Association between perfluoroalkyl and polyfluoroalkyl substance exposure and reproductive lifespan and modifying effect of physical activity

Objective: To understand the association between the exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) and reproductive lifespan in women, and evaluate the modifying effects of physical activity (PA). Methods: Data were obtained from National Health and Nutrition Examination Survey during 1999-2000 and during 2003-2018. According to the inclusion and exclusion criteria, a total of 2 037 postmenopausal women were included. Reproductive lifespan of woman was defined as the number of years between age at menopause and age at menarche. Weighted generalized linear models (GLMs) and restricted cubic spline analyses were used to evaluate the associations between individual PFAS exposure and reproductive lifespan. The effect of modification by PA was evaluated by using stratified analyses and interaction terms (PFAS×PA) in GLM models. Weighted quantile sum regression and Bayesian kernel machine regression models were used to evaluate the effects of PFAS mixtures. Toxicogenomic analyses were performed by screening genes related to PFAS, PA, and reproductive lifespan. Results: The median reproductive lifespan of the study participants was 37.0 years. After adjusting for sociodemographic characteristics, lifestyles, and BMI, the higher serum concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and PFAS mixture were negatively associated with the reproductive lifespan (PFOS: β=-2.20, 95%CI:-3.50- -0.92; PFOA:β=-1.40, 95%CI: -2.70- -0.04; PFHxS: β=-1.70, 95%CI: -2.90- -0.50). PA might mitigate these adverse effects, with the strongest protective effect observed in those with high-level PA (PFOS: β=-1.10, 95%CI: -4.20-1.90; PFOA: β=2.70, 95%CI: -0.23-5.50; PFHxS: β=0.76, 95%CI: -1.70-3.20). Lipid metabolism and inflammatory responses were identified as key mechanisms. Conclusions: Higher PFAS exposure might shorten reproductive lifespan, and PA might mitigate this effect. The results indicated that lipid metabolism and inflammatory responses might be biological mechanisms underlying PFAS effects on reproductive lifespan. PA might mitigate these effects by modulating shared molecular targets.