Azoxystrobin induces progressive testicular damage in dose-dependent manners via disrupting androgen receptor and TGF-β signaling pathway: A biochemical, histological, and hormonal evidence.

Azoxystrobin (AZO) is a broad-spectrum fungicide that has been reported to induce severe organ toxicity in non-target organisms. The current research project explored the dose-response toxic effects of AZO on testicular tissues. Forty-eight male Sprague Dawley rats were divided into control, AZO (125 mg/kg), AZO (250 mg/kg), and AZO (500 mg/kg) treated group. AZO intoxication at all the tested doses upregulated the gene expression of TGF-β1, SMAD2, CYP19A1, FKBP5, SMAD3, COL1A1 and TGFBR1 while suppressing the expression of 3β-HSD, AR, SRD5A1, StAR, 17β-HSD, and KLK3. The levels of ROS and MDA were promoted coupled with significant reduction in the activities of HO-1, CAT, GPx, GSR, GST, and SOD after AZO administration. Besides, AZO exposure adversely altered sperm count, viability, and morphology at all the administered doses. Similarly, the levels of LH, FSH, and testosterone were suppressed following the administration of AZO. Testicular tissues showed severe pro-inflammatory response as indicated by high levels of NF-κB, TNF-α, IL-6, IL-1β, and COX-2 in response to AZO exposure. Histopathological analysis showed testicular disruptions including reduced diameter of seminiferous tubules, degeneration of Leydig cells, thinning of germinal epithelium, vascular congestion, and necrosis in dose-dependent manners of AZO exposure. Our biochemical and histological findings are further supported by computation analysis which revealed that AZO have strong affinity to bind with key regulatory genes thereby influencing their expressions.