Ferulic acid mitigates 2-methoxyethanol-induced testicular oxidative stress via combined downregulation of FoxO1, PTEN, and modulation of Nrf2-Hmox1-NQO1 signaling pathway in rats

Abstract

Introduction: Ferulic acid (FERA) is a natural antioxidant that is richly found in herbs, including Ligusticum chuangxiong, Cimicifuga heracleifolia, and female ginseng (Angelica sinensis), which are utilized in modern Chinese medicine, and in cereals/grains including rice, which is mostly consumed by humans. 2METE on the other hand, is a ubiquitous substance that has many industrial applications, including use in the preparation of dyes for textiles, hydraulic fluid for automobiles, paints, and liquid soaps. It is a testicular toxin, which can induce oxidative stress in the testis of rats. Therefore, this study investigated the effect of FERA, which was concomitantly administered, against 2-methoxyethanol (2METE)-induced testicular oxidative stress in rats. Methods: Male Wistar rats totaling twenty (20), separated into four (4) groups, were used for the study. Rats in group one served as the control, rats in groups two and three were administered 100 mg/kg of 2METE only for 30 consecutive days, but only rats in group three were concomitantly treated with 50 mg/kg of FERA for the same duration, while rats in group four were treated with 50 mg/kg of FERA only. Results: Following analysis, 2METE administration caused a significant reduction in the relative testes weight (RTW), NAD(P)H quinone oxidoreductase 1 (NQO1), and reduced glutathione (GSH) levels, as well as superoxide dismutase (SOD) and glutathione S-transferase (GST) activities in the testis of rats compared with the control. Moreover, 2METE administration also significantly increased the testicular levels of malondialdehyde (MDA), nitric oxide (NO), and RNA gene expressions of heme oxygenase 1 (Hmox1), nuclear factor erythroid 2-related factor 2 (Nrf2), forkhead box protein O1 (FoxO1), and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) compared with the control. FERA treatment, on the other hand, significantly decreased the testicular levels of MDA, as well as Nrf2, Hmox1, PTEN, and FoxO1 gene expressions, and significantly increased the testicular GSH and NQO1 levels, activities of GST, SOD, glutathione peroxidase (GPx), and catalase (CAT) compared with 2METE only administered rats. Conclusion: 2METE-induced testicular oxidative stress, marked by the depletion of the endogenous antioxidant systems, was recorded, which resulted in the activation of PTEN, FoxO1, and Nrf2 genes in rats. FERA demonstrated a strong antioxidant effect by restoring the levels and activities of the endogenous antioxidants as well as downregulating the expressions of PTEN, FoxO1, and Nrf2 in the testis of rats.

Keywords

• Ferulic acid
• 2-methoxyethanol
• Oxidative stress
• Antioxidants