A systems toxicology approach implicates post-transcriptional regulatory networks in reproductive defects from PFAS...

Per- and polyfluoroalkyl substances (PFAS) are highly persistent in the environment and widespread in consumer products, environmental media, and biological samples. However, limited toxicology data exist for many of the over 15,000 chemicals belonging to the PFAS family. Data are particularly lacking for exposures during germ cell development, which can have consequences for later-life fecundity. Here, we leverage the tractability of the model organism Caenorhabditis elegans to compare a "legacy" PFAS, i.e. perfluorooctane sulfonic acid (PFOS), with a chlorinated ether analog, 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA). We consistently observed negative effects of both PFOS and 6:2 Cl-PFESA on germ cell numbers along with increases in germline apoptosis and defective meiotic progression. These cellular observations corresponded with increases in embryonic lethality in offspring from developmentally exposed adults. Messenger RNA and small RNA sequencing revealed a clear signature of perturbation of the non-coding RNA-mediated germline regulatory network consistent with observed ex vivo disruption of P granules, liquid-like assemblages of RNA, and protein. Remarkably, we identified a strong gene-environment interaction between PFOS and 6:2 Cl-PFESA with another liquid-like structure, the synaptonemal complex (SC); syp3(OK758) hypomorphic mutants exhibited near-complete embryonic lethality with PFAS exposure. Thus, while performed at relatively high concentrations to ensure robust effect detection, our mechanistic findings provide a foundation for understanding the reproductive toxicity of PFAS across exposure scenarios. Altogether, our data show that the impacts of PFAS on germ cell development and function are associated with perturbation of liquid-like condensates, suggesting that PFAS physicochemical properties may contribute to their pleiotropic effects on biological systems.