Involvement of Nrf2-PPAR- signaling in Coenzyme Q10 protecting effect against methotrexate-induced testicular oxidative damage

Studies have identified Coenzyme Q10 (CoQ10) as a promising agent in improving idiopathic male infertility; however, its role in chemically or environmentally induced testicular dysfunction is not well-established. We investigated the potential of CoQ10 to attenuate methotrexate (MTX)-induced testicular damage and to identify molecular targets of CoQ10 effects. Wistar rats received a single intraperitoneal dose of 20 mg/kg MTX on the fifth day of the 10-day experimental protocol. 100 mg/kg CoQ10 was given orally daily for ten days, alone or combined with MTX. The testes of MTX-treated animals showed thickened tunica albuginea, distortion of seminiferous tubules with a marked reduction of germinal lining, a few primary spermatocytes with no spermatozoa, apoptotic cells, congested sub-capsular and interstitial blood vessels, and interstitial edema. Reduction of reproductive hormones and increased oxidative, inflammatory, and apoptotic biomarkers levels were also seen in the MTX-treated rats. CoQ10 + MTX-treated rats were protected against MTX-induced testicular histological changes and showed improvement in testosterone, luteinizing-, and follicle-stimulating hormone serum levels compared to the MTX group. The testes of the CoQ10 + MTX-treated rats showed reduced malondialdehyde, myloperoxidase, tumor necrosis factor-alpha, interleukin-6 and-1 beta and Bax: Bcl2 ratio and enhanced glutathione, and catalase compared to MTX alone. CoQ10 enhanced MTX-induced downregulation of Nrf2 and PPAR-gamma signaling and modulated its downstream targets, the inducible nitric oxide synthase, NF-kappa B, Bax, and Bcl2. In conclusion, CoQ10 targeted the Nrf2-PPAR-gamma signaling loop and its downstream pathways, mitigating MTXinduced oxidative stress-related damages and alleviating the testicular dysfunction MTX caused. Our data suggest Nrf2-PPAR-gamma signaling as a potential therapeutic target in testicular toxicity, where oxidative stress, inflammation, and apoptosis trigger damage.