Faculty Bibliography

Persistent organic pollutants (POPs) are believed to alter metabolic homeostasis during fetal development, leading to childhood obesity. However, limited studies have explored how fetal chemical exposures relate to birth and infant weight outcomes in low-income Hispanic families at the highest risk of obesity. Therefore, we sought to determine associations between neonatal POPs exposure measured in newborn dried blood spots (DBS) and prenatal diet quality, birth weight, and overweight status at 18 months old. We conducted a case-control study nested within the Starting Early Program randomized controlled trial comparing POPs concentrations in infants with healthy weight (n = 46) and overweight status (n = 52) at age 18 months. Three categories of POPs, organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFASs) were measured in archived newborn DBS. We assessed correlations between prenatal diet quality and neonatal POPs concentrations. Multivariable regression analyses examined associations between POPs (dichotomized at the mean) and birth weight z-score and weight status at 18 months, controlling for confounders. Seven of eight chemicals had detectable levels in greater than 94% of the sample. Higher protein, sodium and refined grain intake during pregnancy were correlated with lower POPs in newborn DBS. We found that high concentrations of perfluorooctanesulfonate (unstandardized coefficient [B]: -0.62, 95% confidence interval [CI]: -0.96 to -0.29) and perfluorohexanesulfate (B: -0.65, 95% CI: -0.99 to -0.31) were related to lower birth weight z-scores compared to those with low concentrations. We did not find associations between PBDEs, OCPs, and the other PFASs with birth weight z-scores, or between any POPs and weight status at 18 months. In conclusion, two PFASs were associated with lower birth weight, an important indicator of child health and growth, although direct associations with infant overweight status were not found. Whether neonatal POPs exposures contribute to economic and ethnic disparities in early obesity remains unclear.

BACKGROUND:Most pregnant women are exposed to bisphenols, a group of chemicals that can interfere with various components of the thyroid system. OBJECTIVES/OBJECTIVE:To investigate the association of maternal urinary bisphenol concentrations during pregnancy with maternal, newborn and early childhood thyroid function. METHODS:This study was embedded in Generation R, a prospective, population-based birth cohort (Rotterdam, the Netherlands). Maternal urine samples were analyzed for eight bisphenols at early (<18), mid (18-25) and late (>25 weeks) pregnancy. Maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and total thyroxine (TT4) were measured in early pregnancy and child TSH and FT4 were measured in cord blood and childhood. RESULTS: = 0.08). DISCUSSION/CONCLUSIONS:Our findings show that exposure to bisphenols may interfere with the thyroid system during pregnancy. Furthermore, the potential developmental toxicity of exposure to bisphenols during pregnancy could affect the thyroid system in the offspring in a sex-specific manner.

BACKGROUND:Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. METHODS AND FINDINGS/RESULTS:Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. CONCLUSIONS:Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

OBJECTIVES/OBJECTIVE:Fetal exposure to phthalates and bisphenols might have long-lasting effects on growth and fat development. Not much is known about the effects on general and organ fat development in childhood. We assessed the associations of fetal exposure to phthalates and bisphenols with general and organ fat measures in school-aged children. METHODS:In a population-based, prospective cohort study among 1128 mother-child pairs, we measured maternal urinary phthalate metabolites and bisphenol concentrations in first, second, and third trimester. Offspring body mass index, fat mass index by dual-energy X-ray absorptiometry, and visceral and pericardial fat indices and liver fat fraction were measured by magnetic resonance imaging at 10 years. RESULTS:After adjustment for confounders and correction for multiple testing, an interquartile range increase in first trimester phthalic acid concentrations remained associated with a 0.14 (95% confidence interval: 0.05, 0.22) standard deviation score increase in pericardial fat index. We also observed tendencies for associations of higher maternal low molecular weight phthalate urinary concentrations in second trimester with childhood pericardial fat index, but these were not significant after adjustment for multiple testing. High molecular weight phthalate, di-2-ethylhexyl phthalate, and di-n-octyl phthalate concentrations were not associated with childhood outcomes. Maternal urinary bisphenol concentrations were not associated with childhood adiposity. CONCLUSIONS:Maternal first trimester phthalic acid concentrations are associated with increased childhood pericardial fat index at 10 years of age, whereas maternal bisphenol concentrations are not associated with childhood adiposity. We did not find significant sex-specific effects. These findings should be considered as hypothesis generating and need further replication and identification of underlying mechanisms.

BACKGROUND AND AIMS/OBJECTIVE:Fetal exposure to endocrine disruptors such as phthalates and bisphenols may lead to developmental metabolic adaptations. We examined associations of maternal phthalate and bisphenol urine concentrations during pregnancy with lipids, insulin, and glucose concentrations at school age. METHODS:In a population-based, prospective cohort study among 757 mother-child pairs, we measured maternal phthalate and bisphenol urine concentrations in first, second and third trimester of pregnancy. We measured non-fasting lipids, glucose and insulin blood concentrations of their children at a mean age of 9.7 (standard deviation 0.2) years. Analyses were performed for boys and girls separately. RESULTS:An interquartile range (IQR) higher natural log transformed third trimester maternal urine phthalic acid concentration was associated with a 0.20 (95% confidence interval (CI) 0.07-0.34) standard deviation score (SDS) higher triglycerides concentration among boys. Maternal bisphenol urine concentrations were not associated with non-fasting lipid concentrations during childhood. An IQR higher natural log transformed second trimester maternal high molecular weight phthalates (HMWP) and di-2-ethylhexylphthalate (DEHP) urine concentration were associated with a 0.19 (95% CI 0.31-0.07) respectively 0.18 (95% CI 0.31-0.06) SDS lower glucose concentration among boys. An IQR higher natural log transformed third trimester maternal bisphenol F urine concentration was associated with a 0.22 (95% CI 0.35-0.09) SDS lower non-fasting insulin concentration among boys. CONCLUSIONS:Our results suggest potential persisting sex specific effects of fetal exposure to phthalates and bisphenols on childhood lipid concentrations and glucose metabolism. Future studies are needed for replication and exploring underlying mechanisms.

BACKGROUND:Statistical methods to study the joint effects of environmental factors are of great importance to understand the impact of correlated exposures that may act synergistically or antagonistically on health outcomes. This study proposes a family of statistical models under a unified partial-linear single-index (PLSI) modeling framework, to assess the joint effects of environmental factors for continuous, categorical, time-to-event, and longitudinal outcomes. All PLSI models consist of a linear combination of exposures into a single index for practical interpretability of relative direction and importance, and a nonparametric link function for modeling flexibility. METHODS:We presented PLSI linear regression and PLSI quantile regression for continuous outcome, PLSI generalized linear regression for categorical outcome, PLSI proportional hazards model for time-to-event outcome, and PLSI mixed-effects model for longitudinal outcome. These models were demonstrated using a dataset of 800 subjects from NHANES 2003-2004 survey including 8 environmental factors. Serum triglyceride concentration was analyzed as a continuous outcome and then dichotomized as a binary outcome. Simulations were conducted to demonstrate the PLSI proportional hazards model and PLSI mixed-effects model. The performance of PLSI models was compared with their counterpart parametric models. RESULTS:PLSI linear, quantile, and logistic regressions showed similar results that the 8 environmental factors had both positive and negative associations with triglycerides, with a-Tocopherol having the most positive and trans-b-carotene having the most negative association. For the time-to-event and longitudinal settings, simulations showed that PLSI models could correctly identify directions and relative importance for the 8 environmental factors. Compared with parametric models, PLSI models got similar results when the link function was close to linear, but clearly outperformed in simulations with nonlinear effects. CONCLUSIONS:We presented a unified family of PLSI models to assess the joint effects of exposures on four commonly-used types of outcomes in environmental research, and demonstrated their modeling flexibility and effectiveness, especially for studying environmental factors with mixed directional effects and/or nonlinear effects. Our study has expanded the analytical toolbox for investigating the complex effects of environmental factors. A practical contribution also included a coherent algorithm for all proposed PLSI models with R codes available.

BACKGROUND:Experimental evidence suggests that exposures to phthalates and bisphenols may interfere with processes related to glucose and lipid metabolism, insulin sensitivity, and body weight. Few studies have considered the possible influence of chemical exposures during pregnancy on maternal weight gain or metabolic health outcomes postpartum. OBJECTIVE:To examine the associations of early and mid-pregnancy bisphenol and phthalate urine concentrations with maternal weight gain 6 years postpartum. METHODS:We analyzed urine samples for bisphenol, phthalate and creatinine concentrations from early and mid-pregnancy in 1192 women in a large, population-based birth cohort in Rotterdam, the Netherlands, and examined postpartum weight gain using maternal anthropometrics before pregnancy and 6 years postpartum. We have used covariate-adjusted linear regressions to evaluate associations of early and mid-pregnancy bisphenols and phthalate metabolites with weight change. Mediator and interaction models have been used to assess the role of gestational weight gain and breastfeeding, respectively. Sensitivity analysis is performed among women without subsequent pregnancies. RESULTS:Among all 1192 mothers included in the analysis, each log unit increase in the average bisphenol A and all assessed phthalate groupings were associated with increased maternal weight gain. As a proxy for phthalate exposure, each log unit increase in averaged phthalic acid was associated with 734 g weight gain (95% CI 273-1196 g) between pre-pregnancy and 6 years postpartum. Mediation by gestational weight gain was not present. Breastfeeding and ethnicity did not modify the effects. Stratification revealed these associations to be strongest among overweight and obese women. Among women without subsequent pregnancies (n = 373) associations of bisphenols, HMW phthalate metabolites and di-2-ethylhexylphthalate metabolites attenuated. For phthalic acid, LMW phthalate metabolites and di-n-octylphthalate metabolites associations increased. Similarly to the whole group, stratification yielded significant results among overweight and obese women. DISCUSSION/CONCLUSIONS:In a large population-based birth cohort, early and mid-pregnancy phthalate exposures are associated with weight gain 6 years postpartum, particularly among overweight and obese women. These data support ongoing action to replace phthalates with safer alternatives.

BACKGROUND:Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS/RESULTS:We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS:We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.