Faculty Bibliography

Perfluoroalkyl substances (PFAS) are widely distributed suspected obesogens that cross the placenta. However, few data are available to assess potential fetal effects of PFAS exposure on children's adiposity in diverse populations. To address the data gap, we estimated associations between gestational PFAS concentrations and childhood adiposity in a diverse mother-child cohort. We considered 6 PFAS in first trimester blood plasma, measured using ultra-high-performance liquid chromatography with tandem mass spectrometry, collected from non-smoking women with low-risk singleton pregnancies (n = 803). Body mass index (BMI), waist circumference (WC), fat mass, fat-free mass, and % body fat were ascertained in 4-8 year old children as measures of adiposity. We estimated associations of individual gestational PFAS with children's adiposity and overweight/obesity, adjusted for confounders. There were more non-Hispanic Black (31.7 %) and Hispanic (42.6 %) children with overweight/obesity, than non-Hispanic white (18.2 %) and Asian/Pacific Islander (16.4 %) children (p < 0.0001). Perfluorooctane sulfonate (PFOS; 5.3 ng/mL) and perfluorooctanoic acid (2.0 ng/mL) had the highest median concentrations in maternal blood. Among women without obesity (n = 667), greater perfluoroundecanoic acid (PFUnDA) was associated with their children having higher WC z-score (β = 0.08, 95%CI: 0.01, 0.14; p = 0.02), fat mass (β = 0.55 kg, 95%CI: 0.21, 0.90; p = 0.002), and % body fat (β = 0.01 %; 95%CI: 0.003, 0.01; p = 0.004), although the association of PFUnDA with fat mass attenuated at the highest concentrations. Among women without obesity, the associations of PFAS and their children's adiposity varied significantly by self-reported race-ethnicity, although the direction of the associations was inconsistent. In contrast, among the children of women with obesity, greater, PFOS, perfluorononanoic acid, and perfluorodecanoic acid concentrations were associated with less adiposity (n = 136). Our results suggest that specific PFAS may be developmental obesogens, and that maternal race-ethnicity may be an important modifier of the associations among women without obesity.

Vitamin D has been linked to various physiological functions in pregnant women and their fetuses. Previous studies have suggested that some per- and polyfluoroalkyl substances (PFAS) may alter serum vitamin D concentrations. However, no study has investigated the relationship between PFAS and vitamin D in pregnant women. This study aims to evaluate the associations of serum PFAS with serum total and free 25-hydroxyvitamin D (25(OH)D) during pregnancy in a cohort of African American women in Atlanta, GA. Blood samples from 442 participants were collected in early pregnancy (8-14 weeks of gestation) for PFAS and 25(OH)D measurements, and additional samples were collected in late pregnancy (24-30 weeks) for the second 25(OH)D measurements. We fit multivariable linear regressions and weighted quantile sum (WQS) regressions to estimate the associations of individual PFAS and their mixtures with 25(OH)D concentrations. We found mostly positive associations of total 25(OH)D with PFHxS (perfluorohexane sulfonic acid), PFOS (perfluorooctane sulfonic acid), PFDA (perfluorodecanoic acid), and NMeFOSAA (N-methyl perfluorooctane sulfonamido acetic acid), and negative associations with PFPeA (perfluoropentanoic acid). For free 25(OH)D, positive associations were observed with PFHxS, PFOS, PFOA (perfluorooctanoic acid), and PFDA, and a negative association with PFPeA among the women with male fetuses in the models using 25(OH)D measured in late pregnancy. In mixture models, a quartile increase in WQS index was associated with 2.88 ng/mL (95%CI 1.14-4.59) and 5.68 ng/mL (95%CI 3.31-8.04) increases in total 25(OH)D measured in the early and late pregnancy, respectively. NMeFOSAA, PFDA, and PFOS contributed the most to the overall effects among the eight PFAS. No association was found between free 25(OH)D and the PFAS mixture. These results suggest that PFAS may affect vitamin D biomarker concentrations in pregnant African American women, and some of the associations were modified by fetal sex.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants. Urinary concentrations of mono-hydroxylated metabolites of PAHs (OH-PAHs) have been used as biomarkers of these chemicals' exposure in humans. Little is known, however, with regard to intra- and inter-individual variability in OH-PAH concentrations and their association with oxidative stress. We conducted a longitudinal study of measurement of urinary concentrations of 15 OH-PAHs and 7 oxidative stress biomarkers (OSBs) of DNA damage [8-hydroxy-2'-deoxyguanosine (8-OHdG)], lipid [malondialdehyde (MDA) and F₂-isoprostanes (PGF_2α)] and protein [o,o'-dityrosine (diY)] peroxidation in 19 individuals for 44 consecutive days. Metabolites of naphthalene (OHNap), fluorene (OHFlu), phenanthrene (OHPhe), and pyrene (OHPyr) were found in >70% of 515 urine samples analyzed, at sum concentrations (∑OH-PAH) measured in the range of 0.46-60 ng/mL. After adjusting for creatinine, OHNap and ∑OH-PAH concentrations exhibited moderate predictability, with intra-class correlation coefficients (ICCs) ranging from 0.359 to 0.760. However, ICC values were low (0.001-0.494) for OHFlu, OHPhe, and OHPyr, which suggested poor predictability for these PAH metabolites. Linear mixed-effects analysis revealed that an unit increase in ∑OH-PAH concentration corresponded to 4.5%, 5.3%, 20%, and 21% increase in respective urinary 8-OHdG, MDA, PGF_2α, and diY concentrations, suggesting an association with oxidative damage to DNA, lipids, and proteins. The daily intakes of PAHs, calculated from urinary concentrations of OH-PAHs, were 10- to 100-fold below the current reference doses. This study provides valuable information to design sampling strategies in biomonitoring studies and in assigning exposure classifications of PAHs in epidemiologic studies.

CONTEXT/BACKGROUND:Postpartum depression (PPD) is a serious psychiatric disorder. While causes remain poorly understood, perinatal sex hormone fluctuations are an important factor, and allopregnanolone in particular has emerged as a key determinant. While synthetic environmental chemicals such as bisphenols and phthalates are known to affect sex hormones, no studies have measured allopregnanolone and the consequences of these hormonal changes on PPD have not been interrogated. OBJECTIVE:To investigate associations of repeated measures of urinary bisphenols and phthalates in early- and mid-pregnancy with serum pregnenolone, progesterone, allopregnanolone, and pregnanolone concentrations in mid-pregnancy and PPD symptoms at four months postpartum. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION/UNASSIGNED:Prospective cohort study of 139 pregnant women recruited between 2016-18. Bisphenols and phthalates were measured in early- and mid-pregnancy urine samples. Serum sex steroid hormone concentrations were measured in mid-pregnancy. PPD was assessed at 4 months postpartum using the Edinburgh Postnatal Depression Scale (EPDS). Multiple informant models were fit using generalized estimating equations. MAIN OUTCOME MEASURES/METHODS:Serum levels of allopregnanolone, progesterone, pregnanolone, and pregnenolone were examined as log-transformed continuous variables. PPD symptoms were examined as continuous EPDS scores and dichotomously with scores ≥10 defined as PPD. RESULTS:Di-n-octyl phthalate (DnOP) and diisononyl phthalate (DiNP) metabolites were associated with reduced progesterone concentrations. Log-unit increases in ∑DnOP and ∑DiNP predicted 8.1% (95% Confidence Interval (CI): -15.2%, -0.4%) and 7.7% (95% CI: -13.3%, -1.7%) lower progesterone, respectively. ∑DnOP was associated with increased odds of PPD (odds ratio=1.48 (95% CI: 1.04, 2.11)). CONCLUSIONS:Endocrine disrupting chemicals may influence hormonal shifts during pregnancy as well as contribute to PPD.

Biomonitoring of human exposure to environmental chemicals has gained momentum in recent years. Biomonitoring methods often include analysis of a single class of chemicals with similar chemical properties. In this study, we describe a method that involves solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and capable of measuring 121 environmental chemicals comprising plasticizers (PMs; n = 45), environmental phenols (EPs; n = 45), and pesticides (n = 31) through a single extraction of urine. Urine samples were incubated with 20 µL of β-glucuronidase/arylsulfatase (4000 units/mL urine) (from Helix pomatia) buffered at pH 5.5 for 2 h at 37 °C for optimal deconjugation conditions. We compared two extraction methods, namely liquid-liquid extraction and SPE, and the latter with ABS Elut NEXUS® cartridges was optimized to yield best extraction efficiencies. For increased resolution and chromatographic separation, two methods involving Ultra AQ C18® and Betasil™ C18® columns were used. The MS/MS analyses were performed under both negative and positive ionization modes. The optimized method yielded excellent intra- and inter-day variabilities (relative standard deviation: 0.40-11%) and satisfactory recoveries (80-120%) for >95% of the analytes. The limits of detection were ≤ 0.1 ng/mL for 101 analytes and between 0.1 and 1.0 ng/mL for 18 analytes. The optimized SPE LC-MS/MS method was validated through the analysis of standard reference materials and proficiency test urine samples and further applied in the analysis of 21 real urine samples to demonstrate simultaneous determination of 121 environmental chemicals in urine samples.

Preeclampsia, a pregnancy disorder that includes hypertension and proteinuria, is a major cause of maternal and fetal morbidity and mortality. Some studies, but not all, have found that women with preeclampsia have significantly lower iodine levels than healthy pregnant women. Resolving this issue is important because iodine deficiency in pregnancy is common in the USA and parts of Europe including Finland. We conducted a nested case-control study to determine whether the risk for preeclampsia is associated with iodine status. We measured serum iodine, thyroglobulin (Tg), and thyroid stimulating hormone (TSH) at 10-14 weeks gestational age in 204 women with preeclampsia and 246 unaffected controls selected from all births in Finland. We found no significant difference in iodine (case mean = 26.04 ng/mL, control mean = 27.88 ng/mL, p = 0.995), Tg (case mean = 31.11 ng/mL, control mean = 29.61 ng/mL, p = 0.996), and TSH (case mean = 1.30 mIU/L, control mean = 1.24 mIU/L, p = 0.896) levels between cases and controls. There was no significant relationship between preeclampsia risk and iodine, Tg, or TSH after adjustment for known risk factors. These results are reassuring given the high prevalence of iodine deficiency in pregnancy.

BACKGROUND:Exposure to bisphenols may affect fetal growth and development. The trimester-specific effects of bisphenols on repeated measures of fetal growth remain unknown. Our objective was to assess the associations of maternal bisphenol urine concentrations with fetal growth measures and birth outcomes and identify potential critical exposure periods. METHODS:In a population-based prospective cohort study among 1379 pregnant women, we measured maternal bisphenol A, S and F urine concentrations in the first, second and third trimester. Fetal head circumference, length and weight were measured in the second and third trimester by ultrasound and at birth. RESULTS:An interquartile range increase in maternal pregnancy-averaged bisphenol S concentrations was associated with larger fetal head circumference (difference 0.18 (95% confidence interval (CI) 0.01 to 0.34) standard deviation scores (SDS), p-value< 0.05) across pregnancy. When focusing on specific critical exposure periods, any detection of first trimester bisphenol S was associated with larger second and third trimester fetal head circumference (difference 0.15 (95% CI 0.05 to 0.26) and 0.12 (95% CI 0.02 to 0.23) SDS, respectively) and fetal weight (difference 0.12 (95% CI 0.02 to 0.22) and 0.16 (95% CI 0.06 to 0.26) SDS, respectively). The other bisphenols were not consistently associated with fetal growth outcomes. Any detection of bisphenol S and bisphenol F in first trimester was also associated with a lower risk of being born small size for gestational age (Odds Ratio 0.56 (95% CI 0.38 to 0.74) and 0.55 (95% CI 0.36 to 0.85), respectively). Bisphenols were not associated with risk of preterm birth. CONCLUSIONS:Higher maternal bisphenol S urine concentrations, especially in the first trimester, seem to be related with larger fetal head circumference, higher weight and a lower risk of being small size for gestational age at birth.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Prenatal exposure to environmental tobacco smoke (ETS) is associated with increased attention problems in children, however, the effects of such exposure on children's brain structure and function have not been studied. Herein, we probed effects of prenatal ETS on children's cognitive control circuitry and behavior. METHODS:Forty-one children (7-9 years) recruited from a prospective longitudinal birth cohort of non-smoking mothers completed structural and task-functional magnetic resonance imaging to evaluate effects of maternal ETS exposure, measured by maternal prenatal urinary cotinine. Attention problems and externalizing behaviors were measured by parent report on the Child Behavior Checklist. RESULTS:Compared to non-exposed children, exposed children had smaller left and right thalamic and inferior frontal gyrus (IFG) volumes, with large effect sizes (p-FDR < .05, Cohen's D range from 0.79 to 1.07), and increased activation in IFG during the resolution of cognitive conflict measured with the Simon Spatial Incompatibility Task (38 voxels; peak t(25) = 5.25, p-FWE = .005). Reduced thalamic volume was associated with increased IFG activation and attention problems, reflecting poor cognitive control. Mediation analyses showed a trend toward left thalamic volume mediating the association between exposure and attention problems (p = .05). CONCLUSIONS:Our findings suggest that maternal ETS exposure during pregnancy has deleterious effects on the structure and function of cognitive control circuitry which in turn affects attentional capacity in school-age children. These findings are consistent with prior findings documenting the effects of active maternal smoking on chidlren's neurodevleoment, pointing to the neurotixicity of nicotine regardless of exposure pathway.

BACKGROUND:Growing evidence suggests that exposure to environmental chemicals, such as pesticides, impacts renal function and chronic kidney disease (CKD). However, it is not clear if pesticides may affect CKD progression and no studies exist in children. OBJECTIVES/OBJECTIVE:The objective of this study was to examine associations between serially measured urinary OP pesticide metabolites and clinical and laboratory measures of kidney function over time among children with CKD. METHODS:-isoprostane) were determined in the same specimens. Estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure were assessed annually. RESULTS:DAPs were associated with increased KIM-1 and 8-OHdG throughout follow-up. A standard deviation increase in ∑diethyl metabolites was associated with increases of 11.9% (95% Confidence Interval (CI): 4.8%, 19.4%) and 13.2% (95% CI: 9.3%, 17.2%) in KIM-1 and 8-OHdG over time, respectively. DAPs were associated with lower eGFR at baseline and higher eGFR over subsequent years. CONCLUSIONS:These findings provide preliminary evidence suggesting that urinary DAP metabolites are associated with subclinical kidney injury among children with CKD, which may signal the potential for clinical events to manifest in the future. The results from this study are significant from both a clinical and public health perspective, given that OP pesticide exposure is a modifiable risk factor.