Faculty Bibliography

OBJECTIVE: DESIGN/METHODS:Pooled pregnancy cohort studies. SETTING/METHODS:Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020. PARTICIPANTS/METHODS:A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use. RESULTS:. never). CONCLUSIONS:-3 supplement use was uncommon, even among those who did not consume fish.

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.

BACKGROUND:Phthalates are synthetic chemicals widely used in consumer products and have been identified to contribute to preterm birth. Existing studies have methodological limitations and potential effects of di-2-ethylhexyl phthalate (DEHP) replacements are poorly characterised. Attributable fractions and costs have not been quantified, limiting the ability to weigh trade-offs involved in ongoing use. We aimed to leverage a large, diverse US cohort to study associations of phthalate metabolites with birthweight and gestational age, and estimate attributable adverse birth outcomes and associated costs. METHODS:In this prospective analysis we used extant data in the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program from 1998 to 2022 to study associations of 20 phthalate metabolites with gestational age at birth, birthweight, birth length, and birthweight for gestational age z-scores. We also estimated attributable adverse birth outcomes and associated costs. Mother-child dyads were included in the study if there were one or more urinary phthalate measurements during the index pregnancy; data on child's gestational age and birthweight; and singleton delivery. FINDINGS/RESULTS:increase were higher for phthalic acid (2·71 [1·91-3·83]), DiNP (2·25 [1·67-3·00]), DiDP (1·69 [1·25-2·28]), and DnOP (2·90 [1·96-4·23]). We estimated 56 595 (sensitivity analyses 24 003-120 116) phthalate-attributable preterm birth cases in 2018 with associated costs of US$3·84 billion (sensitivity analysis 1·63- 8·14 billion). INTERPRETATION/CONCLUSIONS:In a large, diverse sample of US births, exposure to DEHP, DiDP, DiNP, and DnOP were associated with decreased gestational age and increased risk of preterm birth, suggesting substantial opportunities for prevention. This finding suggests the adverse consequences of substitution of DEHP with chemically similar phthalates and need to regulate chemicals with similar properties as a class. FUNDING/BACKGROUND:National Institutes of Health.

Obesity in children remains a major public health problem, with the current prevalence in youth ages 2-19 years estimated to be 19.7%. Despite progress in identifying risk factors, current models do not accurately predict development of obesity in early childhood. There is also substantial individual variability in response to a given intervention that is not well understood. On April 29-30, 2021, the National Institutes of Health convened a virtual workshop on "Understanding Risk and Causal Mechanisms for Developing Obesity in Infants and Young Children." The workshop brought together scientists from diverse disciplines to discuss (1) what is known regarding epidemiology and underlying biological and behavioral mechanisms for rapid weight gain and development of obesity and (2) what new approaches can improve risk prediction and gain novel insights into causes of obesity in early life. Participants identified gaps and opportunities for future research to advance understanding of risk and underlying mechanisms for development of obesity in early life. It was emphasized that future studies will require multi-disciplinary efforts across basic, behavioral, and clinical sciences. An exposome framework is needed to elucidate how behavioral, biological, and environmental risk factors interact. Use of novel statistical methods may provide greater insights into causal mechanisms.

CONTEXT/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

STUDY QUESTION/OBJECTIVE:Do children born to mothers with polycystic ovary syndrome (PCOS) have an adverse cardiometabolic profile including arterial stiffness at 9 years of age compared to other children? SUMMARY ANSWER/CONCLUSIONS:Children of mothers with PCOS did not have differing cardiometabolic outcomes than children without exposure. WHAT IS KNOWN ALREADY/BACKGROUND:While women with PCOS themselves have higher risk of cardiometabolic conditions such as obesity and diabetes, the evidence on intergenerational impact is unclear. Given in utero sequalae of PCOS (e.g. hyperandrogenism, insulin resistance), the increased risk could be to both boys and girls. STUDY DESIGN, SIZE, DURATION/METHODS:The Upstate KIDS cohort is a population-based birth cohort established in 2008-2010 to prospectively study the impact of infertility treatment on children's health. After ∼10 years of follow-up, 446 mothers and their 556 children attended clinical visits to measure blood pressure (BP), heart rate, arterial stiffness by pulse wave velocity (PWV), mean arterial pressure, lipids, high-sensitivity C-reactive protein (hsCRP), hemoglobin A1c (HbA1c), and anthropometrics. PARTICIPANTS/MATERIALS, SETTING, METHODS/METHODS:Women self-reported ever diagnoses of PCOS ∼4 months after delivery of their children in 2008-2010. Linear regression models applying generalized estimating equations to account for correlation within twins were used to examine associations with each childhood cardiometabolic outcome. MAIN RESULTS AND THE ROLE OF CHANCE/RESULTS:In this cohort with women oversampled on infertility treatment, ∼14% of women reported a PCOS diagnosis (n = 61). We observed similarities in BP, heart rate, PWV, lipids, hsCRP, HbA1c, and anthropometry (P-values >0.05) among children born to mothers with and without PCOS. Associations did not differ by child sex. LIMITATIONS, REASONS FOR CAUTION/CONCLUSIONS:The sample size of women with PCOS precluded further separation of subgroups (e.g. by hirsutism). The population-based approach relied on self-reported diagnosis of maternal PCOS even though self-report has been found to be valid. Participants were predominantly non-Hispanic White and a high proportion were using fertility treatment due to the original design. Differences in cardiometabolic health may be apparent later in age, such as after puberty. WIDER IMPLICATIONS OF THE FINDINGS/CONCLUSIONS:Our results provide some reassurance that cardiometabolic factors do not differ in children of women with and without self-reported PCOS during pregnancy. STUDY FUNDING/COMPETING INTEREST(S)/BACKGROUND:Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (contracts #HHSN275201200005C, #HHSN267200700019C, #HHSN275201400013C, #HHSN275201300026I/27500004, #HHSN275201300023I/27500017). The authors have no conflicts of interest. REGISTRATION NUMBER/BACKGROUND:NCT03106493.

The aim was to investigate the concentrations of some per- and polyfluoroalkyl substances (PFAS) in patients with pancreatic cancer from New York, and to compare them with a group of controls from the general population of the United States. We selected 50 cases of pancreatic cancer from donors to the New York University Pancreatic Biorepository. Controls were selected from the 2017"“18 National Health and Examination Survey sample (n = 167), matched to cases on age, sex, and race and ethnicity. Six PFAS were analyzed in serum samples using high performance liquid chromatography in conjunction with mass spectrometry. PFAS concentrations were categorized into tertiles to explore non-linear associations, and odds ratios (OR) were estimated using conditional logistic regression, adjusting by BMI. Most PFAS were not associated with pancreatic cancer risk. Serum perfluorohexane sulfonic acid (PFHxS) was associated with a decreased risk (OR for upper tertile = 0.24, 95% CI: 0.09, 0.67). In contrast, participants with the highest tertile of perfluoroundecanoic acid (PFUnDA) had a higher risk (OR = 2.60, 95% CI: 1.11, 6.09). Adjusting for BMI did not materially change the results. Study limitations include: in pancreatic cancer patients, blood used to measure PFAS was collected around the time of diagnosis; cases and controls could not be sampled from the same geographic location; slightly different laboratory methods were used to analyze PFAS in cases and controls. Most PFAS studied were not significantly associated with pancreatic cancer, except for PFHxS and PFUnDA, which exhibited opposite trends. Findings and limitations of the present study warrant further investigation with improved study designs and data on complex PFAS mixtures.