ATRA-mediated RAR-α activation attenuates acrylamide-induced testicular toxicity

Acrylamide (ACR) is an environmental reproductive toxicant with unclear testicular toxicity mechanisms. Retinoids are a group of compounds associated with vitamin A that function by stimulating retinoid receptors. We aimed in this study to further explore All-trans retinoic acids (ATRA) protective response against an acrylamide-induced testicular insult model and the underlying possible mechanisms. Fifty male rats were allocated into control, DMSO, ACR (40 mg/kg bwt, i.p. daily for 14 days), ATRA (7.5 mg/kg bwt, i.p. daily), and ACR + ATRA groups. Body and testes weights, sperm parameters, testosterone level, and lactate dehydrogenase-X (LDH-X) activity were measured. In addition, testicular levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), caspase-3, Bax, and Bcl-2 were determined. Also, tissues were examined for histopathologic changes and immune expression of retinoic acid receptor-alpha (RAR-α). ACR exposure resulted in decreased body and testis weights, sperm parameters, and lower LDH-X activity and testosterone levels, while GSH, CAT, and SOD activities decreased and MDA, TNF-α, IL-1β, and IL-6 increased. ACR induced apoptosis by raising caspase-3 and Bax and lowering Bcl-2 levels, along with reduced testicular RAR-α expression. In contrast, ATRA improved sperm parameters and testosterone levels, mitigated oxidative stress, and decreased inflammation and apoptosis markers, while restoring RAR-α expression. Morphometric and histopathologic studies supported these biochemical observations. Collectively, ATRA protects against ACR-induced testicular toxicity via RAR-α pathway, reducing oxidative stress, inflammation, and apoptosis, suggesting retinoid signaling as a treatment target in treating ACR-induced reproductive toxicities.