consensus standards for the conduct, analysis, and reporting of epidemiologic studies in general, and for those evaluating the effects of potential neurotoxic exposures in particular.
Objective: Potential neurotoxic effects of perfluorinated compounds (PFCs) have been reported in highly exposed animals, but whether these chemicals are neurotoxic in humans is not known. We therefore investigated whether prenatal exposure to perfluorooctanoic acid (PFOA) or perfluorooctane sulfate (PFOS), two of the most prevalent PFCs, are associated with behavioral or coordination problems in early childhood.
Methods: We used data from the Danish National Birth Cohort, which enrolled mothers in early pregnancy, and we measured maternal blood levels of PFOA and PFOS using specimens drawn around 8 weeks of gestation. When the children reached 7 years of age, mothers completed the Strengths and Difficulties Questionnaire (SDQ, n = 787) and the Developmental Coordination Disorder Questionnaire (DCDQ, n = 526) to assess behavioral health and motor coordination of their children. SDQ scores above the 90th percentile were a priori defined to identify behavioral problems and DCDQ scores below the 10th percentile were defined as a potential DCD.
Results: The median concentrations of PFOS and PFOA in maternal blood were 34.4 ng/mL [interquartile range (IQR), 26.6–44.5] and 5.4 ng/mL (IQR, 4.0–7.1), respectively, similar to distributions reported for populations without occupational exposure. We found no association between higher SDQ scores and maternal levels of PFOS or PFOA, nor did we see any statistically significant association with motor coordination disorders.
Conclusion: The findings suggest that background levels of PFOA and PFOS are not associated with behavioral and motor coordination problems in childhood. However, effects on other developmental end points, including cognitive, attentional, and clinical mental disorders not measured in this study, cannot be ruled out.
Background: Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants and are becoming a ubiquitous environmental contaminant. Adverse effects in the developing brain are of great health concern.
Objective: We investigated the effect of PBDEs/hydroxylated PBDEs (OH-PBDEs) on thyroid hormone (TH) receptor (TR)-mediated transcription and on TH-induced dendrite arborization of cerebellar Purkinje cells.
Methods: We examined the effect of PBDEs/OH-PBDEs on TR action using a transient transfection-based reporter gene assay. TR–cofactor binding was studied by the mammalian two-hybrid assay, and TR–DNA [TH response element (TRE)] binding was examined by the liquid chemiluminescent DNA pull-down assay. Chimeric receptors generated from TR and glucocorticoid receptor (GR) were used to identify the functional domain of TR responsible for PBDE action. The change in dendrite arborization of the Purkinje cell in primary culture of newborn rat cerebellum was also examined.
Results: Several PBDE congeners suppressed TR-mediated transcription. The magnitude of suppression correlated with that of TR–TRE dissociation. PBDEs suppressed transcription of chimeric receptors containing the TR DNA binding domain (TR-DBD). We observed no such suppression with chimeras containing GR-DBD. In the cerebellar culture, PBDE significantly suppressed TH-induced Purkinje cell dendrite arborization.
Conclusions: Several PBDE congeners may disrupt the TH system by partial dissociation of TR from TRE acting through TR-DBD and, consequently, may disrupt normal brain development.
Background: Paraoxonase 1 (PON1) detoxifies oxon derivatives of some organophosphate (OP) pesticides, and its genetic polymorphisms influence enzyme activity and quantity. We previously reported that maternal urinary concentrations of dialkyl phosphate (DAP) metabolites, a marker of OP pesticide exposure, were related to poorer mental development and maternally reported symptoms consistent with pervasive developmental disorder (PDD) in 2-year-olds participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study.
Objective: We determined whether PON1 genotypes and enzyme measurements were associated with child neurobehavioral development and whether PON1 modified the association of in utero exposure to OPs (as assessed by maternal DAPs) and neurobehavior.
Methods: We measured DAP concentrations in maternal urine during pregnancy, PON1192 and PON1−108 genotypes in mothers and children, and arylesterase (ARYase) and paraoxonase (POase) in maternal, cord, and 2-year-olds’ blood. We assessed 353 2-year-olds on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development and queried their mothers on the Child Behavior Checklist to obtain a score for PDD.
Results: Children with the PON1−108T allele had poorer MDI scores and somewhat poorer PDI scores. Children were less likely to display PDD when they or their mothers had higher ARYase activity and when their mothers had higher POase activity. The association between DAPs and MDI scores was strongest in children with PON1−108T allele, but this and other interactions between DAPs and PON1 polymorphisms or enzymes were not significant.
Conclusion: PON1 was associated with child neurobehavioral development, but additional research is needed to confirm whether it modifies the relation with in utero OP exposure.
Background: Identifying windows of vulnerability to environmental toxicants is an important area in children’s health research.
Objective: We compared and contrasted statistical approaches that may help identify windows of vulnerability by formally testing differences in exposure effects across time of exposure, incorporating continuous time metrics for timing of exposure, and efficiently incorporating incomplete cases.
Methods: We considered four methods: 1) window-specific and simultaneously adjusted regression; 2) multiple informant models; 3) using features of individual exposure patterns to predict outcomes; and 4) models of population exposure patterns depending on the outcome. We illustrate them using a study of prenatal vulnerability to lead in relation to Bayley’s Mental Development Index at 24 months of age (MDI24).
Results: The estimated change in MDI24 score with a 1-loge-unit increase in blood lead during the first trimester was −2.74 [95% confidence interval (CI), −5.78 to 0.29] based on a window-specific regression. The corresponding change in MDI24 was −4.13 (95% CI, −7.54 to −0.72) based on a multiple informant model; estimated effects were similar across trimesters (p = 0.23). Results from method 3 suggested that blood lead levels in early pregnancy were significantly associated with reduced MDI24, but decreasing blood leads over the course of pregnancy were not. Method 4 results indicated that blood lead levels before 17 weeks of gestation were lower among children with MDI24 scores in the 90th versus the 10th percentile (p = 0.08).
Conclusions: Method 2 is preferred over method 1 because it enables formal testing of differences in effects across a priori–defined windows (e.g., trimesters of pregnancy). Methods 3 and 4 are preferred over method 2 when there is large variability in the timing of exposure assessments among participants. Methods 3 and 4 yielded smaller p-values for tests of the hypothesis that not only level but also timing of lead exposure are relevant predictors of MDI24; systematic power comparisons are warranted.
Background: Airborne polycyclic aromatic hydrocarbons (PAH) are widespread urban pollutants that can bind to DNA to form PAH–DNA adducts. Prenatal PAH exposure measured by personal monitoring has been linked to cognitive deficits in childhood in a prospective study conducted by the Columbia Center for Children’s Environmental Health.
Objectives: We measured PAH–DNA and other bulky aromatic adducts in umbilical cord white blood cells using the P-postlabeling assay to determine the association between this molecular dosimeter and behavioral/attention problems in childhood.
Methods: Children born to nonsmoking African-American and Dominican women residing in New York City (NYC) were followed from in utero to 7–8 years of age. At two time points before 8 years of age (mean ages, 4.8 years and 7 years), child behavior was assessed using the Child Behavior Checklist (CBCL). To estimate and test the association between adducts and behavioral outcomes, both CBCL continuous raw scores and dichotomized T-scores were analyzed.
Results: Higher cord adducts were associated with higher symptom scores of Anxious/Depressed at 4.8 years and Attention Problems at 4.8 and 7 years, and with Diagnostic and Statistical Manual of Mental Disorders, 4th edition–oriented Anxiety Problems at 4.8 years.
Conclusions: These results suggest that PAH exposure, measured by DNA adducts, may adversely affect child behavior, potentially affecting school performance.
Background: In a longitudinal birth cohort study of inner-city mothers and children (Columbia Center for Children’s Environmental Health), we have previously reported that prenatal exposure to chlorpyrifos (CPF) was associated with neurodevelopmental problems at 3 years of age.
Objective: The goal of the study was to estimate the relationship between prenatal CPF exposure and neurodevelopment among cohort children at 7 years of age.
Methods: In a sample of 265 children, participants in a prospective study of air pollution, we measured prenatal CPF exposure using umbilical cord blood plasma (picograms/gram plasma) and 7-year neurodevelopment using the Wechsler Intelligence Scale for Children, 4th edition (WISC-IV). Linear regression models were used to estimate associations, with covariate selection based on two alternate approaches.
Results: On average, for each standard deviation increase in CPF exposure (4.61 pg/g), Full-Scale intelligence quotient (IQ) declined by 1.4% and Working Memory declined by 2.8%. Final covariates included maternal educational level, maternal IQ, and quality of the home environment. We found no significant interactions between CPF and any covariates, including the other chemical exposures measured during the prenatal period (environmental tobacco smoke and polycyclic aromatic hydrocarbons).
Conclusions: We report evidence of deficits in Working Memory Index and Full-Scale IQ as a function of prenatal CPF exposure at 7 years of age. These findings are important in light of continued widespread use of CPF in agricultural settings and possible longer-term educational implications of early cognitive deficits.
Background: Exposure to organochlorine compounds (OCs) can alter thyroid function in humans, and hypothyroidism during early life can adversely affect a child’s neurodevelopment.
Objectives: In this study we aimed to assess the relationship between developmental organochlorine exposures and thyroid function and the relationship between thyroid function and subsequent neurodevelopment.
Methods: A population-based birth cohort of 182 children was followed annually up to 5.5 years of age. The assessments included OC concentrations in maternal pregnancy serum and milk, clinical thyroid parameters in maternal and cord serum, and subsequent neuropsychological outcomes of the child, along with sociodemographic cofactors. Resin triiodothyronine uptake ratio (T3RU) was also assessed as an estimate of the amount of thyroxine-binding globulin (TBG) sites unsaturated by thyroxine. The T3RU is high in hyperthyroidism and low in hypothyroidism.
Results: The findings showed consistent inverse and monotonic associations between organochlorine exposure and T3RU after covariate adjustments. We observed no associations with other thyroid parameters. T3RU was positively associated with improved performance on most of the neuropsychological tests. For other thyroid parameters, the findings were less consistent.
Conclusions: The results suggest that OC exposures may decrease the T3RU during early life, which is a proxy measure of the binding capacity of TBG. In addition, minor decreases of the thyroid function may be inversely associated with a child’s neurodevelopment.
Context: Organophosphate (OP) pesticides are neurotoxic at high doses. Few studies have examined whether chronic exposure at lower levels could adversely affect children’s cognitive development.
Objective: We examined associations between prenatal and postnatal exposure to OP pesticides and cognitive abilities in school-age children.
Methods: We conducted a birth cohort study (Center for the Health Assessment of Mothers and Children of Salinas study) among predominantly Latino farmworker families from an agricultural community in California. We assessed exposure to OP pesticides by measuring dialkyl phosphate (DAP) metabolites in urine collected during pregnancy and from children at 6 months and 1, 2, 3.5, and 5 years of age. We administered the Wechsler Intelligence Scale for Children, 4th edition, to 329 children 7 years of age. Analyses were adjusted for maternal education and intelligence, Home Observation for Measurement of the Environment score, and language of cognitive assessment.
Results: Urinary DAP concentrations measured during the first and second half of pregnancy had similar relations to cognitive scores, so we used the average of concentrations measured during pregnancy in further analyses. Averaged maternal DAP concentrations were associated with poorer scores for Working Memory, Processing Speed, Verbal Comprehension, Perceptual Reasoning, and Full-Scale intelligence quotient (IQ). Children in the highest quintile of maternal DAP concentrations had an average deficit of 7.0 IQ points compared with those in the lowest quintile. However, children’s urinary DAP concentrations were not consistently associated with cognitive scores.
Conclusions: Prenatal but not postnatal urinary DAP concentrations were associated with poorer intellectual development in 7-year-old children. Maternal urinary DAP concentrations in the present study were higher but nonetheless within the range of levels measured in the general U.S. population.
Background: Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals.
Objectives: We prospectively studied manganese–lead interactions in early childhood to examine whether manganese–lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone.
Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development–II.
Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 μg/L and 21.5 ± 7.4 μg/L for manganese and 5.1 ± 2.6 μg/dL and 5.0 ± 2.9 μg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile × continuous lead; mental development score, β = –1.27 [95% confidence interval (CI): –2.18, –0.37]; psychomotor development score, β = –0.92 (95% CI: –1.76, –0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels.
Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood.
Background: Environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs), lead, and mercury are released by combustion of coal and other fossil fuels.
Objectives: In the present study we evaluated the association between prenatal exposure to these pollutants and child development measured by the Gesell Developmental Schedules at 2 years of age.
Methods: The study was conducted in Tongliang, Chongqing, China, where a seasonally operated coal-fired power plant was the major source of ambient PAHs and also contributed lead and mercury to the air. In a cohort of nonsmoking women and their newborns enrolled between March 2002 and June 2002, we measured levels of PAH–DNA adducts, lead, and mercury in umbilical cord blood. PAH–DNA adducts (specifically benzo[a]pyrene adducts) provided a biologically relevant measure of PAH exposure. We also obtained developmental quotients (DQs) in motor, adaptive, language, and social areas.
Results: Decrements in one or more DQs were significantly associated with cord blood levels of PAH–DNA adducts and lead, but not mercury. Increased adduct levels were associated with decreased motor area DQ (p = 0.043), language area DQ (p = 0.059), and average DQ (p = 0.047) after adjusting for cord lead level, environmental tobacco smoke, sex, gestational age, and maternal education. In the same model, high cord blood lead level was significantly associated with decreased social area DQ (p = 0.009) and average DQ (p = 0.038).
Conclusion: The findings indicate that exposure to pollutants from the power plant adversely affected the development of children living in Tongliang; these findings have implications for environmental health policy.
Background: Low-level environmental cadmium exposure in children may be associated with adverse neurodevelopmental outcomes.
Objective: Our aim was to evaluate associations between urinary cadmium concentration and reported learning disability (LD), special education utilization, and attention deficit hyperactivity disorder (ADHD) in U.S. children using National Health and Nutrition Examination Survey (NHANES) data.
Methods: We analyzed data from a subset of participants in NHANES (1999–2004) who were 6–15 years of age and had spot urine samples analyzed for cadmium. Outcomes were assessed by parent or proxy-respondent report. We fit multivariable-adjusted logistic regression models to estimate associations between urinary cadmium and the outcomes.
Results: When we compared children in the highest quartile of urinary cadmium with those in the lowest quartile, odds ratios adjusted for several potential confounders were 3.21 [95% confidence interval (CI): 1.43, 7.17] for LD, 3.00 (95% CI: 1.12, 8.01) for special education, and 0.67 (95% CI: 0.28, 1.61) for ADHD. There were no significant interactions with sex, but associations with LD and special education were somewhat stronger in males, and the trend in the ADHD analysis was only evident among those with blood lead levels above the median.
Conclusions: These findings suggest that children who have higher urinary cadmium concentrations may have increased risk of both LD and special education. Importantly, we observed these associations at exposure levels that were previously considered to be without adverse effects, and these levels are common among U.S. children.
Background: The impact of environmental chemicals on children’s neurodevelopment is sometimes dismissed as unimportant because the magnitude of the impairments are considered to be clinically insignificant. Such a judgment reflects a failure to distinguish between individual and population risk. The population impact of a risk factor depends on both its effect size and its distribution (or incidence/prevalence).
Objective: The objective was to develop a strategy for taking into account the distribution (or incidence/prevalence) of a risk factor, as well as its effect size, in order to estimate its population impact on neurodevelopment of children.
Methods: The total numbers of Full-Scale IQ points lost among U.S. children 0–5 years of age were estimated for chemicals (methylmercury, organophosphate pesticides, lead) and a variety of medical conditions and events (e.g., preterm birth, traumatic brain injury, brain tumors, congenital heart disease).
Discussion: Although the data required for the analysis were available for only three environmental chemicals (methylmercury, organophosphate pesticides, lead), the results suggest that their contributions to neurodevelopmental morbidity are substantial, exceeding those of many nonchemical risk factors.
Conclusion: A method for comparing the relative contributions of different risk factors provides a rational basis for establishing priorities for reducing neurodevelopmental morbidity in children.
Background: Environmental tobacco smoke (ETS) exposure is linked to developmental deficits and disorders with known cerebellar involvement. However, direct biological effects and underlying neurochemical mechanisms remain unclear.
Objectives: We sought to identify and evaluate underlying neurochemical change in the rat cerebellum with ETS exposure during critical period development.
Methods: We exposed rats to daily ETS (300, 100, and 0 µg/m total suspended particulate) from postnatal day 8 (PD8) to PD23 and then assayed the response at the behavioral, neuroproteomic, and cellular levels.
Results: Postnatal ETS exposure induced heightened locomotor response in a novel environment on par initially with amphetamine stimulation. The cerebellar mitochondrial subproteome was significantly perturbed in the ETS-exposed rats. Findings revealed a dose-dependent up-regulation of aerobic processes through the modification and increased translocation of Hk1 to the mitochondrion with corresponding heightened ATP synthase expression. ETS exposure also induced a dose-dependent increase in total Dnm1l mitochondrial fission factor; although more active membrane-bound Dnm1l was found at the lower dose. Dnm1l activation was associated with greater mitochondrial staining, particularly in the molecular layer, which was independent of stress-induced Bcl-2 family dynamics. Further, electron microscopy associated Dnm1l-mediated mitochondrial fission with increased biogenesis, rather than fragmentation.
Conclusions: The critical postnatal period of cerebellar development is vulnerable to the effects of ETS exposure, resulting in altered behavior. The biological effect of ETS is underlain in part by a Dnm1l-mediated mitochondrial energetic response at a time of normally tight control. These findings represent a novel mechanism by which environmental exposure can impact neurodevelopment and function.
An international workshop titled “Assessing Endocrine-Related Endpoints within the First Years of Life” was held 30 April–1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions.
Background: Early-life exposure to p,p′-DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] is associated with a decrease in cognitive skills among preschoolers at 4 years of age. We hypothesized that genetic variability in glutathione S-transferase (GST) genes (GSTP1, GSTM1, and GSTT1) could influence the effects of prenatal exposure to p,p′-DDT.
Methods: We used data from 326 children assessed in a prospective population-based birth cohort at the age of 4 years. In that study, the McCarthy Scales of Children’s Abilities were administrated by psychologists, organochlorine compounds were measured in cord serum, and genotyping was conducted for the coding variant Ile105Val from GSTP1 and for null alleles from GSTM1 and GSTT1. We used linear regression models to measure the association between organochlorines and neurodevelopmental scores by GST polymorphisms.
Results: p,p′-DDT cord serum concentration was inversely associated with general cognitive, memory, quantitative, and verbal skills, as well as executive function and working memory, in children who had any GSTP1 Val-105 allele. GSTP1 polymorphisms and prenatal p,p′-DDT exposure showed a statistically significant interaction for general cognitive skills (p = 0.05), quantitative skills (p = 0.02), executive function (p = 0.01), and working memory (p = 0.02). There were no significant associations between p,p′-DDT and cognitive functioning at 4 years of age according to GSTM1 and GSTT1 polymorphisms.
Conclusions: Results indicate that children with GSTP1 Val-105 allele were at higher risk of the adverse cognitive functioning effects of prenatal p,p′-DDT exposure.