Naringenin Modulates Sertoli Cell Dysfunction and Altered SCF/c-kit Ligand System in the Setting of Combination Antiretroviral Therapy

Combination Antiretroviral Therapy (cART) has been shown in previous studies to induce histopathological changes in the testes. An essential function of the c-kit signalling system is to control cell survival, proliferation, differentiation, and death. Consequently, certain male infertility may be explained by deregulating the SCF/c-kit system by attenuating or overactivating its signaling strength. This study examined the effects of antiretroviral drugs and a bioactive flavonoid, Naringenin on testicular ultrastructure, function and the SCF/c-kit ligand system. Six groups of five Sprague Dawley rats were assigned into cART (H), distilled water (DW), naringenin 40 mg/kg (N40), naringenin 80 mg/kg (N80), cART+naringenin 40 mg/kg (HN40), and cART+naringenin 80 mg/kg (HN80). Electron microscopy was employed to study testicular ultrastructural changes. The expressions of intratesticular SCF and c-kit mRNA were evaluated using quantitative PCR. The apoptotic assay and levels of intratesticular antioxidant enzymes were studied using ELISA. Using cART resulted in nuclear membrane breakdown, anomalies in the ultrastructural appearance of the germinal epithelium, and distortion of the progressive cellular growth. These changes were reduced with the co-administration of Naringenin. Co-administration of Naringenin limited the identified dysfunction of Sertoli cells as a sign of testicular toxicity from cART and this study suggests that as an adjuvant therapy, naringenin might help prevent testicular toxicity associated with long-term use of cART.

Key Words: testis; combination antiretroviral therapy; Naringenin; Sertoli cell, Stem cell factor, c-kit