Histone\nMethylation-Mediated Reproductive Toxicity\nto Consumer Product Chemicals in <i>Caenorhabditis elegans</i>: An Epigenetic Adverse Outcome Pathway (AOP)

The significance\nof histone methylation in epigenetic inheritance\nunderscores its relevance to disease and the chronic effects of environmental\nchemicals. However, limited evidence of the causal relationships between\nchemically induced epigenetic changes and organismal-level effects\nhinders the application of epigenetic markers in ecotoxicological\nassessments. This study explored the contribution of repressive histone\nmarks to reproductive toxicity induced by chemicals in consumer products\nin <i>Caenorhabditis elegans</i>, applying the adverse outcome\npathway (AOP) framework. Triclosan (TCS) and tetrabromobisphenol A\n(TBBPA) exposures caused reproductive toxicity and altered histone\nmethyltransferase (HMT) and histone demethylase (HDM) activities,\nincreasing the level of trimethylation of H3K9 and H3K27. Notably,\ntreatment with an H3K27-specific HMT inhibitor alleviated reproductive\ndefects and the transcriptional response of genes related to vitellogenin,\nxenobiotic metabolism, and oxidative stress. Comparison of points\nof departure (PODs) based on calculated benchmark concentrations (BMCs)\nrevealed the sensitivity of histone-modifying enzyme activities to\nthese chemicals. Our findings suggest that the ‘disturbance\nof HMT and HDM’ can serve as the molecular initiating event\n(MIE) leading to reproductive toxicity in the epigenetic AOP for TCS\nand TBBPA. The study extended the biological applicability of these\nenzymes by identifying model species with analogous protein sequences\nand functions. This combined approach enhances the essentiality, empirical\nsupport, and taxonomic domain of applicability (tDOA), which are crucial\nconsiderations for ecotoxicological AOPs. Given the widespread use\nand environmental distribution of chemicals in consumer products,\nthis study proposes histone-modifying enzyme activity as an effective\nscreening tool for reproductive toxicants and emphasizes the integration\nof epigenetic mechanisms into a prospective ERA.