Protective effect of iron against cadmium-induced lesions in rat testis via downregulation of NQO1/Nrf2 and NF-κB

Abstract At low concentrations, cadmium (Cd) stimulates expression of cytoprotective genes. Cadmium induces the mRNA of NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), which are nuclear factor (erythroid-derived 2)-like (Nrf2) transcription enzymes. Hence, the current study was designed to evaluate the probable protective role of iron (Fe) on Cd toxicity on the gonads of male rats. Twenty adult male albino rats were divided into four groups. The groups were designated as group A-control (rats exposed to exogenous Cd- and Fe-free water), group B (rats exposed to Cd-tainted water), group C (rats exposed to Fe-tainted water) and group D (rats exposed to Cd and Fe-tainted water concomitantly). The rats were initially gavaged with 0.229 mg/L Cd and 1.900 mg/L Fe tainted water, and the remaining solution was provided as drinking for the 4-week duration. Biochemical assays, hormone profiling, gene expression analysis, and histopathological evaluations were conducted on serum, plasma and testicular tissues. The study reveals that Cd induces oxidative stress, evidenced by decreased catalase (CAT) activities, whereas iron exposure showed antioxidant effects with alterations in malondialdehyde (MDA) levels. Concomitant exposure to Cd + Fe shows a reversal in the CAT activity in the serum of Cd-exposed rats. The levels of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) were significantly increased (p ≤ 0.05) in the plasma of rats exposed to Cd and Cd + Fe relative to the control. The testosterone and estradiol levels were significantly modulated in the plasma of rats exposed to Cd and Cd + Fe relative to the control. Exposure of rats to Cd only and Cd + Fe significantly downregulated HO-1 relative to the control. The mRNA level of NQO1 was significantly upregulated in the Cd only group relative to the control, but downregulated in the Cd + Fe group. The levels of Nrf2 and nuclear transcription factor kappa B (NF-κB) were upregulated in Cd only but downregulated in the Cd + Fe group relative to the control. Cadmium-induced alteration in mRNA levels in NQO1, Nrf2 and NF-κB was reversed in the presence of Fe. Histological changes in the testis of Cd-intoxicated rats were ameliorated in the presence of Fe. In conclusion, iron has the potential to offer protection against Cd-induced lesions in rat testis via a mechanism involving downregulation of NQO1/Nrf2 and NF-κB.