Zingerone modulates the circulating steroids hormone levels and testicular steroidogenic markers expression in mice: An in vivo and in silico study

Abstract

Zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) is a phytochemical with potent anti-inflammatory and antioxidant properties. It has been shown that zingerone protects testis under pathological conditions by its antioxidant and anti-inflammatory effects. However, there is no direct evidence that zingerone specifically affects the testicular steroidogenesis in normal conditions. Therefore, in this study, we have investigated the effects of zingerone on testicular steroidogenesis by using in vivo and silico approaches. The mice were divided into four groups: Control, 10, 25, and 50 mg/kg dosages of zingerone, which were administered orally for 35 days. It was observed that zingerone treatment modulates both circulating hormone levels and the expression of steroidogenic protein markers. Specifically, the higher doses of zingerone resulted in an increase in the circulating estrogen and androstenedione levels, while progesterone, testosterone, and follicle-stimulating hormone levels were reduced. Further, no significant change was observed in the circulating LH level. The higher doses of zingerone resulted in an increased expression and localisation of 3βHSD, CYP19A1, LHR and decreased expression and localisation of StAR, CYP11A1, and 17βHSD protein. Our silico studies showed that the steroidogenic proteins (CYP11A1, 3βHSD, 17βHSD) when double docked with zingerone alongside its native ligands (cholesterol, pregnenolone, androstenedione) showed an increase in the binding affinity. In contrast, StAR, CYP19A1 when double docked with zingerone and its native ligands exhibited a lesser binding affinity compared to when these proteins were single docked with their native ligand and zingerone. In conclusion, in vivo study showed zingerone stimulates androstenedione, estrogen secretion and up-regulates the expression of CYP19A1, LHR and 3βHSD proteins, whereas it down-regulates the expression of StAR, CYP11A1 and 17βHSD proteins and circulating testosterone, progesterone, follicle-stimulating hormone levels. Furthermore, in silico study has also shown the binding affinities of zingerone with the steroidogenic markers. Thus, zingerone has modulatory effects on testicular steroid biosynthesis in normal mice.