Mitigation of radiation mediated testicular dysfunction by α-tocopheryl succinate: PPAR-γ related pathway

Radiation exposure of sensitive organs during radiotherapy merits extraordinary consideration, particularly when the concern is about fertility. Although alpha-tocopheryl (vitamin E) is a potent antioxidant, many studies have demonstrated the radioprotective impact of alpha-tocopheryl acetate ester, emphasizing its antioxidant and anti-apoptotic effects; fewer studies were conducted using the succinate ester without any declaration of its anti-inflammatory effect in the concerned pathology. Accordingly, the current study was conducted to evaluate the dual antioxidant and anti-inflammatory role of alpha-tocopheryl succinate (α-TCS) in reproductive toxicity induced by gamma-irradiation.

Animals were subjected to 6 Gy of whole-body gamma radiation and received α-TCS (200 mg/kg, P.O.) pre- and post-radiation. After the termination of the experiment, serum testosterone was estimated, and the testis weight was recorded. Besides, the testicular content of oxidative balance markers [malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT)] and inflammatory response markers [interleukin-1β (IL-1β), nuclear factor-kappa B (NF-κB) p65, peroxisome proliferator-activated receptor-γ (PPAR-γ)] were assessed.

Irradiated (IR) rats showed disturbances in the testicular function and abnormal incidental lesions, as demonstrated in the histopathological examinations. They exhibited marked alterations in the testicular oxidative balance, verified by the rise of lipid peroxidation end product (MDA) and depletion of antioxidant enzymes (CAT and SOD). Also, radiation exposure triggered an inflammatory response, which was evidenced by suppression of PPAR-γ and intensified expression of NF-κB p65 subunit, with subsequent elevation in IL-1β testicular content. Conversely, administering α-TCS to IR rats maintained the testicular architecture and ultrastructure while also preserving testicular function. Treatment with α-TCS restored the oxidative balance (MDA, SOD and CAT) and reduced testicular content of pro-inflammatory cytokine IL-1β via interference with the NF-κB p65/ PPAR-γ signaling pathway.

The current study sheds light on the crucial radioprotective role of α-TCS as a PPAR-γ agonist in maintaining testicular function partially through suppressing NF-κB activation and its downstream pro-inflammatory mediators.