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

Abstract

Abstract Acrylamide (ACR) is an environmental reproductive toxicant with unclear testicular toxicity mechanisms. Retinoids are a group of vitamin A-related compounds that function by activating retinoid receptors. We aimed in this study to further explore All-trans retinoic acid’s (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 led to reduced body and testicular weights, impaired sperm parameters, and suppressed reproductive hormones (testosterone, FSH, LH). Testicular LDH-X activity decreased, along with reduced testicular RAR-α expression. Oxidative stress resulted in GSH depletion, reduced CAT and SOD activities, and increased MDA. ACR also triggered inflammation and apoptosis, with elevated TNF-α, IL-1β, IL-6, caspase-3, Bax. In contrast, ATRA improved sperm parameters and levels of hormones, restored RAR-α expression, mitigated oxidative stress, and decreased inflammation and apoptosis markers. Morphometric and histopathologic studies supported these biochemical observations. Overall, RAR-α agonist (ATRA) is linked to attenuation against ACR-induced testicular damage, along with a reduction in oxidative stress, inflammation, and cell death. These findings suggest that retinoid signaling might serve as a possible therapeutic target for reproductive toxicities induced by ACR, necessitating further mechanistic exploration.