Faculty Bibliography

BACKGROUND:Phthalate exposure may contribute to hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PE/E), but epidemiologic studies are lacking. OBJECTIVES/OBJECTIVE:To evaluate associations of pregnancy phthalate exposure with development of PE/E and HDP. METHODS:Using data from 3,430 participants in eight Environmental influences on Child Health Outcomes (ECHO) Program cohorts (enrolled from 1999 to 2019), we quantified concentrations of 13 phthalate metabolites (8 measured in all cohorts, 13 in a subset of four cohorts) in urine samples collected at least once during pregnancy. We operationalized outcomes as PE/E and composite HDP (PE/E and/or gestational hypertension). After correcting phthalate metabolite concentrations for urinary dilution, we evaluated covariate-adjusted associations of individual phthalates with odds of PE/E or composite HDP via generalized estimating equations, and the phthalate mixture via quantile-based g-computation. We also explored effect measure modification by fetal sex using stratified models. Effect estimates are reported as odds ratios (OR) with 95% confidence intervals (95% CIs). RESULTS:In adjusted analyses, a doubling of mono-benzyl phthalate (MBzP) and of mono (3-carboxypropyl) phthalate (MCPP) concentrations was associated with higher odds of PE/E as well as composite HDP, with somewhat larger associations for PE/E. For example, a doubling of MCPP was associated with 1.12 times the odds of PE/E (95%CI 1.00, 1.24) and 1.02 times the odds of composite HDP (95%CI 1.00, 1.05). A quartile increase in the phthalate mixture was associated with 1.27 times the odds of PE/E (95%CI 0.94, 1.70). A doubling of mono-carboxy isononyl phthalate (MCiNP) and of mono-carboxy isooctyl phthalate (MCiOP) concentrations were associated with 1.08 (95%CI 1.00, 1.17) and 1.11 (95%CI 1.03, 1.19) times the odds of PE/E. Effect estimates for PE/E were generally larger among pregnancies carrying female fetuses. DISCUSSION/CONCLUSIONS:In this study, multiple phthalates were associated with higher odds of PE/E and HDP. Estimates were precise and some were low in magnitude. Interventions to reduce phthalate exposures during pregnancy may help mitigate risk of these conditions.

BACKGROUND:Phthalates are endocrine-disrupting chemicals with anti-androgenic qualities and studies reported associations between prenatal phthalate exposure and infant genitalia. This study investigated whether increased prenatal phthalate exposure is associated with decreased fetal penile measures. METHODS:Data was from the New York University Children's Health and Environment Study (2016-2019). Maternal urinary concentrations of 16 phthalate metabolites were quantified at <18 weeks gestation as a proxy for fetal exposure (n = 334 male pregnancies). We retrospectively measured penile length and width using ultrasounds conducted 18-24 weeks gestation (n = 173 fetuses). Associations of maternal urinary levels of phthalates with fetal penile length and width were determined using linear regression models. RESULTS:57.2% of women were Hispanic, 31.8% Non-Hispanic White, 6.4% Asian, 2.3% Non-Hispanic Black, and 2.3% multiple races. Mean maternal age was 32 years (standard deviation [SD] = 5.7). Mean penile length was 7.13 mm (SD = 1.47) and width was 6.16 mm (SD = 0.87). An inverse relationship was observed between maternal levels of mono-ethyl phthalate and fetal penile length, and mono-(7-carboxy-n-heptyl) phthalate and penile width, though estimates were small and not significant when considering correction for multiple comparisons. CONCLUSIONS:In our cohort we found no clinically meaningful associations between early pregnancy phthalate exposure and fetal penile length or width. IMPACT/CONCLUSIONS:First-trimester phthalate metabolites were assessed in pregnant women in New York City. Penile length and width were retrospectively measured on clinically assessed ultrasounds conducted ≥18 weeks and <24 weeks of gestation. In this cohort, no clinically meaningful associations were observed between first-trimester prenatal phthalate exposure and fetal penile length. This study contributes to the limited but growing research on the impact of prenatal phthalate exposure on male fetal genital development. The results emphasize that there may not be a clear association between prenatal phthalate exposure and fetal penile length and width, and further research on this topic may be required.

BACKGROUND/UNASSIGNED:Estimates for the effects of environmental exposures on health outcomes, including secondhand smoke (SHS) exposure, often present considerable variability across studies. Knowledge of the reasons behind these differences can aid our understanding of effects in specific populations as well as inform practices of combining data from multiple studies. OBJECTIVES/UNASSIGNED:This study aimed to assess the presence of effect modification by measured sociodemographic characteristics on the effect of SHS exposure during pregnancy on birth weights that may drive differences observed across cohorts. We also aimed to quantify the extent to which differences in the cohort mean effects observed across cohorts in the Environmental influences on Child Health Outcomes (ECHO) consortium are due to differing distributions of these characteristics. METHODS/UNASSIGNED:We assessed the presence of effect modification and transportability of effect estimates across five ECHO cohorts in a total of 6,771 mother-offspring dyads. We assessed the presence of effect modification via gradient boosting of regression trees based on the H-statistic. We estimated individual cohort effects using linear models and targeted maximum likelihood estimation (TMLE). We then estimated transported effects from one cohort to each of the remaining cohorts using a robust nonparametric estimation approach relying on TMLE estimators and compared them to the original effect estimates for these cohorts. RESULTS/UNASSIGNED: DISCUSSION/UNASSIGNED:Our findings of weak to moderate evidence of effect modification and transportability indicate that unmeasured individual-level and contextual factors and sources of bias may be responsible for differences in the effect estimates observed across ECHO cohorts. https://doi.org/10.1289/EHP13961.

Organophosphate esters (OPEs) are a class of chemicals now widely used as flame retardants and plasticizers after the phase-out of polybrominated diphenyl ethers (PBDEs). However, OPEs carry their own risk of developmental toxicity, which poses concern for recent birth cohorts as they have become ubiquitous in the environment. In this review, we summarize the literature evaluating the association between OPE exposure and maternal, perinatal, and child health outcomes. We included original articles investigating associations of OPE exposure with any health outcome on pregnant women, newborns, children, and adolescents. We found 48 articles on this topic. Of these, five addressed maternal health and pregnancy outcomes, 24 evaluated prenatal OPE exposure and child health, 18 evaluated childhood OPE exposure and child/adolescent health, and one article evaluated both prenatal and childhood OPE exposure. These studies suggest that OPE exposure is possibly associated with a wide range of adverse health outcomes, including pregnancy loss, altered gestational duration and smaller birthweight, maternal and neonatal thyroid dysfunction, child metabolic dysregulation and abnormal growth, impaired neurodevelopment, and changes in immune response. Many of the reported outcomes associated with OPE exposure varied by child sex. Findings also varied substantially by OPE metabolite and exposure time. The OPEs most frequently measured, detected, and found to be associated with health outcomes were triphenyl phosphate (TPHP, metabolized to DPHP) and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP, metabolized to BDCIPP). The extensive range of health outcomes associated with OPEs raises concern about their growing use in consumer products; however, these findings should be interpreted considering the limitations of these epidemiological studies, such as possible exposure misclassification, lack of generalizability, insufficient adjustment for covariates, and failure to consider chemical exposures as a mixture.

RATIONALE & OBJECTIVE/UNASSIGNED:This study aimed to assess the effect of exposure to organic pollutants in adults with chronic kidney disease (CKD). STUDY DESIGN/UNASSIGNED:This was a cross-sectional and longitudinal analysis. SETTING AND PARTICIPANTS/UNASSIGNED:Forty adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURES/UNASSIGNED:Exposure at baseline and longitudinally to various organic chemical pollutants. OUTCOMES/UNASSIGNED:The outcomes were as follows: death; composite of congestive heart failure, myocardial infarction, and stroke; event-free survival from kidney failure or ≥50% decline in estimated glomerular filtration rate (eGFR); and longitudinal trajectory of eGFR. ANALYTICAL APPROACH/UNASSIGNED:We used high-performance liquid chromatography with tandem mass spectrometry to measure urinary concentrations of bisphenols, phthalates, organophosphate pesticides, polycyclic aromatic hydrocarbons, melamine, and cyanuric acid at years 1, 3, and 5 after enrollment in the CRIC. Univariate and multivariable logistic regression were used to examine the association of individual compounds and classes of pollutants with the outcomes. The Cox proportional hazards model and Kaplan-Meier method were used to calculate hazard ratios and 95% CIs for each class of pollutants. RESULTS/UNASSIGNED:and 0.58 mg/g, respectively. Of 52 compounds assayed, 30 were detectable in ≥50% of participants. Urinary chemical concentrations were comparable in patients with CKD and healthy individuals from contemporaneous National Health and Nutrition Examination Survey cohorts. Phthalates were the only class with a trend toward higher exposure in patients with CKD. There was an inverse relationship between exposure and the eGFR slopes for bisphenol F, mono-(3-carboxypropyl) phthalate, mono-benzyl phthalate, mono-[2-(carboxymethyl)hexyl] phthalate, and melamine. There were no associations between organic pollutant exposure and cardiovascular outcomes. LIMITATIONS/UNASSIGNED:Small sample size, evaluation of single rather than combined exposures. CONCLUSIONS/UNASSIGNED:Simultaneous measurement of multiple organic pollutants in adults with CKD is feasible. Exposure levels are comparable with healthy individuals. Select contaminants, especially in the phthalate class, may be associated with more rapid deterioration in kidney function.

A multimorbidity-focused approach may reflect common etiologic mechanisms and lead to better targeting of etiologic agents for broadly impactful public health interventions. Our aim was to identify clusters of chronic obesity-related, neurodevelopmental, and respiratory outcomes in children, and to examine associations between cluster membership and widely prevalent chemical exposures to demonstrate our epidemiologic approach. Early to middle childhood outcome data collected 2011-2022 for 1092 children were harmonized across the ECHO-PATHWAYS consortium of 3 prospective pregnancy cohorts in six U.S. cities. 15 outcomes included age 4-9 BMI, cognitive and behavioral assessment scores, speech problems, and learning disabilities, asthma, wheeze, and rhinitis. To form generalizable clusters across study sites, we performed k-means clustering on scaled residuals of each variable regressed on study site. Outcomes and demographic variables were summarized between resulting clusters. Logistic weighted quantile sum regressions with permutation test p-values associated odds of cluster membership with a mixture of 15 prenatal urinary phthalate metabolites in full-sample and sex-stratified models. Three clusters emerged, including a healthier Cluster 1 (n = 734) with low morbidity across outcomes; Cluster 2 (n = 192) with low IQ and higher levels of all outcomes, especially 0.4-1.8-standard deviation higher mean neurobehavioral outcomes; and Cluster 3 (n = 179) with the highest asthma (92 %), wheeze (53 %), and rhinitis (57 %) frequencies. We observed a significant positive, male-specific stratified association (odds ratio = 1.6; p = 0.01) between a phthalate mixture with high weights for MEP and MHPP and odds of membership in Cluster 3 versus Cluster 1. These results identified subpopulations of children with co-occurring elevated levels of BMI, neurodevelopmental, and respiratory outcomes that may reflect shared etiologic pathways. The observed association between phthalates and respiratory outcome cluster membership could inform policy efforts towards children with respiratory disease. Similar cluster-based epidemiology may identify environmental factors that impact multi-outcome prevalence and efficiently direct public policy efforts.

Context: Chemicals used in plastics have been described to contribute to disease and disability, but attributable fractions have not been quantified to assess specific contributions. Without this information, interventions proposed as part of the Global Plastics Treaty cannot be evaluated for potential benefits. Objective: To accurately inform the tradeoffs involved in the ongoing reliance on plastic production as a source of economic productivity in the United States, we calculated the attributable disease burden and cost due to chemicals used in plastic materials in 2018. Methods: We first analyzed the existing literature to identify plastic-related fractions (PRF) of disease and disability for specific polybrominated diphenylethers (PBDE), phthalates, bisphenols, and polyfluoroalkyl substances and perfluoroalkyl substances (PFAS). We then updated previously published disease burden and cost estimates for these chemicals in the United States to 2018. By uniting these data, we computed estimates of attributable disease burden and costs due to plastics in the United States. Results: We identified PRFs of 97.5% for bisphenol A (96.25-98.75% for sensitivity analysis), 98% (96%-99%) for di-2-ethylhexylphthalate, 100% (71%-100%) for butyl phthalates and benzyl phthalates, 98% (97%-99%) for PBDE-47, and 93% (16%-96%) for PFAS. In total, we estimate $249 billion (sensitivity analysis: $226 billion-$289 billion) in plastic-attributable disease burden in 2018. The majority of these costs arose as a result of PBDE exposure, though $66.7 billion ($64.7 billion-67.3 billion) was due to phthalate exposure and $22.4 billion was due to PFAS exposure (sensitivity analysis: $3.85-$60.1 billion). Conclusion: Plastics contribute substantially to disease and associated social costs in the United States, accounting for 1.22% of the gross domestic product. The costs of plastic pollution will continue to accumulate as long as exposures continue at current levels. Actions through the Global Plastics Treaty and other policy initiatives will reduce these costs in proportion to the actual reductions in chemical exposures achieved.

Rapidly advancing evidence documents that a broad array of synthetic chemicals found ubiquitously in the environment contribute to disease and disability across the lifespan. Although the early literature focused on early life exposures, endocrine-disrupting chemicals (EDCs) are now understood to contribute substantially to chronic disease in adulthood, especially metabolic, cardiovascular, and reproductive consequences as well as endocrine cancers. The contribution to mortality is substantial, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the United States (US) due to exposure to certain phthalates that are used as plasticizers in food packaging. Importantly, exposures are disproportionately high in low-income and minoritized populations, driving disparities in these conditions. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. Many of these exposures can be modified through safe and simple behavioral changes supported by proactive government action to both limit known hazardous exposures and to proactively screen new industrial chemicals prior to their use. Routine healthcare maintenance should include guidance to reduce EDC exposures, and a recent report by the Institute of Medicine suggests that testing be conducted, particularly in populations heavily exposed to perfluoroalkyl substances-chemicals used in nonstick coatings as well as oil- and water-resistant clothing.

Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients generally being treated as a uniform group, for whom the strategy is to bypass the causality using medically assisted reproduction (MAR) techniques. In doing so, opportunities to prevent co-morbidity are missed and the burden of MAR is shifted to the woman. To advance understanding of men's reproductive health, longitudinal and multi-national centres for data and sample collection are essential. Such programmes must enable an integrated view of the consequences of genetics, epigenetics and environmental factors on fertility and offspring health. Definition and possible amelioration of the consequences of MAR for conceived children are needed. Inherent in this statement is the necessity to promote fertility restoration and/or use the least invasive MAR strategy available. To achieve this aim, protocols must be rigorously tested and the move towards personalized medicine encouraged. Equally, education of the public, governments and clinicians on the frequency and consequences of infertility is needed. Health options, including male contraceptives, must be expanded, and the opportunities encompassed in such investment understood. The pressing questions related to male reproductive health, spanning the spectrum of andrology are identified in the Expert Recommendation.