New insights on the role of some biometals in mancozeb induced hematological and hepatorenal toxicity in rats and the protective effect of naringin

Prolonged exposure to mancozeb (MZ), a frequently used fungicide, may cause oxidative stress damage to several organs; however, the mechanism of toxicity remains obscure. So, the present work sought to assess the contribution of some biometals, including Mn, Zn, Ca, and Fe, to the subacute hepatic and renal injury prompted by MZ-mediated oxidative stress and to evaluate the protective impact of naringin (NAR), a citrus-derived flavonoid, against this toxicity. Twenty-eight male Wistar rats were divided into four groups (n = 7) as follows: (1) control, (2) NAR (20 mg/kg bwt), (3) MZ (250 mg/kg bwt), and (4) NAR + MZ. The daily oral intake of MZ for 54 days induced marked hematological alterations, elevation in some hepatorenal markers, and alteration of the redox status of both liver and kidney tissues. There were marked histopathological alterations in both liver and kidney tissues that were confirmed by the immunohistochemical staining, which demonstrated strong iNOS and Bax along with weak Bcl-2 immunoexpression. The repeated exposure to MZ significantly increased the levels of Mn and decreased the levels of Ca, Zn, and Fe in both liver and kidney tissues, which attributed to upregulation of the mRNA levels of MT-1, CYP1A1, and casp-3 genes. On the other hand, the co-administration of NAR with MZ significantly reversed these toxic effects via improving the hematological profile, restoring antioxidant enzyme activity, and mitigating both hepatorenal function and structure. The data indicated that NAR had considerable protective effects against MZ-induced hepatorenal damage, mostly through enhanced antioxidant capacity, preservation of trace element equilibrium, and modulation of oxidative, inflammatory, and apoptotic pathways.