Faculty Bibliography

Experimental studies suggest that prenatal exposure to endocrine disrupting chemicals interferes with developmental processes in the fetal brain. Yet, epidemiological evidence is inconclusive. In a birth cohort (2008-2010, upstate New York), we quantified concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and bisphenol A (BPA) in stored newborn dried blood spots using liquid chromatography/tandem mass spectrometry. Mothers reported on children's behavior using the Strengths and Difficulties Questionnaire at age 7 (650 singletons and 138 twins). Difficulties in total behavior (i.e., emotional, conduct, hyperactivity, and peer problems) and prosocial behavior were classified using validated cut-offs. We used logistic regression with generalized estimating equations to estimate the odds of having difficulties per exposure category. In total, 111 children (12.1%) had total behavioral difficulties and 60 (6.5%) had difficulties in prosocial behavior. The median (interquartile range) of PFOS, PFOA, and BPA were 1.74 ng/ml (1.33), 1.12 ng/ml (0.96), and 7.93 ng/ml (10.79), respectively. Higher PFOS levels were associated with increased odds of having behavioral difficulties (OR per SD of log PFOS = 1.30, 95%CI: 1.03-1.65). We observed associations between PFOS in the highest relative to the lowest quartile and behavioral difficulties (OR for PFOS_1.14-1.74 = 1.65, 95%CI: 0.84-3.34; PFOS_1.75-2.47 = 1.73, 95%CI: 0.87-3.43; and PFOS_>2.47 = 2.47, 95%CI: 1.29-4.72 compared to PFOS_<1.41). The associations between higher concentrations of PFOS and behavioral difficulties at age 7 years were driven by problems in conduct and emotional symptoms. Higher PFOA levels were associated with difficulties in prosocial behavior (OR = 1.35, 95%CI: 1.03-1.75). There was an inverse association between BPA concentrations and difficulties in prosocial behavior but only in the 2nd and 4th quartiles. We found no interactions between sex and chemical concentrations. Increasing prenatal exposure to PFOS and PFOA, as reflected in neonatal concentrations, may pose risk for child behavioral difficulties.

BACKGROUND:Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear. METHODS:We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations. RESULTS:Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF-AA. Analyses with developmental service use revealed similar null findings. CONCLUSIONS:Immune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood.

BACKGROUND:Exposure to air pollution during pregnancy may increase attention-deficit/ hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS:Air pollution concentrations [nitrogen dioxide (NO2) and particulate matter (PM)] were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cut-offs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputation and applied inverse probability weighting methods to correct for loss to follow-up. RESULTS:We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio (OR) for ADHD symptoms of 0.95, 95% confidence interval (CI) 0.89-1.01 per 10µg/m increase in NO2 and 0.98, 95%CI 0.80-1.19 per 5µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS:There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3 to 10 years.

Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3-4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.

Gestational inflammation may contribute to brain abnormalities associated with childhood neuropsychiatric disorders. Limited knowledge exists regarding the associations of maternal cytokine levels during pregnancy with offspring neurocognitive development. We assayed the concentrations of five cytokines (interleukin (IL)-6, IL-1β, IL-8, tumor necrosis factor alpha (TNF-α), and IL-10) up to four times in the 2nd and 3rd trimesters of pregnancy using stored prenatal sera from 1366 participants in the New England Family Study (enrollment 1959-1966). Intelligence (IQ), academic achievement, and neuropsychological functioning of singleton offspring were assessed at age 7 years using standardized tests. We used linear mixed models with random effects to estimate the cumulative exposure to each cytokine during 2nd and 3rd trimesters, and then related cumulative cytokine exposure to a wide range of offspring neurocognitive outcomes. We found that children of women with higher levels of the pro-inflammatory cytokine, TNF-α, in the 2nd and 3rd trimesters had lower IQ (B = -2.51, 99% CI: -4.84,-0.18), higher problem scores in visual-motor maturity (B = 0.12, 99% CI: 0.001,0.24), and lower Draw-a-Person test scores (B = -1.28, 99% CI: -2.49,-0.07). Higher gestational levels of IL-8, another pro-inflammatory molecule, were associated with better Draw-a-Person test scores and tactile finger recognition scores. Other cytokines were not associated with our outcome of interest. The opposing directions of associations observed between TNF-α and IL-8 with childhood outcomes suggest pleiotropic effects of gestational inflammation across the domains of neurocognitive functioning. Although the path to psychopathological disturbances in children is no doubt multifactorial, our findings point to a potential role for immune processes in the neurocognitive development of children.

Using a population-based birth cohort in upstate New York (2008-2010), we examined the determinants of brain-derived neurotrophic factor (BDNF) measured in newborn dried blood spots (n = 2,637). We also examined the association between neonatal BDNF and children's development. The cohort was initially designed to examine the influence of infertility treatment on child development but found no impact. Mothers rated children's development in five domains repeatedly through age 3 years. Socioeconomic and maternal lifestyle determinants of BDNF were examined using multivariable linear regression models. Generalized linear mixed models estimated odds ratios for neonatal BDNF in relation to failing a developmental domain. Smoking and drinking in pregnancy, nulliparity, non-White ethnicity/race, and prepregnancy obesity were associated with lower neonatal BDNF. Neonatal BDNF was not associated with failure for developmental domains; however, there was an interaction between BDNF and preterm birth. In preterm infants, a higher BDNF was associated with lower odds of failing any developmental domains, after adjusting for confounders and infertility treatment. This result was particularly significant for failure in communication. Our findings suggest that BDNF levels in neonates may be impacted by maternal lifestyle characteristics. More specifically, lower neonatal BDNF might be an early marker of aberrant neurodevelopment in preterm infants.

Children raised in economically disadvantaged households face increased risks of poor health in adulthood, suggesting that inequalities in health have early origins. From the child's perspective, exposure to economic hardship may begin as early as conception, potentially via maternal neuroendocrine-immune responses to prenatal stressors, which adversely impact neurodevelopment. Here we investigate whether socioeconomic disadvantage is associated with gestational immune activity and whether such activity is associated with abnormalities among offspring during infancy. We analyzed concentrations of five immune markers (IL-1β, IL-6, IL-8, IL-10, and TNF-α) in maternal serum from 1,494 participants in the New England Family Study in relation to the level of maternal socioeconomic disadvantage and their involvement in offspring neurologic abnormalities at 4 mo and 1 y of age. Median concentrations of IL-8 were lower in the most disadvantaged pregnancies [-1.53 log(pg/mL); 95% CI: -1.81, -1.25]. Offspring of these pregnancies had significantly higher risk of neurologic abnormalities at 4 mo [odds ratio (OR) = 4.61; CI = 2.84, 7.48] and 1 y (OR = 2.05; CI = 1.08, 3.90). This higher risk was accounted for in part by fetal exposure to lower maternal IL-8, which also predicted higher risks of neurologic abnormalities at 4 mo (OR = 7.67; CI = 4.05, 14.49) and 1 y (OR = 2.92; CI = 1.46, 5.87). Findings support the role of maternal immune activity in fetal neurodevelopment, exacerbated in part by socioeconomic disadvantage. This finding reveals a potential pathophysiologic pathway involved in the intergenerational transmission of socioeconomic inequalities in health.

BACKGROUND:Maternal retinol-binding protein 4 (RBP4) and lipids may relate to preeclampsia and preterm birth risk but longitudinal data are lacking. This study examines these biomarkers longitudinally during pregnancy in relation to preeclampsia and preterm birth risk. METHODS:Maternal serum samples from the Calcium for Preeclampsia Prevention (CPEP) trial were analyzed at baseline: average 15 gestational weeks; mid-pregnancy: average 27 weeks; and at >34 weeks. We measured RBP4, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides and lipoprotein (a) (Lp(a)). Cross-sectional logistic regression analyses estimated the odds ratio (OR) and 95% confidence intervals (CI) for preterm preeclampsia (n = 63), term preeclampsia (n = 104), and preterm delivery (n = 160) associated with RBP4 and lipids at baseline and mid-pregnancy compared with controls (n = 136). Longitudinal trajectories across pregnancy were assessed using mixed linear models with fixed effects. Adjusted models included clinical and demographic factors. RESULTS:RBP4 concentrations at baseline and mid-pregnancy were associated with a 4- to 8-fold increase in preterm preeclampsia risk but were not associated with term preeclampsia. RBP4 measured mid-pregnancy was also associated with preterm birth (OR = 6.67, 95% CI: 1.65, 26.84). Higher triglyceride concentrations in mid-pregnancy were associated with a 2- to 4-fold increased risk for both preeclampsia and preterm birth. Longitudinal models demonstrate that both preterm preeclampsia and preterm birth cases had elevated RBP4 throughout gestation. CONCLUSIONS:Elevated RBP4 is detectable early in pregnancy and its strong relation with preterm preeclampsia merits further investigation and confirmation to evaluate its potential use as a predictor, particularly among high-risk women.