Mechanistic aspects of ameliorative effects of Eicosapentanoic acid ethyl ester on methotrexate-evoked testiculopathy in rats

• DOI: 10.1007/s00210-023-02577-4
• Publication Date: 2023-07-14T08:02:01Z
• Authors: Noha A. T. Abbas; Shaimaa S. El-Sayed; Samaa Salah Abd E...; Walaa M. Sarhan; Eman M. A. Abdelg...; Omnia Sarhan; Shireen S. Mahmoud
• Keywords: Pharmacology; Research; Public Health, Environmental and Occupational Health; Ethyl ester; Organic chemistry; Epidemiology and Treatment of Childhood Leukemia; Hematology; Pathology and Forensic Medicine; Chemistry; Methotrexate; Health Sciences; Medicine; Hemophagocytic Lymphohistiocytosis and Related Disorders; Mechanisms and Renoprotective Strategies for Cisplatin Nephrotoxicity; Internal medicine; Etoposide Treatment

Abstract Disrupted spermatogenesis and testicular injury are among the devastating outcomes of methotrexate. A major contributor to methotrexate-induced testiculopathy is oxidative damage which triggers apoptosis and altered autophagy responses. Eicosapentaenoic acid ethyl ester (EPA-E) is an antihyperlipidemic derivative of omega-3 fatty acids that exhibited affinity to peroxisome proliferator-activated receptor-γ (PPAR-γ) that possesses both antioxidant and autophagy modulating properties. This is an exploratory study aiming at assessing the effectiveness of EPA-E to alleviate testicular damage induced by methotrexate. The specific exploratory hypothesis of this experiment is: EPA-E administration for 1 week to methotrexate-treated rats reduces testicular damage compared to control rats. As a secondary outcome, we were interested in identifying the implicated mechanism that mediates the action of EPA-E. In adult male Wistar rats, testiculopathy was achieved by a single methotrexate injection (20 mg/kg, ip). Rats received vehicle, EPA-E (0.3 g/kg/day, po) alone or with selective PPAR-γ antagonist (bisphenol A diglycidyl ether, BADGE) at 30 mg/kg/day, ip for 1 week. EPA-E recuperated methotrexate-attenuated serum total testosterone while reduced testicular inflammation and oxidative stress, restoring superoxide dismutase (SOD) while reducing malondialdehyde (MDA) and 8–hydroxy–2′-deoxyguanosine (8-OHdG). Methotrexate-induced testicular apoptosis (caspase-3 and p53) was suppressed upon EPA-E treatment. Besides, EPA-E curbed methotrexate-induced abnormal autophagy by downregulating LC3A/B and beclin-1. Interestingly, BADGE-coadministration reversed EPA-E beneficial actions. Collectively, our findings suggest PPAR-γ role in EPA-E-mediated mitigation of methotrexate-evoked testiculopathy via suppression of oxidative stress, apoptosis, as well as abnormal autophagy. Furthermore, EPA-E could be used as a preventive therapy for some testiculopathies mediated by oxidative stress. Graphical Abstract