Exposure of mice to environmentally relevant per- and polyfluoroalkyl substances (PFAS) alters the sperm epigenome

Abstract Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent synthetic chemicals and ubiquitous environmental contaminants. Mounting evidence demonstrates that PFAS can bioaccumulate and induce adverse health outcomes, including compromising male reproduction. Despite this, the mechanisms by which PFAS elicits these effects remain unclear. Here, we investigate how an environmentally relevant PFAS cocktail impacts the reproductive function of male Swiss CD1 mice. Following twelve weeks of continuous exposure, we collected blood samples for hormone and PFAS quantification and processed reproductive tissues and spermatozoa for histological and functional assessment. PFAS exposure significantly reduced the rate of daily sperm production, likely due to decreased circulating testosterone and dihydrotestosterone. Further, PFAS-exposed spermatozoa displayed marked alterations to their small non-coding RNA profile, which were linked to dysregulation of early-embryonic gene expression. Notably, these changes occured without significant alteration in sperm viability, motility, or the ability to undergo capacitation or support embryonic development. These findings provide new mechanistic insight into how PFAS exposure impacts male reproductive health.