Transcriptomic Insights into Developmental Toxicity of Per- and polyfluoroalkyl Substances (PFAS) in <i>Caenorhabditis elegans</i> : The Potential Key Role of Xenobiotic Detoxification Pathway

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants known to induce developmental toxicity across multiple species, yet the molecular mechanisms are still not fully understood. This study aims to evaluate the developmental toxicity of four long-chain legacy PFAS (PFOA, PFOS, PFNA, PFDA) and one short-chain alternative (PFBA) at concentrations relevant to highly contaminated scenarios (1–5 μM) using the model organism Caenorhabditis elegans, with a focus on elucidating the underlying molecular mechanisms. Phenotypic analysis indicated that PFDA and PFOS significantly delayed development of worms, and reduced the number of fertilized eggs in the uterus. RNA-seq and subsequent bioinformatic analysis revealed strong impacts of PFDA and PFOS on physiological age. A core set of xenobiotic detoxification genes (e.g., cyp-13A4, cyp-13A6, and cyp-13A7), which were found to be primarily regulated by nuclear hormone receptors (NHR-102, NHR-85, NHR-28), showed consistent up-regulation upon PFAS exposure. Gene coexpression network analysis (WGCNA) further linked this detoxification gene signature to developmental impairment. Cross-species comparison using public databases identified several evolutionarily conserved detoxification genes that are associated with PFAS-induced developmental toxicity, among which CYP3A4 and its orthologs appear to be potential biomarkers of PFAS exposure. Our findings demonstrate that activation of conserved xenobiotic detoxification pathways is a central transcriptomic signature of PFAS exposure─particularly PFOS and PFDA, which induced the most severe developmental toxicity among the five tested PFAS─providing mechanistic insights into the structure-dependent developmental toxicity of this kind of pervasive pollutant.