Lycopene Alleviates Atrazine-Induced Mitochondrial Tricarboxylic Acid Cycle Disorder and Associated Cardiac Cell Senescence and Cuproptosis.

Abstract

Atrazine (ATR), a widely employed triazine herbicide, poses multiorgan toxicity through environmental bioaccumulation. The potential link between chronic pesticide exposure and cardiovascular aging remains a critical yet underexplored public health concern. Lycopene (LYC), a natural carotenoid with antioxidative properties, demonstrates therapeutic potential against xenobiotic-induced pathologies, although its cardioprotective mechanisms against ATR require systematic elucidation. This study employed a chicken model to investigate cardiac outcomes following chronic ATR exposure with or without LYC intervention. Histopathological assessments revealed that LYC supplementation substantially mitigated the ATR-induced myocardial structural disorganization and interstitial abnormalities. Ultrastructural analysis confirmed the capacity of LYC to reverse the ATR-triggered mitochondrial architecture disruption. Mechanistic investigations identified that ATR exposure induces tricarboxylic acid (TCA) cycle disorder, leading to pathological copper ion accumulation. These metabolic disturbances were associated with elevated cellular senescence biomarkers and disrupted proteostasis. LYC administration demonstrated dual regulatory effects, effectively normalizing copper homeostasis and restoring mitochondrial metabolic flux. The findings establish that chronic ATR exposure promotes cardiac aging through TCA cycle-impaired-mediated cuproptosis, a novel pathway counteracted by LYC via modulation of copper metabolism and mitochondrial functionality. This study enhances our understanding of environmental-toxicant-induced cardiovascular pathogenesis and positions LYC as a promising therapeutic candidate for mitigating pesticide-associated cardiotoxicity.