From Pesticide Exposure to Persistent Molecular Damage: An Integrated Framework of Genomic Instability, Epigenetic Dysregulation, and Long‐Term Toxicity

Abstract

ABSTRACT Pesticide toxicity is increasingly recognized as a chronic and mechanistically complex process extending beyond acute tissue injury. Evidence concerning cellular stress, genotoxicity, epigenetic alterations, susceptibility, and mixture effects has often been evaluated separately, limiting unified interpretation of persistent biological consequences. This review integrates experimental, epidemiological, and mechanistic evidence using an adverse outcome pathway (AOP)‐informed framework to organize pesticide‐associated molecular initiating events (MIEs), key events (KEs), key event relationships (KERs), and adverse outcomes (AOs), while distinguishing established AOPs from mechanistically plausible AOP‐informed modules. We examine interconnected oxidative, mitochondrial, calcium, endoplasmic reticulum, genomic, and epigenetic responses, with particular emphasis on bidirectional crosstalk between mitochondrial metabolism, redox signaling, and epigenetic regulation. Genetic susceptibility and combined pesticide exposure are also considered as modifiers of these relationships and of the persistence and biological significance of molecular changes. Particular attention is given to transient epigenetic responses, persistent epigenetic alterations, intergenerational effects, and true transgenerational inheritance, for which human evidence remains limited. Rather than assuming a single linear pathway, the review highlights convergent and branching relationships in which different pesticide classes may initiate distinct molecular events affecting overlapping downstream KEs. Molecular associations are not considered evidence of causal KERs without appropriate support from biological plausibility, temporal and dose–response concordance, mechanistic evidence, essentiality, and applicability. The review further considers how multi‐omics approaches, including MOFA/MOFA+, mixOmics, weighted gene co‐expression network analysis (WGCNA), and relevant toxicology/data resources, together with exposure assessment, chemical grouping, read‐across, and cumulative‐risk approaches, can provide complementary evidence within an AOP‐informed framework. The contribution of this review lies primarily in integrating and organizing existing evidence rather than proposing a new toxicological mechanism, AOP, or regulatory framework. Future toxicological strategies should integrate longitudinal evidence, susceptibility factors, exposure mixtures, and quantitative dose–response information to evaluate candidate KEs, their relationships, and relevance to AOs.