Perfluoroalkyl and Polyfluoroalkyl Substances and Women's Health: A Possible Etiology for Earlier Menopause and Accelerated Reproductive Aging

Abstract

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are ubiquitous environmental toxicants used in consumer products and industry, such as non-stick cookware, food packaging materials, personal care products, and aqueous fire-fighting foams. PFAS have received unprecedented attention recently due to nationwide drinking water contamination that impacts up to 110 million residents in the United States. Due to the widespread use and chemical stability of these compounds, more than 98% of the general population in the United States likely has at least one PFAS detectable in their blood. Growing evidence suggests that ovaries may be a potential target for PFAS toxicity. The ovary is a primary regulator of reproductive and endocrine function in females. Menopause marks the cessation of ovarian function, and its timing has physiologic impacts beyond the reproductive system. As age at the final menstrual period reflects a woman’s overall health, investigation of the role of potential endocrine-disrupting chemicals in ovarian aging is warranted.

The overall goal of my dissertation was to explore the impact of PFAS on ovarian aging and timing of natural menopause. The following specific aims were tested using a community-based, longitudinal cohort of midlife women, the Study of Women’s Health Across the Nation (SWAN).

Aim 1 examined temporal variations in serum concentrations of PFAS and determined assessed whether the time trends differed by race/ethnicity, menstruation status and parity to better understand longitudinal changes in PFAS across the menopausal transition. We observed longitudinal declines in serum concentrations of legacy PFAS including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and their precursors but increases in other PFAS compounds such as perfluorononanoic acid (PFNA) from 1999 to 2011. Menstruating women had consistently lower concentrations than non-menstruating women. Temporal trends in PFAS concentrations were not uniform across race/ethnicity and parity groups.

Previous epidemiologic studies of PFAS and menopausal timing conducted in cross-sectional settings were limited by reverse causation bias because PFAS serum concentrations increase after cessation of menstrual bleeding. Aim 2 examined the associations between PFAS exposure and incident natural menopause among 1120 midlife women aged 45-56 years at baseline from 1999 to 2017. Higher serum concentrations of PFOA and PFOS were associated with earlier onset of natural menopause, a risk factor for adverse health outcomes in later life. Women were classified into four clusters based on their overall PFAS concentrations as mixtures: low, low-medium, medium-high, and high. Compared to the low cluster, the high cluster had a HR of 1.66 (95% CI: 1.17-2.36), which is interpreted as 1.8 years earlier experience of natural menopause which is equivalent to the impact of smoking tobacco.

Aim 3 explored the mediating role of follicle-stimulating hormone (FSH) in the associations between PFAS exposure and incident natural menopause to understand potential underlying mechanisms. The proportion of the effect mediated through FSH was 26.9% (95% CI: 15.6%, 38.4%) for linear PFOA and 13.2% (95% CI: 0.0%, 24.5%) for branched PFOS. The effect of PFAS on natural menopause may be partially explained by their association with variations in FSH concentrations.

Overall this dissertation provides evidence that PFAS exposure may accelerate ovarian aging, possibly through endocrinologic mechanisms associated with changing serum concentrations of FSH. Future studies that can confirm these findings and steps to limit exposure to these chemicals appear warranted.