Longitudinal investigation of ovarian aging- the impact of PFAS - SUMMARY Early menopause (< 45 years) increases risks of osteoporosis, cardiovascular disease, and degenerative disorders, including cognitive decline and metabolic syndrome, whilelate menopause (> 55 years) increasestherisk of breast and endometrial cancer. While this points to the natural depletion of ovarian follicles (i.e., ovarian reserve) as a critical primary outcome of women's reproductive health, ovarian reserve decline has largely been ignored as a target to promote healthy aging in women. Despite evidence that environmental exposures such as per- and polyfluoroalkyl substances (PFAS) alter ovarian reserve, affect fertility, cause irregularities in menstrual cycle, and promote early or late menopause, how PFAS influence ovarian reserve remains poorly understood. Further, traditional approaches to PFAS research measure a limited subset of chemicals, failing to capture the breadth and complexity of the thousands of industrially released PFAS chemicals (i.e., the “PFAS-ome”). Therefore, this study leverages the MAternal MexicAns Programming Research in Obesity, GRowth, Environment, and Social Stressors (MAMAs PROGRESS) cohort to investigate the longitudinal relationship between PFAS-ome exposures and ovarian reserve decline. Over a 15-year reproductive window (ages 28–45), we will utilize state-of-the-art hybrid targeted/non-targeted liquid chromatography high-resolution mass spectrometry (LC-HRMS) to profile thousands of PFAS chemicals and endogenous endocrine metabolites. In Aim 1, we will define the integrated PFAS-ome across a reproductive decade (from the average age of 28 to 45) by characterizing temporal exposure patterns, calculating PFAS burden scores (an aggregate PFAS exposure metric), and evaluating the effect of excretion factors such as lactation, pregnancy, and menopause staging on PFAS levels. Aim 2 will determine how ovarian decline, measured via anti-mullerian hormone (AMH) levels, is affected by individual PFAS chemicals and mixtures, identifying critical timing for intervention. Aim 3 will define the endocrine metabolome of PFAS by identifying bile acids, hormones, and other steroids associated with PFAS exposure, as well as the endocrine pathways that mediate associations between PFAS and AMH. We will also develop precision health risk prediction models. This research will provide critical data on how ovarian aging is affected by one of the most prevalent toxic environmental exposures, PFAS. We will identify high-risk women before menopause and lay the foundation for future precision environmental health strategies to screen at-risk women to reduce the subsequent downstream adverse health risks from altered menopause timing.
