Nowadays, exposure to heavy metals and their detrimental effects in humans are grave health concerns. In this study, we investigated the protective effect of resveratrol (RES) against CdCl2 (cadmium chloride)-induced impairment of spermatogenesis, histopathological alterations, and the up-regulation of epidermal growth factor receptor (EGFR) signaling cascade in Swiss albino mice. Two different doses of CdCl2 were injected intraperitoneally into two groups of mice, and in the third group RES was administered orally before injecting CdCl2 (3 times/wk) for 14 days. Sperm motility, count, vitality, and morphology were analyzed. Hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and western blot analyses were performed on testis tissue. In CdCl2-administered animals, significant perturbations of spermatogenesis and histoarchitecture of seminiferous tubules were observed. p-EGFR, p-AKT, AKT1/2/3, NF-κβ (p50), and COX-2 of the EGFR cascade were up-regulated. Although there was significant negative correlation between percentage of motile cells and protein expression, we found positive correlation between morphologically abnormal cells and overexpression of proteins in CdCl2-only treated groups. Marked improvement of sperm parameters and histopathological damages as well as down-regulation of the EGFR signaling cascade were observed in the RES-pretreated mice. Hence, the present study elucidates that RES protects against CdCl2-induced perturbation of spermatogenesis and overexpression of EGFR and its downstream signaling proteins.

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Cadmium and lead are widespread, nonbiodegradable heavy metals of perpetual environmental concerns. The present study aimed to evaluate whether sub‐chronic exposure to cadmium chloride (CdCl2) and lead acetate [Pb(CH3COO)2] induces reproductive toxicity and development of testicular germ cell neoplasia in situ (GCNIS) in swiss albino mice. The effects of resveratrol to reverse the metal‐induced toxicity were also analyzed. The mice were randomly divided into four groups for metal treatments and two groups received two different doses of each metal, CdCl2 (0.25 and 0.5 mg/kg) and Pb(CH3COO)2 (3 and 6 mg/kg). The fourth group received oral doses of 20 mg/kg resveratrol in combination with 0.5 mg/kg CdCl2 or 6 mg/kg Pb(CH3COO)2 for 16 weeks. Toxic effects of both metals were estimated qualitatively and quantitatively by the alterations in sperm parameters, oxidative stress markers, testicular histology, and protein expressions of the treated mice. Pronounced perturbation of sperm parameters, cellular redox balance were observed with severe distortion of testicular histo‐architecture in metal exposed mice. Significant overexpression of Akt cascade and testicular GCNIS marker proteins were recorded in tissues treated with CdCl2. Notable improvements were observed in all the evaluated parameters of resveratrol cotreated mice groups. Taken together, the findings of this study showed that long‐term exposure to Cd and Pb compounds, induced acute reproductive toxicity and initiation of GCNIS development in mice. Conversely, resveratrol consumption abrogated metal‐induced perturbation of spermatogenesis, testicular morphology, and the upregulation of Akt cascade proteins along with GCNIS markers, which could have induced the development of testicular cancer.

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