Long-term exposure to environmentally relevant concentrations of hexafluoropropylene oxide dimer acid (GenX) induces trans-generational motor deficits through H3K27 demethylase jmjd-1.2 /PHF8 in Caenorhabditis elegans

Hexafluoropropylene oxide dimer acid (GenX) is one of many per-/polyfluoroalkyl substances (PFAS). GenX was developed as a shorter-chain alternative to traditional PFAS due to concerns about their documented toxicity. However, GenX contamination persists, and there has been limited research on its generational adverse effects. This study used Caenorhabditis elegans to evaluate adverse effects of long-term GenX exposure, and its trans-generational locomotive defect. The results showed that C. elegans development was significantly delayed when exposed to 10000 and 30000 μM of GenX; this was accompanied by substantial inhibition of reproduction and locomotion at concentrations ranging from 0.0003 to 10000 μM. Additionally, parental (P0 generation) exposure to environmentally relevant concentrations of GenX (0.0003 and 0.1 μM, or 0.1 and 33.0 μg/L, respectively), with no further exposure in the offspring (F1-F4), resulted in significant trans-generational declines in locomotion in the F1-F3 generations. The mRNA expression analysis found significant alterations in the genes associated with locomotive and epigenetic regulation, unc-17, spr-5, jmjd-1.2, damt-1, and nmad-1, in the P0 generation when exposed to 0.1 μM GenX. The changes in damt-1, nmad-1, spr-5 varied across generations, while a significant decrease in jmjd-1.2 persisted in the F1-F3 generations. No trans-generational effects on locomotion were observed in the jmjd-1.2 mutant strain; this indicates that jmjd-1.2 regulates the trans-generational locomotive defect. In conclusion, long-term exposure to environmentally relevant GenX concentrations induces trans-generational locomotor dysfunction in C. elegans. This is likely mediated by the gene jmjd-1.2, which is linked to both locomotion and epigenetic regulation. These findings provide valuable insights for future GenX generational toxicity evaluations and for assessing the mechanisms involved.