Transcriptomic insights into developmental toxicity of per- and poly-fluoroalkyl substances (PFAS)  in Caenorhabditis elegans (PRJCA048336)
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants known to induce developmental toxicity across multiple species, yet their molecular mechanisms remain poorly understood. This study employed the model organism Caenorhabditis elegans to comparatively assess the developmental toxicity of four long-chain legacy PFAS (PFOA, PFOS, PFNA, PFDA) and one short-chain alternative (PFBA) at environmentally relevant concentrations. Phenotypic analysis revealed that PFDA and PFOS significantly delayed organismal development and reduced the number of uterine fertilized eggs. Bulk RNA sequencing and subsequent bioinformatic analysis estimated the impact of PFAS on physiological age, which confirmed the developmental delay induced by PFDA and PFOS. By removing the confounding effect of physiological age on gene expression, we uncovered PFAS-specific transcriptional perturbations. This approach identified a core set of xenobiotic detoxification genes-notably cyp-13A4, cyp-13A6, and cyp-13A7-that were consistently upregulated upon PFAS exposure, and these genes were found to be primarily regulated by nuclear hormone receptors (NHR-102, NHR-85, NHR-28). Gene co-expression network analysis (WGCNA) further linked this detoxification gene signature to developmental impairment. Cross-species comparison using public databases identified several evolutionarily conserved PFAS-responsive detoxification genes linked to developmental toxicity, among which CYP3A4 orthologs emerged as a critical candidate biomarker for PFAS exposure. Our findings demonstrate that activation of conserved xenobiotic detoxification pathways is a central transcriptomic signature of PFAS exposure and provide mechanistic insights into the structure-dependent developmental toxicity of these pervasive pollutants.