Project Summary/Abstract Exposure to endocrine disrupting chemicals (EDCs) is widespread and these compounds can persist in the environment and the human body over decades. The population is aging, and women, in particular, can experience significant morbidity and diminished quality of life with aging. Recent epidemiologic data suggest that the timing of reproductive aging (the gradual decline in ovarian function with age) and the pattern of hormonal change during the menopausal transition influence women’s risk of chronic disease and their long- term health with aging. While numerous studies have examined adverse reproductive health effects and exposure to EDCs, little is known about how EDCs affect the timing or process of reproductive aging. Further, most existing epidemiologic studies on this topic have been cross-sectional with studies of age-at-menopause based on recall, limiting causal inference. In addition, combined exposure to various EDCs and pollutant- pollutant interactions (mixtures), as well as low-dose and non-monotonic dose-responses have been rarely if at all addressed. The proposed new epidemiologic study in a multi-ethnic cohort of women seeks to better understand how EDCs exposure affects the timing and characteristics of reproductive aging. We propose 1) to assess associations between EDC exposure (polychlorinated biphenyls, chlorinated pesticides, brominated flame retardants, and perfluorinated compounds) and timing of reproductive aging, including age at menopause and duration of the menopausal transition; 2) to assess the association between EDC exposure and hormonal characteristics during the menopausal transition, including levels and patterns of change in estradiol, follicle stimulating hormone, testosterone, sex-hormone binding globulin, and anti-Müllerian hormone; and 3) to examine the simultaneous effects of multiple EDCs and their interactions (mixture effects) on these reproductive aging outcomes using regression methods for high-dimensional covariates (multi-pollutant approaches). We will also explore effect modification by race/ethnicity and temporal variations in EDCs. We will capitalize on extensive phenotypic data and biospecimens collected for more than 15 years in an ongoing, large longitudinal cohort of women, the Study of Women’s Health Across the Nation (n=1,800 with a total of ~14,000 observations). This project addresses strategic priorities of the National Institute of Environmental Health Sciences, including disease pathogenesis by combined environmental exposures, as well as environmental health disparities. We will address these issues using innovative analytic approaches likely to yield new insights on the study of pollution mixtures and human health. The knowledge gained from this research may guide disease prevention initiatives; enhance women’s health and wellbeing as they age; and reduce environmental health disparities.

Project Narrative The proposed research is relevant to public health because comprehensive evaluation of the impact of multiple EDCs on reproductive aging will further our understanding of how complex exposures to EDCs may accelerate, delay or disrupt reproductive aging during this critical life stage. Such information would help inform the critical timing of interventions to effectively prevent or reduce the risk of chronic diseases and premature mortality. Thus, the proposed research is relevant to NIEHS’s mission that discovers how EDC exposures affect women’s health with aging in order to promote healthy aging.