Associations of Perinatal Metal and Metalloid Exposures with Early Child Behavioral Development Over Time in the New Hampshire Birth Cohort Study.

Research on the neurodevelopmental effects of metal(loid)s has focused mainly on outcomes assessed at one time point, even though brain development progresses over time. We investigated biomarkers of perinatal exposure to metals and changes in child behavior over time. We followed 268 participants from the prospective New Hampshire Birth Cohort Study between birth and age 5 years. We measured arsenic (As), copper (Cu), manganese (Mn), lead (Pb), selenium (Se), and zinc (Zn) in toenails from 6-week-old infants. The Behavioral Symptoms Index (BSI), externalizing, and internalizing symptoms were assessed using the Behavior Assessment System for Children, 2nd edition (BASC-2) at ages 3 and 5 years. Multivariable linear regression was used to estimate associations of metals with behavior change, calculated as the difference in symptom raw scores between 3 and 5 years, in addition to the associations for symptom scores at 3 and 5 years separately. Sex-specific associations were also explored using stratified models and a sex-metal interaction term. Adjusted associations of metals and change in behavior varied by exposure and outcome. Each 1 µg/g increase in ln toenail Cu was associated with improved behavior between 3 and 5 years [BSI: ß = - 3.88 (95%CI: - 7.12, - 0.64); Externalizing problems: ß = - 2.20 (95%CI: - 4.07, - 0.33)]. Increasing Zn was associated with increased externalizing behavior over time (ß = 3.42 (95%CI: 0.60, 6.25). Sex-stratified analyses suggested more pronounced associations among boys compared to girls. Perinatal exposure to metals may alter behavioral development between ages 3 and 5 years. Findings support the need for more research on associations between metals and neurodevelopment over longer time periods.

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 asthma acute care clinical encounters (hospitalization, emergency department visit, observational stay) using conditional logistic regression with a multivariable smooth 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) were followed through 2011 using the Massachusetts Pregnancy to Early Life Longitudinal data system to identify children ages 5-11 with asthma acute care clinical encounters (265 cases among 7,787 with follow-up). Hazard ratios (HRs) were higher for children living closer to the NBH with higher cord blood Pb levels than children living further away from the NBH with lower Pb levels (P<0.001). HRs were highest for girls (HR=4.17, 95% CI: 3.60, 4.82) compared to boys (HR=1.72, 95% CI: 1.46, 2.02). Our results suggest that prenatal Pb exposure in combination with residential proximity to the NBH is associated with childhood asthma acute care clinical encounters.

Urinary biomarkers of exposure to toxic and essential elements: A comparison of infants fed with human milk or formula.

Background: Early-life exposure to nonessential (toxic) and essential trace elements can influence child development. Although infant formula powders and the water used to reconstitute them can contain higher concentrations of many elements compared with human milk, the influence of feeding mode on reliable biomarkers of infant exposure has rarely been demonstrated. Methods: We evaluated associations between urinary biomarkers and feeding mode (exclusively human milk, exclusively formula, or combination-fed) for four toxic (arsenic, cadmium, nickel, and uranium) and three essential elements (cobalt, molybdenum, and selenium) using general linear models. Results: A total of 462 participants from the rural New Hampshire Birth Cohort Study were on average 6 weeks old between July 2012 and March 2019 and had urine samples, 3-day food diaries, and relevant covariate data available. In adjusted models, urinary arsenic was 5.15 (95% confidence interval = 4.04, 6.58), molybdenum was 19.02 (14.13-25.59), and selenium was 1.51 (1.35-1.68) times higher in infants fed exclusively with formula compared with infants fed exclusively with human milk. By contrast, urinary uranium was 0.59 (0.46-0.75) and cobalt was 0.78 (0.65-0.95) times lower with formula feeding than human milk feeding. Conclusion: Our findings suggest that infant exposure to several potentially toxic elements varies by feeding mode, as concentrations of reliable urinary biomarkers were higher with formula or human milk, depending on the element. Importantly, exposure to arsenic increased with household tap water arsenic regardless of feeding mode, suggesting that all infants could be at risk in populations with high concentrations of arsenic in drinking water.

Pubertal progression in relation to peripubertal exposure to organochlorine chemicals in a cohort of Russian boys.

Background: Peripubertal concentrations of serum dioxins and polychlorinated biphenyls (PCBs) have demonstrated associations with altered age of pubertal onset and sexual maturity in boys, but associations with pubertal progression have received less attention. Methods: The Russian Children's Study is a prospective cohort of 516 boys enrolled in 2003-2005 at age 8 or 9 and followed annually up to 19 years of age. Serum concentrations of dioxin-like toxic equivalents (TEQs), polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and non-dioxin-like PCBs (NDL-PCBs) and whole blood lead levels (BLLs) were quantified from blood samples collected at study entry (age 8-9). Testicular volume (TV) was assessed annually using a Prader orchidometer. Pubertal trajectories were identified by applying Group-Based Trajectory Models (GBTMs) to TV measured from ages 8-19. Associations of peripubertal serum TEQs, PCDDs, PCDFs, and NDL-PCBs with specific progression trajectories were modeled using multinomial logistic regression, adjusting for each boy's birthweight, and for BLL, body mass index and nutritional factors at study entry. Results: Among 489 eligible boys with available exposure measures, we identified three pubertal trajectories using GBTMs: slower (34% of boys), moderate (48%) and faster (18%). Boys with higher peripubertal serum TEQs had higher adjusted odds of being in the moderate versus faster trajectory (adjusted odds ratio (aOR) 1.79, 95% CI 1.01, 3.13) and the slower versus faster trajectory (aOR 1.52, 95% CI 0.82, 2.78) per 1 log unit increase in serum TEQs. Boys with higher peripubertal serum PCDFs had higher adjusted odds of being in the moderate compared to the faster trajectory (aOR 1.92, 95% CI 1.20, 3.03) and of being in the slower versus the faster trajectory (aOR 1.42, 95% CI 0.91, 2.33) per 1 log unit increase. Boys with higher NDL-PCBs had higher adjusted odds of being in the faster trajectory versus the moderate (aOR 2.56, 95% CI 0.91-7.20) or slower (aOR 3.31, 95% CI 1.07, 10.25) trajectory. Boys with higher blood lead levels also had higher adjusted odds of being in the slower trajectory of pubertal progression, compared to either the faster (aOR 1.47, 95% CI 0.89, 2.44) or moderate (aOR 1.20, 95% CI 0.83, 1.75) trajectories, per 1 log unit increase in BLL, although these associations did not attain statistical significance. Conclusion: Boys' peripubertal exposure to dioxins and certain PCBs may alter pubertal progression.

Bacterial Modification of the Association Between Arsenic and Autism-Related Social Behavior Scores.

Arsenic is related to neurodevelopmental outcomes and is associated with the composition of the gut microbiome. Data on the modifying role of the microbiome are limited. We probed suggestive relationships between arsenic and social behaviors to quantify the modifying role of the infant gut microbiome. We followed children for whom arsenic concentrations were quantified in 6-week-old toenail clippings. Scores on the Social Responsiveness Scale (SRS-2), which measures autism-related social behaviors, were provided by caregivers when the child was approximately 3 years of age. Metagenomic sequencing was performed on infant stools collected at 6 weeks and 1 year of age. To evaluate modification by the top ten most abundant species and functional pathways, we modeled SRS-2 total T-scores as a function of arsenic concentrations, microbiome features dichotomized at their median, and an interaction between exposure and the microbiome, adjusting for other trace elements and sociodemographic characteristics. As compared to the standardized population (SRS-2 T-scores = 50), participants in our study had lower SRS-2 scores (n = 78, mean = 44, SD = 5).The relative abundances of several functional pathways identified in 6-week stool samples modified the arsenic-SRS-2 association, including the pathways of valine and isoleucine biosynthesis; we observed no association among those with high relative abundance of each pathway [ß = - 0.67 (95% CI - 1.46, 0.12)], and an adverse association [ß = 1.67 (95% CI 0.3, 3.04), pinteraction= 0.05] among infants with low relative abundance. Our findings indicate the infant gut microbiome may alter neurodevelopmental susceptibility to environmental exposures.

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.

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.

Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. OBJECTIVES: We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. METHODS: We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. RESULTS: We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of ß=-0.15 [95% confidence interval (CI): -0.27, -0.03], ß=-0.14 (95% CI: -0.28, -0.002), ß=-0.22 (95% CI: -0.23, -0.10), ß=-0.06 (95% CI: -0.18, 0.06), and ß=-0.25 (95% CI: -0.37, -0.14), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: ORPFNA=0.56 (95% CI: 0.38, 0.83), ORPFDA=0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [-0.28; 95% highest posterior density (HPD): -0.44, -0.14] and decreased odds of large-for-gestational-age (OR=0.49; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. DISCUSSION: Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

Associations of Prenatal Chemical and Nonchemical Stressors with Early-Adulthood Anxiety and Depressive Symptoms.

BACKGROUND: Prenatal exposure to environmental chemicals may increase risk of childhood internalizing problems, but few studies have explored the potential for longer-term consequences of such exposures. OBJECTIVE: We evaluated associations between prenatal organochlorine and metal levels and early adulthood internalizing symptoms, considering whether sociodemographic/nonchemical stressors modified these associations. METHODS: Participants were 209 young adults, born (1993-1998) to mothers residing in or near New Bedford, Massachusetts. As part of the early-adult assessment, self-reported anxiety (7-item Generalized Anxiety Disorder scale) and depressive (8-item Patient Health Questionnaire) symptoms (≥10: elevated symptoms) were ascertained. We previously analyzed levels of cord serum organochlorines [hexachlorobenzene, dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyls (ΣPCB4: sum of congeners 118, 138, 153, 180)] and whole blood lead shortly after participants' birth, and levels of cord whole blood manganese from archived samples at the time of the adolescent study visit. We used modified Poisson regression models and quantile g-computation, adjusting for sociodemographics, and explored whether biological sex, race/ethnicity (proxy for unmeasured consequences of racism), prenatal social disadvantage (assessed when participants were neonates), and quality of the home environment (assessed during adolescence) modified these associations. RESULTS: Participants were (mean±standard deviation) 22.1±1.5 y old, 76% Non-Hispanic White, and 67% female. Prenatal hexachlorobenzene, p,p'-DDE, and lead exposures were moderately associated with increased risk of elevated anxiety symptoms. There were strata-specific associations for prenatal social disadvantage and quality of home environment such that adverse associations of p,p'-DDE and lead and the overall mixture with anxiety and depressive symptoms were largely only evident in those with lower nonchemical stress [e.g., risk ratio and 95% confidence interval (CI) per doubling p,p'-DDE for anxiety: 1.54 (95% CI: 1.20, 1.99) in high-quality home environments and 0.77 (95% CI: 0.51, 1.16) in low-quality home environments]. Associations between prenatal hexachlorobenzene and p,p'-DDE and anxiety symptoms were stronger for underrepresented racial/ethnic group participants vs. Non-Hispanic Whites. We found minimal evidence for sex-specific effects, and no consistent associations with manganese or ΣPCB4. DISCUSSION: Prenatal organochlorine pesticides and lead exposure possibly increases risk of internalizing problems, particular anxiety symptoms, in young adults. Varying risk was observed by sociodemographic/nonchemical stressor strata, demonstrating the importance of considering interactions between chemical and other stressors. https://doi.org/10.1289/EHP11171.

Early pregnancy essential and non-essential metal mixtures and maternal antepartum and postpartum depressive symptoms.

BACKGROUND: Mood disorders are common during and after pregnancy, and environmental metals may contribute to increased risk. Antepartum metal exposures have not been well characterized in relation to maternal depression. We evaluated the extent to which early pregnancy erythrocyte concentrations of essential and non-essential metals were prospectively associated with antepartum and postpartum depressive symptoms. METHODS: Participants were 1226 women in Project Viva, a longitudinal cohort recruited during pregnancy (1999-2002). We measured concentrations of 11 metals in maternal first trimester erythrocytes (arsenic, barium, cadmium, cesium, copper, mercury, magnesium, manganese, lead, selenium, zinc). Using the Edinburgh Postnatal Depression Scale (EPDS), we assessed elevated depressive symptoms (≥13; 0-30 scale) at mid-pregnancy and at 6 and 12 months postpartum. We applied latent class mixed modeling to identify symptom trajectories. Adjusting for maternal sociodemographics and co-exposures, we examined associations between the metal mixture and depressive symptoms using logistic (for EPDS≥13)/multinomial (for symptom trajectories) regression and quantile g-computation. RESULTS: In this cohort of moderately high socioeconomic status participants (e.g., 72 % college graduate), low-level metal concentrations were weakly to moderately correlated (Spearman: -0.24 to 0.59); the prevalence of depressive symptoms ranged from 9 % (mid-pregnancy) to 6 % (12 months postpartum); and three trajectories (stable low; elevated mid-pregnancy, then decreasing; moderate mid-pregnancy, then increasing) best fit the EPDS data. The early pregnancy erythrocyte metal mixture was not associated with maternal depressive symptoms in logistic, multinomial, or mixture models. For individual metals, most confidence intervals (CI) included the null. There was weak evidence that arsenic, lead, and selenium were moderately associated with elevated odds of depressive symptoms and/or trajectories. However, the odds ratios (95 % CI) per doubling of these three metals were imprecise [e.g., arsenic: 1.13 (0.94, 1.40) for EPDS≥13 at six months postpartum; lead: 1.19 (0.80, 1.77) for EPDS≥13 at mid-pregnancy; selenium: 2.35 (0.84, 6.57) for elevated mid-pregnancy, then decreasing versus stable low trajectory]. DISCUSSION: We did not observe strong, consistent evidence of associations between early pregnancy erythrocyte metal concentrations and subsequent maternal antepartum and postpartum depressive symptoms.

In utero arsenic exposure and early childhood motor development in the New Hampshire Birth Cohort Study.

Introduction: High-level prenatal and childhood arsenic (As) exposure characteristic of several regions in Asia (e.g., Bangladesh), may impact motor function. However, the relationship between lower-level arsenic exposure (characteristic of other regions) and motor development is largely unstudied, despite the potential for deficient motor skills in childhood to have adverse long-term consequences. Thus, we sought to investigate the association between prenatal As exposure and motor function among 395 children in the New Hampshire Birth Cohort Study, a rural cohort from northern New England. Methods: Prenatal exposure was estimated by measuring maternal urine speciated As at 24-28 weeks of gestation using high-performance liquid chromatography (HPLC) inductively coupled plasma mass spectrometry (ICP-MS) and summing inorganic As, monomethylarsonic acid, and dimethylarsinic acid to obtain total urinary As (tAs). Motor function was assessed with the Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) at a mean (SD) age of 5.5 (0.4) years. Results: Children who completed this exam were largely reported as white race (97%), born to married mothers (86%) with a college degree or higher (67%). The median (IQR) gestational urine tAs concentration was 4.0 (5.0) µg/L. Mean (SD) BOT-2 scores were 48.6 (8.4) for overall motor proficiency and 48.2 (9.6) for fine manual control [standard score = 50 (10)], and were 16.3 (5.1) for fine motor integration and 12.5 (4.1) for fine motor precision [standard score = 15 (5)]. We found evidence of a non-linear dose response relationship and used a change-point model to assess the association of tAs with overall motor proficiency and indices of fine motor integration, fine motor precision, and their composite, fine manual control, adjusted for age and sex. In models adjusted for potential confounders, each doubling of urine tAs decreased overall motor proficiency by -3.3 points (95% CI: -6.1, -0.4) for tAs concentrations greater than the change point of 9.5 µg/L and decreased fine motor integration by -4.3 points (95% CI: -8.0, -0.6) for tAs concentrations greater than the change point of 17.0 µg/L. Discussion: In summary, we found that levels of prenatal As exposure above an empirically-derived threshold (i.e., the change point) were associated with decrements in childhood motor development in a US population.

The association of prenatal manganese exposure with problem-solving skills and its mediation by the building blocks of executive function.

BACKGROUND: Problem-solving skills build upon three core executive functions: inhibition, working memory, and cognitive flexibility. There is evidence of adverse associations of prenatal exposure to manganese (Mn) with core executive functions, but less is known about Mn associations with problem-solving or potential mediators of this association. OBJECTIVES: This study aimed to investigate the association of prenatal Mn exposure with problem-solving and to identify potential neuropsychological mechanisms through which this association may be mediated. METHODS: Study participants were 410 adolescents from the New Bedford Cohort (NBC) who have undergone periodic evaluations since their birth (1993-1998) to mothers residing near a Massachusetts Superfund site. We investigated the association of cord blood Mn with problem-solving measured by the Delis-Kaplan Executive Function System (D-KEFS) Sorting and Tower subtests (scores scaled to a mean ± SD of 10 ± 3) using multivariable linear regression. Inhibition and cognitive flexibility were also measured by the D-KEFS; working memory was measured with the Wide Range Assessment of Memory and Learning, 2nd edition. Regression-based causal mediation analysis was used to assess the proportion of the Mn-problem-solving association mediated by inhibition, working memory, and cognitive flexibility individually and jointly. RESULTS: NBC adolescents (mean age 15.5 years) were socio-demographically diverse with 31 % in a low-income household at birth and had cord blood Mn concentrations similar to other general population samples. Mn was associated with Sorting but not Tower scores. Specifically, a doubling of cord blood Mn concentrations was associated with - 0.59 points lower (95 % CI: -1.16, -0.03) Sort Recognition score. In mediation analyses, there was suggestive evidence that inhibition, working memory, and cognitive flexibility combined mediated 30 % of the total effect of Mn on Sorting. When analyzed individually, working memory mediated a larger proportion (24 %) of the effect than inhibition or cognitive flexibility. DISCUSSION: We observed adverse associations of cord blood Mn with problem-solving among adolescents. There was suggestive evidence that the building blocks of executive function jointly, and working memory individually, were potentially important mediators of this association.

Urinary phthalate metabolite concentrations during four windows spanning puberty (prepuberty through sexual maturity) and association with semen quality among young Russian men.

AIM: To prospectively investigate the associations of urinary phthalate metabolite concentrations measured at four time points spanning pubertal development with semen parameters in Russian men. DESIGN: 516 boys were enrolled at ages 8-9 years (2003-2005) and followed annually. METHODS: Urine samples were collected annually and pooled into four exposure windows [prepuberty, early puberty, late puberty and sexual maturity] based on physician assessed Tanner genitalia stages and testicular volume. Fifteen phthalate metabolites were quantified using isotope dilution HPLC-MS/MS at Moscow State University. We calculated molar sums (∑) of di-2-ethylhexyl phthalate (DEHP), di-isononyl phthalate (DiNP), di-isodecyl phthalate (DiDP) and anti-androgenic phthalate (AAP) metabolites. At sexual maturity (ages 18-19 years), the men provided 1-2 semen samples for analysis. We estimated the associations of quintiles of urinary ∑phthalate metabolites as well as mono-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), and mono-benzyl phthalate (MBzP) at each pubertal window, with semen parameters by fitting generalized linear mixed models with random intercepts and adjusting for confounders. RESULTS: A total of 223 men who provided semen samples had phthalates measured at one or more pubertal windows. Higher urinary concentrations of ∑DiNP metabolites during late puberty were related to poorer semen quality (men with the highest quintile of urinary ∑DiNP had 30% lower sperm concentration, 32% lower count and 30% lower progressive motile count, compared to men in the lowest quintile). Also, young men with higher urinary concentrations of MiBP metabolites in early puberty tended to have poorer semen quality. No associations were observed for ∑DEHP metabolites, ∑DiDP metabolites, ∑AAP, MBzP or MnBP metabolites with semen quality parameters. CONCLUSIONS: ∑DiNP metabolites measured during late puberty and MiBP metabolites at early puberty were related to poorer semen quality, highlighting the importance of considering specific windows of exposure when investigating chemical exposures in relation to measures of reproductive health in men.

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.

Maternal tobacco smoking and offspring autism spectrum disorder or traits in ECHO cohorts.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

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.

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.

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.