HFPO homologues, the novel alternatives to PFOA, impair male reproduction in mice through inducing mitochondrial dysfunction

Hexafluoropropylene oxide (HFPO) homologues (HFPOs), presenting HFPO-dimeric acid (DA), HFPO-trimeric acid (TA) and HFPO-tetrameric acid (TeA), are emerging replacements for legacy perfluorooctanoic acid that are increasingly used for a variety of industrial applications. These novel fluorinated compounds have attracted much attention due to their environmental ubiquity and potential toxicities. However, there is a lack of clarity about their toxicological impact on male reproductive health. In our study, the mouse model was used to investigate the toxic effects of HFPOs on male reproductive function and their underlying mechanisms. The results revealed that male mice exposed to HFPOs for 8 weeks presented structural and functional abnormalities in the testis and mature sperm, as evidenced by destructed seminiferous tubule, decreased testosterone levels and sperm quality. Furthermore, treatment with HFPOs elevated reactive oxygen species and malondialdehyde content and diminished superoxide dismutase activity and succinate dehydrogenase levels, along with downregulated anti-apoptotic BCL-2 expression and upregulated pro-apoptotic BAX expression. Moreover, oral administration of HFPOs impaired testicular mitochondrial structure along with reduction in ATP content and mitochondrial DNA copy number and disruption of mitochondrial dynamics. In summary, HFPOs can impair male fertility by disrupting spermatogenesis and reducing sperm quality through multiple mechanisms, including mitochondrial dysfunction-induced oxidative stress, apoptosis, and suppression of steroidogenesis. This work aims to improve our comprehension regarding the potential risks and adverse impacts of exposure to HFPO congeners on male reproductive health.