Selenium Supplementation Mitigates Copper-Induced Systemic Toxicity via Transcriptomic Reprogramming and Redox Homeostasis in Mice

Copper is an essential trace element that supports numerous physiological functions; however, excessive copper accumulation can disrupt cellular and biological processes. In this study, forty-eight male mice were randomly divided into four groups (n = 12): Control (fed normal rice), Cu300 (300 mg/kg copper), Cu300+Se (Cu300 + selenium-enriched rice), and Cu300+iSe (Cu300 + 1 mg/kg iSe), and were treated for 180 days. Copper exposure resulted in reduced body weight, hepatomegaly and nephritis, elevated copper deposition in organs, oxidative stress, and significant declines in RBC, HGB, and WBC counts, leading to anemia and immunosuppression. Selenium supplementation, effectively mitigated these effects by reducing copper accumulation, restoring antioxidant balance, and enhancing selenoprotein-related functions. Histopathological analysis revealed that copper toxicity induced hydropic degeneration and focal necrosis in hepatic and renal tissues, effects that were significantly attenuated by selenium supplementation. Transcriptomic profiling revealed that selenium-enriched rice reversed copper-induced gene expression changes. In the liver, selenium treatment significantly upregulated protective genes such as <i>Slc7a</i>, <i>Bola1</i>, <i>Uqcrq</i>, <i>Dtx1</i>, and <i>Znrd2</i>, while downregulating stress-related genes like <i>Trim75</i>, <i>Dpm3</i>, <i>Moxd1</i>, <i>Tnfrsf25</i>, and <i>Gpr75</i>. In the kidneys, selenium enhanced the expression of detoxification and immune-modulating genes (<i>Mt1</i>, <i>Mt2</i>, <i>Rhbdl1</i>, <i>Crisp3</i>, <i>Mif</i>) and suppressed stress-related genes (<i>Nnt</i>, <i>Ifi44l</i>, <i>NLRP12</i>, <i>Eno1b</i>, <i>Ugt1a</i>), demonstrating its role in mitigating oxidative and inflammatory stress. Collectively, these findings demonstrate that selenium-enriched rice exerts potent protective effects against chronic copper toxicity through multiple mechanisms: (1) restoration of mitochondrial function, (2) attenuation of ER stress and apoptosis, (3) enhancement of antioxidant and detoxification pathways, and (4) modulation of metabolic and immune responses. This study highlights selenium-enriched rice as a promising nutritional intervention for mitigating chronic copper toxicity and maintaining hepatorenal health.