Advances in the mechanisms of histone modification-mediated developmental toxicity induced by organophosphorus pesticides

Organophosphate pesticides (OPPs) are widely used and common environmental contaminants. Certain OPPs can cross the placenta and reach embryonic tissues, and prenatal exposure has been associated with developmental delays, structural abnormalities, and potential multigenerational effects. Beyond the classic mechanism of acetylcholinesterase inhibition, emerging evidence indicates that epigenetic dysregulation may contribute to OPP-induced developmental toxicity. However, the mechanistic evidence remains fragmented across different model systems and experimental designs, and a coherent framework to synthesize these disparate findings is currently lacking. Here, we propose a vertical-horizontal crosstalk framework to integrate current evidence on OPP-mediated histone modification disruption. Vertical crosstalk integrates upstream signaling pathways (e.g., Wnt/β-catenin and NF-κB) with the epigenetic machinery, while horizontal crosstalk encompasses interactions among histone modifications and between DNA methylation and histone modifications. By grading the strength of available evidence, we organize current findings to distinguish experimentally supported mechanisms from hypothetical pathways. We further examine in vitro evidence for non-enzymatic OPP-histone adduct formation, discuss whether this mechanism could contribute to persistent or multigenerational epigenetic effects, and evaluate the potential modulatory effects of co-occurring pollutants on the crosstalk network. Based on this synthesis, several major knowledge gaps remain, including causal validation of signaling-epigenetic mechanisms, clarification of epigenetic crosstalk, in vivo characterization of OPP-histone adducts, and evaluation of environmentally relevant exposure scenarios. Addressing these gaps will advance mechanistic understanding of histone-mediated pathways in OPP-induced developmental toxicity.