Faculty Bibliography

BACKGROUND:Exposure to endocrine-disrupting chemicals such as bisphenols and phthalates might lead to adverse fertility and early pregnancy outcomes. METHODS:This study was embedded in the Generation R Next Study, a population-based cohort study from preconception onwards. Urinary phthalate and bisphenol concentrations were assessed in the preconception period (938 women), defined as the period in which couples were actively trying to conceive, and early pregnancy (1,366 women and 1,202 men, mean gestational age at sampling 8·6 weeks). Time to pregnancy and miscarriage were assessed using questionnaires and ultrasounds. Subfertility was defined as the inability to conceive within 12 months or need for assisted reproductive technologies. FINDINGS/RESULTS:Higher preconception urinary bisphenol S (BPS) and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (mCOCH) concentrations in women were associated with longer time to pregnancy. Higher preconception mono-[(2-carboxymethyl)hexyl] phthalate, mono-2-ethyl-5-oxohexyl phthalate (mEOHP), mono-(7-carboxy-n-heptyl)phthalate (mCHpP), and mono benzyl phthalate (mBzBP) were associated with shorter time to pregnancy, and higher mono-2-ethyl-5-hydroxyhexyl phthalate (mEHHP), mEOHP, and mBzBP with lower odds of subfertility. In men, higher early pregnancy BPS, mCHpP, mono-4-methyl-7-hydroxyoctyl phthalate, mono-4-methyl-7-oxooctyl phthalate, and mono-ethyl phthalate were associated with shorter time to pregnancy or lower odds of subfertility. Higher preconception or early pregnancy BPS, phthalic acid, and mCHpP in women were associated with lower odds of miscarriage, whereas higher mono-carboxy-isoctyl phthalate, mCOCH, and mono-2-(propyl-6-carboxy-hexyl)-phthalate (cxmPHxP) with higher odds of miscarriage (all p-values <0·05). INTERPRETATION/CONCLUSIONS:Preconception and early pregnancy exposure to bisphenols and phthalates may affect couple fertility. Our results should be considered as hypothesis generating and replicated in future studies, possibly including repeated chemical measurements and mixture analysis.

BACKGROUND:New evidence has emerged that plastic polymers and their chemical additives, particularly di-2-ethylhexylphthalate (DEHP), contribute to cardiovascular disease (CVD). Phthalates are commonly used in the production of plastic materials and have been linked to increased oxidative stress, metabolic dysfunction, and cardiovascular disease. Estimates of phthalate-attributable cardiovascular mortality have been made for the US, but global estimates are needed to inform ongoing negotiations of a Global Plastics Treaty. METHODS:Cardiovascular mortality data from the Institute for Health Metrics and Evaluation (IHME) and regional DEHP exposure estimates from several sources were used to estimate burden. Hazard ratios of CV mortality were calculated using published exposure estimates, and country-level cardiovascular mortality rates were used to calculate excess deaths and years of life lost (YLL) due to DEHP exposure. FINDINGS/RESULTS:In 2018, an estimated 356,238 deaths globally were attributed to DEHP exposure, representing 13.497% of all cardiovascular deaths among individuals aged 55-64. Of these, 349,113 were attributed to the use of plastics. Geographic disparities were evident, with South Asia and the Middle East suffering the greatest percentage of cardiovascular deaths attributable to DEHP exposure (16.807%). The Middle East, South Asia, East Asia, and the Pacific accounted for the largest shares of DEHP-attributable CVD deaths (73.163%). Globally, DEHP resulted in 10.473 million YLL. INTERPRETATION/CONCLUSIONS:Plastics pose a significant risk to increased cardiovascular mortality, disproportionately impacting regions which have developing plastic production sectors. The findings underscore the need for urgent global and local regulatory interventions to kerb mortality from DEHP exposure. FUNDING/BACKGROUND:Bloomberg Philanthropies and the National Institutes of Health.

OBJECTIVE:Maternal vitamin D level is an important determinant of pregnancy and child health outcomes. Exposure to air pollution is suspected to increase the risk of vitamin D deficiency, but the evidence is scarce. We investigated the association between air pollution during pregnancy and maternal vitamin D levels. METHODS:A total of 15,935 pregnant women from 5 birth cohorts in Europe and U.S were included. Averaged concentrations of nitrogen oxides, fine and coarse particles, and composition of fine particles from conception until vitamin D measurement were estimated at participants' residential addresses using land-use regression or other spatiotemporal models. Cohorts measured vitamin D as 25(OH)D or 25(OH)D3 levels in serum or plasma at early or mid-pregnancy. We defined suboptimal vitamin D levels as levels below 20 ng/mL. We performed logistic regression models for each cohort to estimate the association between air pollution exposure and suboptimal vitamin D levels and pooled cohort-specific estimates in a random-effect meta-analysis. Models were adjusted for sociodemographic and lifestyle characteristics and month of conception. RESULTS:We found an association between PM2.5 and higher odds of suboptimal vitamin D levels (i.e., below 20 ng/mL) (odds ratio per 5 μg/m3 increase in PM2.5, 1.43 95%CI: 1.02, 1.99). There was no association between other air pollutant exposure and vitamin D levels. CONCLUSIONS:PM2.5 exposure might contribute to suboptimal levels of vitamin D in pregnancy. Reducing air pollution exposure should be a priority because vitamin D deficiency may adversely influence offspring development.

OBJECTIVE:Anogenital distance (AGD) is a postnatal marker of in utero exposure to androgens and anti-androgens, and a predictor of reproductive health. We examined the association between gestational exposure to phthalates and AGD in male and female infants. METHODS:In 506 mother-infant pairs (276 males, 230 females), we measured urinary concentrations of phthalate metabolites at < 18 and 18-25 weeks of gestation and AGD at child age 12.9 months (95 % range 11.4-21.1). Phthalate metabolite concentrations were adjusted for urinary dilution, averaged, and natural log-transformed. We measured anus-clitoris distance (AGDac) and anus-fourchette distance (AGDaf) in females, and anus-scrotum distance, anus-penis distance, and penile width in males. We used linear regression and partial-linear single-index (PLSI) models to examine associations between phthalates and AGD as single pollutants and in mixture. RESULTS:Fifty-eight percent of mothers were Hispanic, followed by 27 % non-Hispanic White. Higher exposures to ∑di-isononyl(phthalate) (∑DiNP) was associated with longer AGDaf [1.28 mm (95 % confidence interval [CI]: 0.52, 2.03) and 0.97 mm (95 %CI: 0.25, 1.69), respectively]. Higher exposures to ∑di(2-ethylhexyl)phthalate (∑DEHP) was associated with longer AGDac [2.80 mm (95 %CI: 1.17, 4.44), and 1.90 mm (95 %CI: 0.76, 3.04), respectively]. No association was observed between phthalate metabolites and AGD in males after multiple testing correction. In mixture analyses, ∑DiNP and ∑DEHP were the main contributors to longer AGD in females. We also detected an interaction between ∑DiNP and ∑DEHP in association with AGD in females. CONCLUSION/CONCLUSIONS:Early pregnancy phthalate exposure was associated with longer AGD in female infants. Biological mechanisms underlying these associations should be further investigated.

Prenatal organophosphate (OP) pesticide exposure may be associated with reduced fetal growth, although studies are limited and have mixed results. We investigated associations between prenatal OP pesticide exposure and fetal size and modification by fetal sex. Maternal urinary concentrations of dialkyl phosphate (DAP) metabolites were measured at three time points. Fetal biometrics were obtained from ultrasounds in the second (n=773) and third (n=535) trimesters. Associations between pregnancy-averaged ΣDAP and fetal biometry z-scores were determined through multiple linear regression. Modification by sex was investigated through stratification and interaction. In the second trimester, one ln-unit increase in ΣDAP was associated with lower estimated fetal weight (-0.15 SD; 95% CI: -0.29, -0.01), head circumference (-0.11 SD; CI: -0.22, 0.01), biparietal diameter (-0.14 SD; CI: -0.27, -0.01), and abdominal circumference (-0.12 SD; CI: -0.26, 0.01) in females. In the third trimester, one ln-unit increase in ΣDAP was associated with lower head circumference (-0.14 SD; CI: -0.28, 0.00) and biparietal diameter (-0.12 SD; CI: -0.26, 0.03) in males. Our results suggest that prenatal OP pesticide exposure is negatively associated with fetal growth in a sex-specific manner, with associations present for females in mid-gestation and males in late gestation.

OBJECTIVE:Poverty and systemic racism within rare intertwined. Children of marginalized racial and ethnic identities experience higher levels of poverty and adverse psychiatric outcomes. Thus, in models of poverty and neurodevelopment, race and ethnicity-as proxies for exposure to systemic disadvantage-are regularly considered confounders. Recently, however, some researchers claimed that using race and ethnicity as confounders is statistically dubious, and potentially socially damaging. Instead, they argue for the use of variables measuring other social determinants of health (SDoH). We explore this approach. METHOD/METHODS:Data are from 7,836 10-year-olds in the Adolescent Brain and Cognitive Development study. We fit mixed regression models for the association of household poverty measures with psychiatric symptoms, magnetic resonance imaging-derived (MRI) cortical measures, and cognition with and without (1) race and ethnicity adjustment; (2); poverty-by-race and ethnicity interaction terms and (3) alternative SDoH variables. Propensity-based weights were used to calibrate the sample to key US demographics. RESULTS:For psychiatric and cognitive outcomes, poverty-outcome relationships differed across racial and ethnic groups (poverty-by-race-and-ethnicity interaction p<0.05). For MRI outcomes, adjusting for race and ethnicity changed the estimate of poverty's impact. Alternative SDoH adjustment could not fully account for the impact of race and ethnicity on the associations explored. CONCLUSION/CONCLUSIONS:Poverty and race and ethnicity combine to influence neurodevelopment. Results suggest effects of poverty are generally inconsistent across race and ethnicity, which supports prior research demonstrating the non-equivalence of SDoH indicators by race and ethnicity. Studies exploring these relationships should assess interaction between poverty and race and ethnicity and/or stratify when appropriate. Replacing race and ethnicity with alternative SDoH may induce bias.

Prenatal exposure to phthalates might influence the development of childhood obesity. Most previous studies used body mass index (BMI) at a specific age instead of BMI development, which might be a better indicator of later health. We aimed to assess the association of prenatal phthalate exposure with longitudinal BMI development from infancy to adolescence. Among 1,379 mother-child pairs from a population-based cohort study, phthalate concentrations were measured in maternal spot urine samples, collected during first, second and third trimester. We estimated age- and sex-adjusted BMI standard deviation scores (SDS) at 6 months and 1, 2, 3, 4, 6, 10 and 13 years. We examined the associations of maternal phthalate urine concentrations during pregnancy with repeated measures of BMI using linear mixed effects models. An interquartile range higher natural log-transformed maternal first trimester high-molecular weight phthalate and di-2-ethylhexylphthalate (DEHP) urine concentrations were associated with a -0.10 (95% confidence interval (CI) -0.15 to -0.04), and -0.09 (95% CI -0.15 to -0.04) lower age- and sex-adjusted BMI at 6 months. An interquartile range higher natural log-transformed maternal first trimester phthalic acid and low-molecular weight phthalate urine concentrations were associated with a 0.11 (95% CI 0.03 to 0.18) and 0.13 (95% CI 0.04 to 0.21) higher age- and sex-adjusted BMI at 13 years old. No significant associations were observed for maternal second and third trimester phthalate urine concentrations with BMI. Thus, higher maternal phthalate metabolites urine concentrations appear to be related to lower BMI at early ages but with higher BMI at later ages.

Many phthalates have been identified as endocrine-disrupting chemicals because they alter hormone functions throughout the lifespan. Nationally representative biomonitoring data are available from the United States, Canada, and Europe, but data elsewhere are sparse, making extrapolations of related disease and disability burdens difficult. We therefore examined trends in urinary phthalate metabolite concentrations in non-occupationally exposed populations in countries other than the United States, Canada, and Europe, where representative data are already available at the country level. We systematically reviewed studies published between 2000 and 2023 and analyzed changes in urinary phthalate metabolite concentrations across time using mixed-effects meta-regression models with and without a quadratic term for time. We controlled for region, age, and pregnancy status, and identified heterogeneity using Cochran's Q-statistic and I² index. Our final analysis consisted of 216 studies. Non-pregnant and youth populations exhibited nearly 2.0-fold or greater difference in concentration compared to pregnant and adult populations. Phthalates with significant regional differences had 10-fold higher concentrations in the Middle East and South Asia than in other regions. Our meta-regressions identified an exponential increase in DBP exposure through MnBP concentration internationally (beta: 0.65 ng/mL/year²) and in Eastern and Pacific Asia (EPA) (beta: 0.78 ng/mL/year²). Most DEHP and DnOP metabolites significantly declined internationally and in EPA, while MEP concentration declined by 10.62 ng/mL in Latin America and 8.98 ng/mL in Africa over time. Our findings fill gaps in phthalate exposure data and set the stage for further analysis of the attributable disease burden and cost at regional and international levels, especially in low- and middle-income countries.