Abstract
The pharmaceutical 17α-ethynylestradiol (EE2) is considered as an endocrine-disrupting chemical that interferes with male reproduction and hormonal activation. In this study, we investigated the molecular mechanism underlying EE2-regulatory testosterone release in vitro and in vivo. The results show that EE2 treatment decreased testosterone release from rat Leydig cells. Treatment of rats with EE2 reduced plasma testosterone levels and decreased the sensitivity of human chorionic gonadotropin (hCG). EE2 reduced luteinizing hormone receptor (LHR) expression associated with decreased cAMP generation by downregulation of adenylyl cyclase activity and decreased intracellular calcium-mediated pathways. The expression levels of StAR and P450scc were decreased in Leydig cells by treatment of rats with EE2 for 7 days. The sperm motility in the vas deferens and epididymis was reduced, but the histopathological features of the testis and the total sperm number of the vas deferens were not affected. Moreover, the serum dihydrotestosterone (DHT) level was decreased by treatment with EE2. The prostate gland and seminal vesicle atrophied significantly, and their expression level of 5α-reductase type II was reduced after EE2 exposure. Taken together, these results demonstrate an underlying mechanism of EE2 to downregulate testosterone production in Leydig cells, explaining the damaging effects of EE2 on male reproduction.
Highlights
Www.nature.com/scientificreports with endogenous endocrine processes by mimicking hormonal action, leading to infertility, metabolic syndrome, and the rise of cancer incidence[3,4,5]
To determine whether testosterone release from Leydig cells was suppressed by EE2 treatment, the primary rat Leydig cells were isolated from adult normal male rats and treated with EE2 using serial concentrations (0.1, 1.0, 10, 100, 1000 nM) for 1 h before measuring the testosterone concentration in the culture medium
The results showed that the basal level of testosterone released into the culture medium was decreased by exposure of the rat Leydig cells to EE2 at the concentrations from 10 to 1000 nM
Summary
Www.nature.com/scientificreports with endogenous endocrine processes by mimicking hormonal action, leading to infertility, metabolic syndrome, and the rise of cancer incidence[3,4,5]. EE2 has been reported to exert a higher estrogenic activity than estradiol (E2), and is extremely stable against oxidation by metabolism or degradation in the human body due to the property of the ethynyl group in the C17 position[11,12,13]. To assess whether EE2 can affect the mechanism of testosterone production through alteration of steroidogenic enzyme activities in mammals, we designed, in the present study, an animal study to evaluate the effects of exposure to EE2 on the steroidogenic pathway activity in rat Leydig cells. The reproductive system of male rats was affected by EE2 exposure These findings present a valuable insight into the mechanism underlying EE2-induced reduction of testosterone production
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