Tissue-specific oxidative stress and protective interventions in malathion-induced toxicity in rodent models: A comprehensive review

Malathion, a widely used organophosphate insecticide, causes occupational and environmental exposures globally. Conventional understanding emphasizes cholinergic toxicity; however, accumulating evidence reveals profound non-cholinergic oxidative stress pathways relevant to chronic, low-dose human exposures. Experimental rodent studies characterizing malathion toxicity and protective interventions remain systematically unsynthesized. This systematic review synthesizes evidence from rodent studies to establish malathion toxicity mechanisms, compare protective intervention efficacy, and identify research gaps with implications for occupational health. Liver and kidney are primary malathion target organs, exhibiting dose-dependent lipid peroxidation increases (30-200 % above controls) and antioxidant depletion (20-50 % glutathione reduction). Brain toxicity involves both cholinergic and oxidative stress-mediated mechanisms with mitochondrial dysfunction contributing to neurobehavioral impairment. Male reproductive toxicity is pronounced, with testicular oxidative stress and decreased testosterone. Developmental exposures via lactation produce persistent multi-organ oxidative damage extending into later postnatal periods. Protective interventions spanning natural phytochemicals (silymarin, quercetin, resveratrol), micronutrients (vitamin E, selenium, zinc), and synthetic antioxidants (N-acetylcysteine) demonstrated consistent protective efficacy in attenuating malathion-induced oxidative damage across organ systems. Protective mechanisms involve Nrf2 pathway activation, antioxidant enzyme upregulation, and modulation of inflammatory and apoptotic signaling. Heterogeneous biomarker platforms, limited dose-response characterization, inadequate organ system coverage, sparse sex-disaggregated data, and insufficient human translational studies impede evidence synthesis and occupational health applications. This systematic review establishes oxidative stress as a central malathion toxicity mechanism and provides the first comprehensive comparison of protective intervention efficacy. Future research priorities include standardizing biomarker assessment, implementing dose-response modeling, conducting longitudinal studies, and validating biomarkers in occupationally exposed populations to support evidence-based occupational exposure limits and protective strategies.