4-Phenylbutyric acid alleviates acrylamide-induced sexual behavioral deficits and testicular damage in male Wistar rats: modulation of ER-stress associated signaling.

Acrylamide (ACR) is an industrial chemical utilized to produce polyacrylamide, a primary flocculant for wastewater treatment. ACR is also classified as a food process contaminant that forms as a byproduct during the processing of carbohydrate-rich foods at high temperatures (> 120 °C). Recent studies show that ACR induces reproductive toxicity, neurotoxicity, and skin irritation through mechanisms including oxidative stress and mitochondrial damage. Despite increasing evidence, ACR-induced testicular damage and its mechanisms remain poorly understood, highlighting the requirement for further investigation. In this study, we aimed to find the ameliorative effect of 4-Phenylbutyric acid (4-PBA) on the ACR-induced reproductive toxicity in male rats. Thirty-two adult male rats were randomly grouped, each containing eight rats: vehicle control group (10 ml/kg of saline; p.o.), ACR group (10 mg/kg of ACR: p.o.), ACR + 4-PBA low dose group (ACR + 4-PBA-500 mg/kg; p.o.), and ACR + 4-PBA high dose group (ACR + 4-PBA-1000 mg/kg; p.o.). ACR was administered for 28 days, while 4-PBA treatment was started on day 15 and continued until day 28. Our findings revealed marked alterations in sexual behavior, as evident by intromission latency, frequency, and ejaculation latency & frequency. Further, ACR exposure elicited significant oxidative stress and endoplasmic reticulum (ER) stress in the testicular tissue. Epididymal sperm count and serum testosterone level were also reduced in ACR-exposed rats. Correlation analysis further supported a close relationship between impaired reproductive performance, oxidative stress, ER stress activation, and testicular structural damage. However, 4-PBA treatment during the last 14 days of treatment significantly improved sexual performance, reversed the decreased testosterone level and sperm count, and restored testicular histopathological damage. Furthermore, these ameliorative effects were accompanied by reduced expression of GRP78, CHOP, and caspase-12, suggesting that modulation of ER stress-associated signaling may contribute to the therapeutic effects of 4-PBA.