Abstract
Network analysis has provided valuable insights into the mechanisms underlying the hepatoprotective effects of manganese (Mn) in rats subjected to atrazine (ATZ) intoxication. Key hub genes, including STAT3, PPARG, GSK3B, HIF1A, ESR1, START1, MTOR, PPARA, PARP1, and MMP2, were identified as being involved in oxidative stress response, signalling pathways, nuclear receptor activity, ligand-activated transcription factor activity, and the prolactin signalling pathway. This study also employed in vivo toxicology methods to elucidate the multifaceted mechanisms of Mn-mediated hepatoprotection. Male Wistar rats (n = 30, ± 150 g) were randomly assigned into five groups and treated by gavage for 28 consecutive days: Control (corn oil), ATZ alone (10 mg/kg), Mn alone (10 mg/kg), ATZ + Mn (2.5 mg/kg each), and ATZ + Mn (10 mg/kg each). On day 29, body weights were measured, and biochemical assessments were conducted to evaluate antioxidant enzyme profiles, inflammatory biomarkers, oxidative stress markers, and liver function. Treatment with ATZ significantly reduced (p < 0.05) body weight gain compared to the control group. Markers of liver and kidney dysfunction (AST, ALT, ALP, LDH, GGT, creatinine, and urea) were significantly elevated (p < 0.05) in the ATZ-treated rats. Exposure to ATZ also decreased (p < 0.05) in endogenous antioxidant defences, including superoxide dismutase, catalase, glutathione peroxidase, total sulfhydryl, reduced glutathione, and glutathione-S-transferase. Furthermore, administration of ATZ increased (p < 0.05) oxidative stress and inflammatory biomarkers (xanthine oxidase, hydrogen peroxide, nitric oxide, myeloperoxidase, reactive oxygen and nitrogen species, and lipid peroxidation), as well as DNA fragmentation. Remarkably, Mn treatment (2.5 and 10 mg/kg) counteracted these alterations, mitigating oxidative stress, inflammation, and DNA damage induced by ATZ. Network toxicology findings corroborated these in vivo results, highlighting the ameliorative effects of Mn on ATZ-induced hepatorenal toxicity through diverse biochemical pathways. In conclusion, this study demonstrates that Mn exerts significant hepatoprotective effects against ATZ-induced toxicity, as evidenced by network pharmacology and experimental data insights. The findings suggest that Mn mitigates oxidative stress, inflammation, and hepatorenal damage through multiple molecular and biochemical mechanisms.