Histone Methylation-Mediated Reproductive Toxicity to Consumer Product Chemicals in Caenorhabditis elegans: An Epigenetic Adverse Outcome Pathway (AOP)

The significance of histone methylation in epigenetic inheritance underscores its relevance to disease and the chronic effects of environmental chemicals. However, limited evidence of the causal relationships between chemically induced epigenetic changes and organismal-level effects hinders the application of epigenetic markers in ecotoxicological assessments. This study explored the contribution of repressive histone marks to reproductive toxicity induced by chemicals in consumer products in Caenorhabditis elegans, applying the adverse outcome pathway (AOP) framework. Triclosan (TCS) and tetrabromobisphenol A (TBBPA) exposures caused reproductive toxicity and altered histone methyltransferase (HMT) and histone demethylase (HDM) activities, increasing the level of trimethylation of H3K9 and H3K27. Notably, treatment with an H3K27-specific HMT inhibitor alleviated reproductive defects and the transcriptional response of genes related to vitellogenin, xenobiotic metabolism, and oxidative stress. Comparison of points of departure (PODs) based on calculated benchmark concentrations (BMCs) revealed the sensitivity of histone-modifying enzyme activities to these chemicals. Our findings suggest that the 'disturbance of HMT and HDM' can serve as the molecular initiating event (MIE) leading to reproductive toxicity in the epigenetic AOP for TCS and TBBPA. The study extended the biological applicability of these enzymes by identifying model species with analogous protein sequences and functions. This combined approach enhances the essentiality, empirical support, and taxonomic domain of applicability (tDOA), which are crucial considerations for ecotoxicological AOPs. Given the widespread use and environmental distribution of chemicals in consumer products, this study proposes histone-modifying enzyme activity as an effective screening tool for reproductive toxicants and emphasizes the integration of epigenetic mechanisms into a prospective ERA.