Perfluoroalkyl and polyfluoroalkyl substances (PFAS) in trace levels via drinking water diminishes mouse embryo mitochondria function across three generations

Perfluoroalkyl and polyfluoroalkyl substances (PFAS), synthetic and resistant to degradation, are present at trace levels in municipal drinking water. PFAS exposure is associated with female infertility and developmental anomalies, yet how these compounds influence ovarian function and embryogenesis is not understood. Thus, the impact of exposure to PFAS via drinking water on oocyte viability and embryo development was examined. The local tap water was found to contain ∼3 ng/L PFAS, primarily PFOS, PFOA, and PFHxS. Female mice were then given purified water containing 5 ng/L or 50 ng/L of these same three PFAS compounds or drinking fountain (tap) water for 4 weeks or 6 months. Ovulation, oocyte quality, embryo development and fetal weight were analyzed across three generations. Embryos from PFAS-exposed females (5 ng/L or 50 ng/L PFAS or tap water) exhibited impaired mitochondrial function, DNA damage and fewer cells, and reduced fetal weight. Embryo phenotypes were similar whether females were PFAS-exposed for 4 weeks, 6 months or just the first 4 weeks of the 6 months. Offspring drank purified water, yet fertility analysis showed similar embryonic and neonatal phenotypes in the F1 'daughters' of the PFAS-exposed females, and in the embryos of F2 females ('granddaughters' of PFAS-exposed females). To determine causality and whether defects are reversible, embryos were treated mitochondria-modulating compounds, with responses indicating that PFAS exposure irreversibly impairs key aspects of mitochondrial function. These findings identify cellular targets and mechanisms by which PFAS disrupt female fertility; reveal that PFAS cause intergenerational changes in mammalian embryos; and have important implications for water quality policies.