A Novel Approach to Assessing the Joint Effects of Mercury and Fish Consumption on Neurodevelopment in the New Bedford Cohort.

Understanding health risks from methylmercury (MeHg) exposure is complicated by its link to fish consumption which may confound or modify toxicities. One solution is to include fish intake and a biomarker of MeHg exposure in the same model, but resulting estimates do not reflect the independent impact of accumulated MeHg or fish exposures. In fish-eating populations, this can be addressed by separating MeHg exposure into fish intake and average Hg content of the consumed fish. We assessed the joint association of prenatal MeHg exposure (maternal hair Hg) and fish intake (among fish-eating mothers) with neurodevelopment in 361 eight-year-olds from the New Bedford Cohort (born 1993-1998). Neurodevelopmental assessments used standardized tests of IQ, language, memory, and attention. Covariate-adjusted regression assessed the association of maternal fish consumption, stratified by tertiles of estimated average fish Hg, with neurodevelopment. Associations between maternal fish intake and child outcomes were generally beneficial for those in the lowest average fish Hg tertile, but detrimental in the highest average fish Hg tertile where, for example, each serving of fish was associated with 1.3 fewer correct responses (95% CI: -2.2, -0.4) on the Boston Naming test. Standard analyses showed no outcome associations with hair Hg or fish intake.

Multiple prenatal exposures and acute-care clinical encounters for asthma among children born to mothers living near a Superfund site.

Prenatal exposures are associated with childhood asthma, and risk may increase with simultaneous exposures. Pregnant women living in lower-income communities tend to have elevated exposures to a range of potential asthma risk factors, which may interact in complex ways. We examined the association between prenatal exposures and the risk of childhood acute-care clinical encounters for asthma (hospitalizations, emergency department visits, observational stays) using conditional logistic regression with a multivariable smoothing term to model the interaction between continuous variables, adjusted for maternal characteristics and stratified by sex. All births near the New Bedford Harbor (NBH) Superfund site (2000-2006) in New Bedford, Massachusetts, were followed through 2011 using the Massachusetts Pregnancy to Early Life Longitudinal (PELL) Data System to identify children aged 5-11 years with acute-care clinical asthma encounters (265 cases among 7787 children with follow-up). Hazard ratios (HRs) were higher for children living closer to the NBH site with higher umbilical cord blood lead levels than in children living further away from the NBH site with lower lead levels (P <.001). HRs were higher for girls (HR = 4.17; 95% CI, 3.60-4.82) than for boys (HR = 1.72; 95% CI, 1.46-2.02). Our results suggest that prenatal lead exposure in combination with residential proximity to the NBH Superfund site is associated with childhood asthma acute-care clinical encounters. This article is part of a Special Collection on Environmental Epidemiology.

Association between maternal stress and child sleep quality: a nationwide ECHO prospective cohort study.

BACKGROUND: Childhood sleep quality is associated with physical, cognitive, and behavioral health and predicts later sleep quality; it has many determinants, including developmental exposures. OBJECTIVES: To examine associations between maternal stress during pregnancy and childhood sleep quality and determine whether postnatal stress mediates the association. METHOD: Data from the Environmental Influences on Child Health Outcomes cohort were used. Perceived Stress Scale (PSS) T-scores were the exposure measure. Outcome measures were preschool Child Behavior Checklist (CBCL) sleep syndrome scale and Patient-Reported Outcomes Measurement Information System Sleep Disturbance Parent Proxy short form 4a (PSD4a) T-scores at ages 4-8 years. Linear mixed-effects regression modeling was performed for each sleep outcome, adjusting for maternal age at delivery and education and child sex, gestational age at birth, and age at outcome ascertainment, with random intercepts for cohorts. RESULTS: Prenatal PSS score was associated with both CBCL (B = 0.09, 95% confidence interval [CI]: 0.06, 0.11; p < 0.01) and PSD4a (B = 0.07, 95% CI: 0.03, 0.12; p < 0.01) scores. Postnatal perceived stress mediated a proportion of the total effect of prenatal stress in both CBCL (66.3%) and PSD4a (95.9%) samples. CONCLUSIONS: Both pre- and postnatal maternal perceived stress appear to influence sleep quality during early life. IMPACT: Prenatal stress significantly associates with child sleep problems and disturbances at ages 4-8 years; postnatal maternal stress is a significant mediator of these associations. Research suggests a range of prenatal affective/distress exposures associated with child sleep problems, but the conclusions remain in doubt due to the mixture of exposures and outcomes employed. Ours is the first US-based effort to explore associations between perceived maternal stress during pregnancy and child sleep problems and disturbance in early and middle childhood. Even a small effect of a prevalent issue like psychosocial stress may have important public health implications at the population level.

Greater Gestational Vitamin D Status is Associated with Reduced Childhood Behavioral Problems in the Environmental Influences on Child Health Outcomes Program.

BACKGROUND: Vitamin D deficiency is common in pregnancy. Vitamin D plays an important role in the developing brain, and deficiency may impair childhood behavioral development. OBJECTIVES: This study examined the relationship between gestational 25(OH)D concentrations and childhood behavior in the Environmental influences on Child Health Outcomes (ECHO) Program. METHODS: Mother-child dyads from ECHO cohorts with data available on prenatal (first trimester through delivery) or cord blood 25(OH)D and childhood behavioral outcomes were included. Behavior was assessed using the Strengths and Difficulties Questionnaire or the Child Behavior Checklist, and data were harmonized using a crosswalk conversion. Linear mixed-effects models examined associations of 25(OH)D with total, internalizing, and externalizing problem scores while adjusting for important confounders, including age, sex, and socioeconomic and lifestyle factors. The effect modification by maternal race was also assessed. RESULTS: Early (1.5-5 y) and middle childhood (6-13 y) outcomes were examined in 1688 and 1480 dyads, respectively. Approximately 45% were vitamin D deficient [25(OH)D < 20 ng/mL], with Black women overrepresented in this group. In fully adjusted models, 25(OH)D concentrations in prenatal or cord blood were negatively associated with externalizing behavior T-scores in middle childhood [-0.73 (95% CI: -1.36, -0.10) per 10 ng/mL increase in gestational 25(OH)D]. We found no evidence of effect modification by race. In a sensitivity analysis restricted to those with 25(OH)D assessed in prenatal maternal samples, 25(OH)D was negatively associated with externalizing and total behavioral problems in early childhood. CONCLUSIONS: This study confirmed a high prevalence of vitamin D deficiency in pregnancy, particularly among Black women, and revealed evidence of an association between lower gestational 25(OH)D and childhood behavioral problems. Associations were more apparent in analyses restricted to prenatal rather than cord blood samples. Interventions to correct vitamin D deficiency during pregnancy should be explored as a strategy to improve childhood behavioral outcomes.

Phenotypically driven subgroups of ASD display distinct metabolomic profiles.

Autism Spectrum Disorder (ASD) is a heterogeneous condition that includes a broad range of characteristics and associated comorbidities; however, the biology underlying the variability in phenotypes is not well understood. As ASD impacts approximately 1 in 100 children globally, there is an urgent need to better understand the biological mechanisms that contribute to features of ASD. In this study, we leveraged rich phenotypic and diagnostic information related to ASD in 2001 individuals aged 4 to 17 years from the Simons Simplex Collection to derive phenotypically driven subgroups and investigate their respective metabolomes. We performed hierarchical clustering on 40 phenotypes spanning four ASD clinical domains, resulting in three subgroups with distinct phenotype patterns. Using global plasma metabolomic profiling generated by ultrahigh-performance liquid chromatography mass spectrometry, we characterized the metabolome of individuals in each subgroup to interrogate underlying biology related to the subgroups. Subgroup 1 included children with the least maladaptive behavioral traits (N = 862); global decreases in lipid metabolites and concomitant increases in amino acid and nucleotide pathways were observed for children in this subgroup. Subgroup 2 included children with the highest degree of challenges across all phenotype domains (N = 631), and their metabolome profiles demonstrated aberrant metabolism of membrane lipids and increases in lipid oxidation products. Subgroup 3 included children with maladaptive behaviors and co-occurring conditions that showed the highest IQ scores (N = 508); these individuals had increases in sphingolipid metabolites and fatty acid byproducts. Overall, these findings indicated distinct metabolic patterns within ASD subgroups, which may reflect the biological mechanisms giving rise to specific patterns of ASD characteristics. Our results may have important clinical applications relevant to personalized medicine approaches towards managing ASD symptoms.

Adolescent endocrine disrupting chemical exposure and academic achievement.

BACKGROUND: Epidemiologic studies support associations of exposure to endocrine disrupting chemicals (EDCs), such as some phthalates, phenols, and parabens with a wide range of cognitive and behavioral traits. While many of these traits are associated with academic achievement, the relationship of EDC exposure specifically with academic achievement in adolescence has not yet been studied. OBJECTIVE: We assessed the association of urinary biomarker concentrations of EDCs with academic achievement in adolescents as well as the potential for psychosocial factors to modify associations. METHODS: We quantified urinary concentrations of select EDCs in 205 adolescent participants from the New Bedford Cohort (NBC), a prospective birth cohort of children born to mothers residing near the New Bedford Harbor Superfund site in Massachusetts, and estimated associations between EDCs and adolescent academic achievement assessed with the Wide Range Achievement Test (WRAT). Measures of socioeconomic status and the home environment were used to estimate psychosocial stress. RESULTS: Urinary concentrations of antiandrogenic phthalates were inversely associated with Math Computation scores. For example, each doubling of the concentration of antiandrogenic phthalate metabolites in urine was associated with a 1.94 point decrease (95% CI: 3.84, -0.05) in Math Computation scores, indicating poorer performance. For the most part, associations were stronger in adolescents with more, as compared to less, social disadvantage, but most of these differences did not achieve statistical significance. CONCLUSION: Our findings support the potential for adolescents' exposure to antiandrogenic phthalates to correlate with poorer academic achievement in math, particularly among participants with greater psychosocial stress.

Early-Life Exposure to Green Space and Mid-Childhood Cognition in the Project Viva Cohort, Massachusetts.

The association between early-life greenness and child cognition is not well understood. Using prospective data from Project Viva (n = 857) from 1999-2010, we examined associations of early-life greenness exposure with mid-childhood cognition. We estimated residential greenness at birth, early childhood (median age 3.1 years), and mid-childhood (7.8 years) using 30-m resolution Landsat satellite imagery (normalized difference vegetation index). In early childhood and mid-childhood, we administered standardized assessments of verbal and nonverbal intelligence, visual-motor abilities, and visual memory. We used natural splines to examine associations of early life-course greenness with mid-childhood cognition, adjusting for age, sex, race, income, neighborhood socioeconomic status, maternal intelligence, and parental education. At lower levels of greenness (greenness <0.6), greenness exposure at early childhood was associated with a 0.48% increase in nonverbal intelligence and 2.64% increase in visual memory in mid-childhood. The association between early-childhood greenness and mid-childhood visual memory was observed after further adjusting for early childhood cognition and across different methodologies, while the association with nonverbal intelligence was not. No other associations between early life-course greenness and mid-childhood cognition were found. Early childhood greenness was nonlinearly associated with higher mid-childhood visual memory. Our findings highlight the importance of nonlinear associations between greenness and cognition.

Association of peripubertal blood lead levels with reproductive hormones and semen parameters in a longitudinal cohort of Russian men.

STUDY QUESTION: Are peripubertal blood lead levels (BLLs) associated with semen parameters and serum reproductive hormones among young Russian men? SUMMARY ANSWER: We observed a suggestion of lower ejaculate volume with higher peripubertal BLL but no associations of BLLs with reproductive hormones measured throughout adolescence or with other sperm parameters measured at adulthood. WHAT IS KNOWN ALREADY: Lead is a known reproductive toxicant and endocrine disruptor. Previous literature has shown associations between high lead exposure and poorer semen quality both in occupationally and environmentally exposed men. However, to our knowledge, no longitudinal studies have explored the association of childhood lead exposure with semen parameters and reproductive hormones in young men. STUDY DESIGN, SIZE, DURATION: The Russian Children's Study is a prospective cohort study that enrolled 516 boys at age 8-9 years in 2003-2005 and followed them annually for 10 years. BLLs were measured at entry and lifestyle and health questionnaires were completed. Reproductive hormones were measured in blood samples collected every 2 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the 516 boys enrolled, 481 had BLLs measured at entry. Of these, 453 had at least one measurement of serum testosterone, follicle stimulating hormone (FSH) or luteinizing hormone (LH) (median = 5 samples per boy) and 223 had semen samples collected ∼10 years after enrolment. Semen assessment included ejaculated volume, sperm concentration, progressive motility and total sperm count, and parameters were categorized using published andrology standards for low semen quality based on sperm count and motility. Linear mixed models were used to examine the associations of log-transformed BLLs (and BLL categories) with reproductive hormones and semen parameters, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 223 young men with peripubertal BLLs and at least one semen sample (total samples = 438), the median (interquartile range) BLL was 3 (2, 5) µg/dl and 27% had BLL ≥5 µg/dl. Overall, 49% of the semen samples fell below reference levels for sperm count and/or motility. Men with peripubertal BLL ≥5 µg/dl had significantly lower ejaculated volume than those with BLL <5 µg/dl (mean = 2.42 vs 2.89 ml, P = 0.02), but this difference was attenuated in adjusted models (mean = 2.60 vs 2.83 ml, P = 0.25). No associations were observed between BLL measured at age 8-9 years and reproductive hormone levels or sperm parameters, including sperm concentration, total count, progressive motility and total progressive motile sperm count, or with the probability of having low semen quality based on sperm count/motility. LIMITATIONS, REASONS FOR CAUTION: Only a subset of the original cohort participated in the semen quality portion of the study, although inverse probability weighting was used to account for possible selection bias. BLLs were only measured at a single time in peripuberty, and other exposure time periods, including later or longer-term childhood exposure, may be more predictive of semen quality. The young men were also exposed to other chemical contaminants before and during pubertal development. WIDER IMPLICATIONS OF THE FINDINGS: While semen volume often receives less attention than other sperm parameters, it is an important component of male fertility. Additional prospective studies covering different exposure windows and including other seminal plasma biomarkers are warranted to explore our finding of potentially lower ejaculated volume with higher BLLs and to confirm the lack of associations for other semen parameters among youth exposed to environmental BLLs. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided through grants R01ES0014370 and P30ES000002 from the National Institute of Environmental Health Sciences, grant R82943701 from the U.S. Environmental Protection Agency, and grant 18-15-00202 from the Russian Science Foundation (O.S and Y.D.). All authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Sex-specific relationships of the infant microbiome and early-childhood behavioral outcomes.

BACKGROUND: A link between the gut microbiome and behavior is hypothesized, but most previous studies are cross-sectional or in animal models. The modifying role of host sex is poorly characterized. We aimed to identify sex-specific prospective associations between the early-life gut microbiome and preschool-age neurobehavior. METHODS: In a prospective cohort, gut microbiome diversity and taxa were estimated with 16S rRNA sequencing at 6 weeks, 1 year, and 2 years. Species and gene pathways were inferred from metagenomic sequencing at 6 weeks and 1 year. When subjects were 3 years old, parents completed the Behavioral Assessment System for Children, second edition (BASC-2). A total of 260 children contributed 523 16S rRNA and 234 metagenomics samples to analysis. Models adjusted for sociodemographic characteristics. RESULTS: Higher diversity at 6 weeks was associated with better internalizing problems among boys, but not girls [ßBoys = -1.86 points/SD Shannon diversity; 95% CI (-3.29, -0.42), pBoys = 0.01, ßGirls = 0.22 (-1.43, 1.87), pGirls = 0.8, pinteraction = 0.06]. Among other taxa-specific associations, Bifidobacterium at 6 weeks was associated with Adaptive Skills scores in a sex-specific manner. We observed relationships between functional features and BASC-2 scores, including vitamin B6 biosynthesis pathways and better Depression scores. CONCLUSIONS: This study advances our understanding of microbe-host interactions with implications for childhood behavioral health. IMPACT: This is one of the first studies to examine the early-life microbiome and neurobehavior, and the first to examine prospective sex-specific associations. Infant and early-childhood microbiomes relate to neurobehavior including anxiety, depression, hyperactivity, and social behaviors in a time- and sex-specific manner. Our findings suggest future studies should evaluate whether host sex impacts the relationship between the gut microbiome and behavioral health outcomes.

Prenatal exposure to chemical mixtures and working memory among adolescents.

Working memory is the ability to keep information in one's mind and mentally manipulate it. Decrements in working memory play a key role in many behavioral and psychiatric disorders, therefore identifying modifiable environmental risk factors for such decrements is important for mitigating these disorders. There is some evidence that prenatal exposure to individual chemicals may adversely impact working memory among children, but few studies have explored the association of co-exposure to multiple chemicals with this outcome in adolescence, a time when working memory skills undergo substantial development. We investigated the association of organochlorines (DDE, HCB, PCBs) and metals (lead, manganese) measured in cord serum and cord blood, respectively, with working memory measured with the Wide Range Assessment of Memory and Learning, 2nd Edition among 373 adolescents living near a Superfund site in New Bedford, Massachusetts. We used Bayesian Kernel Machine Regression (BKMR) and linear regression analyses and assessed effect modification by sex and prenatal social disadvantage. In BKMR models, we observed an adverse joint association of the chemical mixture with Verbal, but not Symbolic, Working Memory. In co-exposure and covariate-adjusted linear regression models, a twofold increase in cord blood manganese was associated with lower working memory scaled scores, with a stronger association with Verbal Working Memory (difference = -0.75; 95% CI: -1.29, -0.20 points) compared to Symbolic Working Memory (difference = -0.44; 95% CI: -1.00, 0.12 points). There was little evidence of effect modification by sex and some evidence associating organochlorine pesticides with poorer working memory scores among those with greater prenatal social disadvantage. This study provided evidence of an adverse joint association of a chemical mixture with a verbal working memory task among adolescents, as well as an adverse association of prenatal manganese exposure with working memory.

Prenatal exposure to a mixture of organochlorines and metals and internalizing symptoms in childhood and adolescence.

BACKGROUND: Although prenatal chemical exposures influence neurobehavior, joint exposures are not well explored as risk factors for internalizing disorders through adolescence. OBJECTIVE: To evaluate associations of prenatal organochlorine and metal exposures, considered individually and as a mixture, with mid-childhood and adolescent internalizing symptoms. METHODS: Participants were 468 children from a prospective cohort recruited at birth (1993-1998) in New Bedford, Massachusetts. Organochlorines (hexachlorobenzene, p,p'-dichlorodiphenyl dichloroethylene, polychlorinated biphenyls) and metals (lead, manganese) were analyzed in cord blood. Internalizing symptoms (anxiety, depressive, somatic) were assessed via multiple informants on the Conners' Rating Scale (CRS) at 8-years and Behavior Assessment System for Children, Second Edition (BASC-2) at 15-years; higher T-scores indicate greater symptoms. Overall and sex-specific covariate-adjusted associations were evaluated using Bayesian Kernel Machine Regression (BKMR) and five-chemical linear regression models. RESULTS: The cohort was socioeconomically diverse (35% household income <$20,000; 55% maternal ≤ high school education at birth). Most chemical concentrations were consistent with background levels [e.g., median (range) cord blood lead: 1.1 (0-9.4) µg/dL]. BKMR suggested linear associations and no interactions between chemicals. The overall mixture was positively associated with Conners' Parent Rating Scale (CPRS) and BASC-2 Self Report of Personality (SRP) anxiety and depressive symptoms, and negatively with somatic symptoms. Prenatal lead was positively associated with adolescent anxiety symptoms [1.56 (95% CI: 0.50, 2.61) BASC-2 SRP Anxiety score increase per doubling lead]. For CRPS and BASC-2 SRP, a doubling of cord blood manganese was positively associated with internalizing symptoms for girls [e.g., 3.26 (95% CI: 0.27, 6.25) BASC-2 SRP Depression score increase], but not boys. Organochlorine exposures were not adversely associated with internalizing symptoms. DISCUSSION: Low-level prenatal lead exposure was positively associated with adolescent anxiety symptoms, and prenatal manganese exposure was positively associated with internalizing symptoms for girls from mid-childhood through adolescence. In utero neurotoxicant metal exposures may contribute to the emergence of anxiety and depression.

Associations of prepubertal urinary phthalate metabolite concentrations with pubertal onset among a longitudinal cohort of boys.

BACKGROUND: Although phthalate exposures have been associated with adverse effects on male reproductive health, few studies have explored longitudinal associations with male pubertal development. OBJECTIVES: We examined the association of prepubertal urinary concentrations of phthalate metabolites with age at pubertal onset in a prospective cohort of Russian boys. METHODS: At enrollment at ages 8-9 years, medical history, dietary, and demographic information was collected. At entry and annually, physical examinations and pubertal staging [Genitalia (G), Pubarche (P), and testicular volume (TV, in ml)] were conducted and spot urines were collected. Prepubertal urine samples (defined as either TV = 1, 2 and G = 1, 2 or TV = 3 and G = 1) were pooled for each boy and phthalate metabolite concentrations were quantified using isotope dilution LC-MS/MS at Moscow State University. We measured 15 metabolites including those from anti-androgenic parent phthalates (AAPs) such as di (2-ethylhexyl) (DEHP) and di-isononyl (DiNP) phthalates as well as monobenzyl (MBzP), mono-n-butyl (MnBP), and mono-isobutyl (MiBP) metabolites. We calculated the molar sums of DEHP (∑DEHP), DiNP (∑DiNP), and AAP (∑AAP) metabolites. Separate interval-censored models were used to assess associations of quartiles of prepubertal phthalate metabolites with each pubertal onset indicator, G2+, P2+ and TV > 3 mL, adjusted for covariates and urine specific gravity. RESULTS: 304 boys had 752 prepubertal urine samples (median 2, range: 1-6) for pooling. In adjusted models, higher urinary AAPs were consistently associated with later pubertal onset (P2) with mean shifts ranging from 8.4 to 14.2 months for the highest versus lowest quartiles. Significantly later onset for G2 and TV > 3 mL was observed for higher versus lower quartiles of MiBP, MBzP, ∑DEHP and ∑DiNP. CONCLUSIONS: On average, boys with higher concentrations of prepubertal urinary AAPs had later pubertal onset by six months to over a year. The impact of AAPs on timing of male puberty may be attributable to disruption of androgen-dependent biological pathways.

Early infant behavioural correlates of social skills in adolescents.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder typically diagnosed after the second year of life; however, differences in brain structure and function associated with ASD have been ascertained in early infancy. Identifying behavioural markers of ASD risk in early infancy has the potential to facilitate early detection and intervention. OBJECTIVES: We examined associations between infant behaviour and adolescent behaviours associated with ASD. METHODS: Analyses leveraged data available on 370 participants from the New Bedford Cohort, a sociodemographically diverse prospective birth cohort of children born from 1993 to 1998 to mothers residing near the New Bedford Harbor Superfund site in Massachusetts. Longitudinal assessments were used to examine the associations between behaviours when children were approximately 2 weeks old (measured by the Neonatal Behavioral Assessment Scale [NBAS]), and subsequent maladaptive behaviours associated with ASD at approximately 15 years old [measured by the Behavior Assessment System for Children, 2nd Edition-Teacher Rating Scale (BASC-2 TRS) scores which are standardised to a mean (SD) of 50 (10)]. RESULTS: Poorer performance on select individual items and cluster scales of the NBAS was associated with an increase in behaviours associated with ASD in adolescents. Associations were strongest for neonatal measures of self-regulation, response to auditory input, and autonomic nervous system regulation. For example, in covariate-adjusted models, infants with Regulation of State NBAS cluster scores in the lowest tertile (poorest performance) compared to infants with scores in the higher two tertiles had adolescent BASC-2 TRS Developmental Social Disorders T-scores that were 2.9 points higher (95% CI: 0.8, 4.9), indicating more behaviours associated with ASD. CONCLUSION: The NBAS is an established and accessible instrument that assesses a broad range of behaviours in very young infants, and may be a useful tool for newborn assessments of developmental risk, including risk of ASD-associated behaviours.

Maternal methylmercury exposure through rice ingestion and child neurodevelopment in the first three years: a prospective cohort study in rural China.

BACKGROUND: Rice is an important dietary source for methylmercury; however, rice does not contain the same beneficial nutrients as fish. Our main objective was to assess associations of prenatal methylmercury exposure through rice ingestion with child neurodevelopment in rural China. METHODS: Eligible peripartum women were enrolled (n = 391), provided peripartum hair samples, and children's neurodevelopment was assessed at 12 months (n = 264, 68%) and 36 months (n = 190, 48%) using the Bayley Scales of Infant Development, 2nd Edition, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). Associations between prenatal methylmercury exposure during the third trimester [log2 maternal hair total mercury (THg)] and child's neurodevelopment were assessed using linear mixed models for repeated measures. RESULTS: In adjusted models, a doubling in maternal hair THg corresponded to a 1.3-point decrement in the MDI score [95% confidence interval (CI): - 2.6, - 0.14], and a 1.2-point decrement in the PDI score (95% CI: - 2.6, 0.14). Overall, adverse associations between maternal hair THg and MDI scores attenuated over time. However, associations were robust and stable over time among children whose primary caregiver was their parent(s). During the study follow-up, an increasing proportion of children were raised by grandparents (12 months: 9% versus 36 months: 27%), a trend associated with rural-to-urban parental migration for work. CONCLUSIONS: For young children living in rural China, a biomarker of prenatal methylmercury exposure was associated with decrements in cognitive function assessed between 12 and 36 months of age. Changes in the family structure over the study follow-up time interval potentially impacted children's sensitivity to prenatal methylmercury exposure.

Relation between in utero arsenic exposure and growth during the first year of life in a New Hampshire pregnancy cohort.

BACKGROUND: We have previously reported that in utero arsenic exposure is associated with increased length and other anthropometric outcomes at birth in a U.S. cohort. However, it is unknown whether these anthropometric differences persist through early life. OBJECTIVES: We assessed in utero arsenic exposure in relation to attained anthropometry and growth trajectories through the first year of life. METHODS: Among 760 mother-infant pairs from the New Hampshire Birth Cohort Study, we assessed in utero arsenic exposure using maternal second trimester urinary arsenic and assessed infant growth from medical records. RESULTS: Median maternal second trimester total urinary arsenic (tAs; inorganic arsenic + monomethylarsonic acid + dimethylarsinic acid) was 3.96 µg/L (IQR: 2.02, 6.72). In adjusted linear mixed effects models, each doubling of maternal urinary tAs was associated with a 0.05 increase in length WHO Z score (95% CI: 0, 0.09) over the first year of life which corresponds to an approximately 0.12 cm increase in males and 0.13 cm increase in females at 12 months. No associations were observed between urinary tAs and attained weight, weight-for-length, or head circumference. In adjusted piecewise linear mixed effects models, each doubling of urinary tAs was associated with a 0.07 (95% CI: 0.02, 0.12) cm per month decreased length growth rate through 3.5 months with no evidence of an association thereafter. No associations were observed between urinary tAs and infant weight gain or change in weight-for-length and head circumference through one year. CONCLUSIONS: On average, infants exposed to higher in utero arsenic attained modestly longer length during the first year, despite having slower linear growth in the first 3.5 months of life. This suggests that the previously demonstrated arsenic-associated longer length among study infants at birth persists through the first year of life. No other anthropometric associations with in utero arsenic exposure were observed across the full study population.

Reported environmental exposures are inversely associated with obtaining a genetic diagnosis in the Undiagnosed Diseases Network.

The Undiagnosed Diseases Network (UDN) aims to achieve a unifying etiologic diagnosis for patients with mysterious conditions. Although the UDN has focused on the identification of genetic determinants, environmental etiologies may be causative or modifying agents that interact with predisposing genes. We developed and implemented a screening questionnaire to assess environmental exposures in UDN patients. We hypothesized that patients with potentially adverse environmental exposures would be less likely to have a genetic basis for their undiagnosed disease. Among seven postnatal environmental exposure categories assessed in 269 UDN participants, patients with a confirmed or strong candidate genetic diagnosis were significantly less likely to report exposures to metals, dust, or chemicals (p < 0.05). A composite variable of the seven exposure categories was substantially more common (40%) in patients without a genetic diagnosis than in those with a genetic diagnosis (18.4%) (p = 0.004). In multivariable analysis adjusting for age and sex, the composite variable of any positive environmental exposure was associated with a reduced odds of finding a genetic diagnosis (OR 0.41, 95% CI 0.18-0.96, p = 0.04). These results were generally robust to exclusion of patients with early life disease onset. Our results suggest a possible approach to increase the yield of genetic etiologies for adult undiagnosed diseases by first focusing on patients without significant environmental exposures. Still, there is ample reason to expect cases in which specific environmental exposures impact the risk of clinically evident genetic disease. Our findings emphasize the importance of systematic investigations of potential environmental risk factors for undiagnosed diseases.

Endocrine disrupting chemical exposure and maladaptive behavior during adolescence.

BACKGROUND: Studies suggest that exposure to endocrine disrupting chemicals (EDCs), including phthalates, phenols, and parabens may influence childhood behavior, but the relationship during adolescence has not been assessed. OBJECTIVE: We investigated the association between urinary biomarker concentrations of potential EDCs, including some phthalate and bisphenol A replacement chemicals, and behavior in adolescents. METHODS: Participants were from the New Bedford Cohort (NBC), a prospective birth cohort of residents near the New Bedford Harbor Superfund site in Massachusetts. We measured urinary concentrations of 16 phthalate metabolites or replacements, 8 phenols, and 4 parabens in 205 NBC adolescents and estimated associations between select EDCs and adolescent behavior assessed with the Behavior Assessment System for Children, Second Edition -Teacher Rating Scale (BASC-2). Of note, up to 32 of the 205 in our assessment had missing outcome information imputed. RESULTS: Increased urinary concentrations of the sum of 11 antiandrogenic phthalate metabolites were associated with an increase in maladaptive behaviors (Externalizing Behavior, Behavioral Symptoms Index, and Developmental Social Disorders or DSD), and a decrease in Adaptive Skills. For example, a doubling of urinary concentrations of antiandrogenic phthalate metabolites was associated with an increased risk of Externalizing Behavior (RR=1.04; 95% CI: 1.01-1.08). While associations were generally stronger in males, sex differences were not statistically significant. Urine concentrations of phenols and parabens were not associated with adverse behavior. CONCLUSION: Our findings support the importance of exposure to antiandrogenic phthalates during adolescence as a potential correlate of maladaptive behaviors including Externalizing Behavior, DSD behaviors, and decrements in Adaptive Skills.

Prenatal exposure to mercury in relation to infant infections and respiratory symptoms in the New Hampshire Birth Cohort Study.

BACKGROUND: Mechanistic studies support the potential for mercury (Hg) to alter immunity, including via in utero exposure. As yet, there are few prospective studies of in utero Hg exposure and subsequent immune-related outcomes, especially in infancy. OBJECTIVES: We investigated the association of biomarkers of prenatal Hg exposure and maternal silver-mercury dental amalgams with the occurrence of infant allergy, respiratory infection, and respiratory symptoms in the first year of life. METHODS: The New Hampshire Birth Cohort Study (NHBCS) ascertained information on infant allergies, infections and symptoms through telephone interviews at 4, 8 and 12 months postpartum and measured total Hg in maternal toenails collected at ~28-30 weeks gestation. Information on maternal fish consumption and presence of dental amalgams was obtained from a questionnaire administered at study enrollment at 24-28 weeks. A total of 1321 NHBCS mother-infant pairs had at least one Hg exposure measure (toenail Hg or information on dental amalgams) and information on dietary fish intake. Generalized linear models and generalized estimating equation models with Poisson regression adjusted for potential confounders (maternal age, level of education, parity, smoking, alternative Healthy Eating Index-2010, infant sex, gestational age, feeding mode, and day care attendance) were used to assess the association between infant outcomes and prenatal toenail Hg levels. We subsetted this analysis on mothers who consumed fish (n = 706) as a measure of in utero methylmercury (MeHg) exposure. Associations between infant outcomes and dental amalgams as a measure of in utero inorganic Hg exposure were assessed among mothers who did not consume fish (n = 218). RESULTS: Among women who ate fish during pregnancy, higher maternal toenail Hg concentrations were associated with an increased risk of lower respiratory infections and respiratory symptoms requiring a doctor visit among infants age 9-12 months (relative risk (RR) 1.4 (95% CI: 1.1, 1.9) and 1.2 (95% CI: 1.0, 1.4) respectively), whereas a reduced risk of lower respiratory infections was observed among infants 0-4 months of age (RR = 0.7 (95% CI: 0.5, 1.0). We found little to no evidence of associations of toenail Hg with upper respiratory infections, allergy or eczema at any age to one year. Among infants of mothers who did not consume fish, we found an elevated risk of upper respiratory infections requiring a doctor visit in relation to having dental amalgams during pregnancy (RR = 1.5 (95% CI: 1.1, 2.1)). Overall, weaker associations were observed with lower respiratory infections, respiratory symptoms, and medically confirmed allergies, and there was no association with eczema. CONCLUSIONS: Our analyses of a US birth cohort, along with prior mechanistic work, raise the possibility that gestational Hg exposure through fish/seafood consumption and dental amalgams may alter respiratory infections and respiratory symptoms in infants.

Spatial Variability in ADHD-Related Behaviors Among Children Born to Mothers Residing Near the New Bedford Harbor Superfund Site.

Attention-deficit/hyperactivity disorder (ADHD) has an uncertain etiology, with potential contributions from different risk factors such as prenatal environmental exposure to organochlorines and metals, social risk factors, and genetics. The degree to which geographic variability in ADHD is independent of, or explained by, risk factors may provide etiological insight. We investigated determinants of geographic variation in ADHD-related behaviors among children living near the polychlorinated biphenyl-contaminated New Bedford Harbor (NBH) Superfund site in Massachusetts. Participants were 573 children recruited at birth (1993-1998) who were born to mothers residing near the NBH site. We assessed ADHD-related behaviors at age 8 years using Conners' Teacher Rating Scale-Revised: Long Version. Adjusted generalized additive models were used to smooth the association of pregnancy residence with ADHD-related behaviors and assess whether prenatal organochlorine or metal exposures, sociodemographic factors, or other factors explained spatial patterns. Models that adjusted for child's age and sex displayed significantly increased ADHD-related behavior among children whose mothers resided west of the NBH site during pregnancy. These spatial patterns persisted after adjusting for prenatal exposure to organochlorines and metals but were no longer significant after controlling for sociodemographic factors. The findings underscore the value of spatial analysis in identifying high-risk subpopulations and evaluating candidate risk factors.

The influence of obesity on blood mercury levels for U.S. non-pregnant adults and children: NHANES 2007-2010.

BACKGROUND: In animal studies obesity is associated with higher blood and tissue mercury concentrations; however human studies are lacking. Although the mechanism underlying this association is uncertain, obesity may alter the metabolism and distribution of methylmercury. OBJECTIVES: We determined whether obesity influenced blood mercury levels, the majority of which was methylmercury, for U.S. non-pregnant adults (≥20 years) and children (2-19 years) after controlling for methylmercury intake through fish and shellfish consumption, and other confounders. METHODS: We completed secondary data analysis of the National Health and Nutrition Examination Survey (NHANES) (2007-2010) for participants who consumed fish/shellfish within 24h of blood collection for mercury analysis. Weighted least squares regression models related blood mercury levels (the dependent variable) to methylmercury exposure (µg) from fish consumed in the previous 24h, body mass index (BMI) (for adults), BMI z-scores (for children), and other confounders. RESULTS: In adjusted models, blood mercury levels were inversely correlated with BMI for adults [ß, 95% confidence interval (CI)=-0.54 (-0.90, -0.18)]. For children, blood mercury levels were inversely correlated with BMI z-scores but the trend was not significant [ß (95% CI)=-0.016 (-0.066, 0.035)]. When obese adults or children were compared with those who were overweight/normal weight, blood mercury averaged 22% lower for obese adults (95% CI: -33%, -8.2%), while blood mercury did not differ significantly for obese children [ß (95% CI)=-1.7% (-31%, +39%)]. CONCLUSIONS: After adjusting for the main, if not exclusive, exogenous source of methylmercury exposure (through fish/shellfish intake) and other confounders, our results support potential changes in the metabolism, distribution or excretion of methylmercury with increasing BMI (for adults).