Counteracting Cadmium Toxicity: Selenium and Zinc as Modulators of Histological and Molecular Responses in Zebrafish

Aquatic ecosystems face growing threats from heavy metals, with cadmium (Cd) among the most toxic due to its persistence, lack of biological function, and ability to bio-accumulate. The liver, as the central organ for detoxification and trace element regulation, is particularly vulnerable. Selenium (Se) and zinc (Zn) are essential micronutrients with established roles in antioxidant defense and metal detoxification, yet their combined protective capacity against Cd-induced hepatotoxicity remains poorly defined. Here, we investigated the effects of dietary Se and Zn supplementation on Cd-exposed female zebrafish (Danio rerio). Growth indices, tissue metal levels, histological architecture, and expression of Zn transporters (zip8, zip10, znt1, znt5) and metal-responsive transcription factor 1 (mtf-1) were evaluated in groups of six fish each (n = 6). Cd exposure caused pronounced hepatic accumulation, depletion of Se, and disruption of Zn homeostasis, accompanied by histopathological lesions in liver, gills, and kidneys. At the molecular level, Cd strongly induced Zn transporters and mtf-1 expression, suggesting exploitation of Zn pathways for Cd handling. Se supplementation normalized Se balance and preserved hepatocyte architecture, while Zn enhanced transporter regulation. Notably, Se-Zn co-supplementation provided the most robust protection, limiting histological damage, and stabilizing trace element homeostasis across organs. These findings highlight a synergistic interplay in which Se reinforces micronutrient stability while Zn activates detoxification pathways. Together, Se and Zn emerge as promising complementary modulators of Cd toxicity, with relevance for ecotoxicological risk assessment and potential applications in aquaculture and environmental health.