PFHxS Mediates Paternal Metabolic Disorders and Reproductive Abnormalities in Male Mouse Offspring through Sperm sncRNA

Abstract Perfluorohexanesulfonate (PFHxS), a widely used per- and polyfluoroalkyl substance, has been shown to impair testicular and hepatic function in mammals. Whether paternal PFHxS exposure exerts intergenerational effects on offspring health remains unclear. Here, we examined the impact of paternal PFHxS exposure on reproductive and hepatic health in male offspring and explored the underlying molecular mechanisms. Paternal PFHxS exposure induced reproductive dysfunction (notably reduced sperm motility and progressive motility) and hepatic dysfunction (hepatic lipid accumulation) in male offspring, mirroring paternal phenotypes. Mechanistically, paternal PFHxS exposure was associated with changes in epididymal nuclease expression and remodeling of the sperm sncRNA profile. After RNase L or Dicer knockdown, some sncRNAs changed in the same direction as observed in vivo, with greater agreement for miRNAs than for tsRNAs. These findings suggest that RNase L and Dicer may be among the key molecules involved in regulating PFHxS-associated sperm sncRNA remodeling. Overall, our data support a possible role of altered sperm RNA cargo in the intergenerational reproductive and hepatic effects associated with paternal PFHxS exposure. These data underscore the pivotal role of sncRNAs in mediating intergenerational effects of environmental contaminants and highlight the importance of preconception paternal interventions to mitigate PFHxS-related health risks.