Multigenerational exposure to per- and polyfluoroalkyl substances (PFAS) negatively impacts the reproductive health of male mice.

Widespread exposure to per- and polyfluoroalkyl substances (PFAS) poses substantial health risks to humans and animals. PFAS have the propensity to bioaccumulate in organs such as the testes, wherein they have been implicated in adverse effects on sperm production and quality. Here, we sought to understand the multigenerational implications of such effects by chronically subjecting three generations of mice to an environmentally relevant PFAS cocktail and subsequently investigating impacts on reproduction, behavior and offspring development. This strategy confirmed that testicular accumulation of PFAS is correlated with compromised rates of sperm production and alterations to the sperm epigenome but did not compromise the overall fertility or behavioral outcomes explored in PFAS-exposed males. Notably, the negative effects were more pronounced in F1 offspring compared with subsequent F2 and F3 generations. These data support mounting evidence of adverse associations between PFAS exposure and reproductive capacity, but suggest the risk posed by PFAS is not amplified across three generations.