Exposure of Xenopus laevis tadpoles to finasteride, an inhibitor of 5-α reductase activity, impairs spermatogenesis and alters hypophyseal feedback mechanisms

Abstract

Sexual steroids have major regulatory functions in gonadal development, maturation of gametes and sexual differentiation in vertebrates. Previous studies in amphibians provided evidence that dihydrotestosterone and activity of 5-a reductases might play a significant role in androgen-mediated reproductive biology. To test the involvement of 5-a reductases in maturation of gametes in amphibians, Xenopus laevis was exposed to finasteride (FIN), a known inhibitor of 5-a reductase enzyme activity. In a long-term exposure from stage 46 to 66, severe disruption of spermatogenesis was observed in histological analysis of testes as detected by occurrence of empty spermatocysts, while ovaries remained unaffected. Real-time PCR analyses of male and female brain revealed an increase of LHb mRNA and a decrease of FSHb mRNA in males, suggesting a signalling on testes that could result in increased steroidogenesis and reduced Sertoli cell proliferation. Accordingly, the mRNA expression of P450 side chain cleavage enzyme and 5-a reductase type 2 was increased in testes, while no effects could be observed on steroidogenic genes in ovaries. A short-term exposure to testosterone, FIN and testosteroneCFIN showed that transient effects of FIN targeted males selectively and, in particular, interfered with the hypothalamus-pituitary-gonad axis. Furthermore, a negative feedback of testosterone on LHb was observed on males and females. This study provides evidence that exposure of X. laevis to FIN, an inhibitor of 5-a reductases, impaired spermatogenesis and involved sex-specific hypophyseal feedback mechanisms.

The Antiestrogens Tamoxifen and Fulvestrant Abolish Estrogenic Impacts of 17α-ethinylestradiol on Male Calling Behavior of Xenopus laevis

“…In a previous study on X. laevis , TAM exposure was shown to affect vitellogenin (Vtg) and aromatase mRNA expression [11], [52], as well as plasma E2 levels and mRNA expression of LH and FSH [10]–[12] of female but not male X. laevis . Urbatzka and colleagues [12] suggested that this discrepancy between the sexes might be due to the naturally low endogenous estrogen levels in males, which might be too low to be altered by TAM severely enough to affect estrogen feedback.…”

Seasonal changes in gene expression of steroidogenic enzymes, androgen and estrogen receptors in frog testis

“…Furthermore, the exposure of X. laevis tadpoles to finasteride, an inhibitor of 5α‐reductase activity, impaired spermatogenesis and altered hypophyseal feedback mechanisms (Urbatzka et al . ). In the Rana rugosa, sexual steroids could be the key factor for sex determination and gonadal activity of P450 aromatase, which is correlated with the feminization of gonads (Maruo et al .…”

Transcriptomic profiling in Silurana tropicalis testes exposed to finasteride

“…In humans, finasteride induced side effects involved overall reproductive health effects such as infertility; whereas in rodents, erectile dysfunction and change in prostate tissue histoarchitecture were observed after treatment (Traish, 2012). Both Duarte-Guterman et al (2009) and Urbatzka et al (2009) showed that amphibians exposed to finasteride displayed disrupted spermatogenesis, intersex phenotype, and female-biased sex ratio. Hence, finasteride induces adverse effects .…”

“…Recently, adverse effects of using finasteride have become well established and data suggests that, in humans, it not only impairs sexual function, but also that it is associated with male breast cancer, various skin conditions, and depression, while in rodents, finasteride is linked to erectile dysfunction and change in prostate tissue histoarchitecture (reviewed in Traish, 2012). Aquatic amphibian species exposed to this 5a-reductase inhibitor also showed disrupted spermatogenesis, intersex animals, and a female biased sex ratio (Duarte-Guterman et al, 2009;Urbatzka et al, 2009). At the molecular level, gene expression endpoints have shown that finasteride alters the mRNA levels of gonadotropins-, androgen-, and thyroid hormone-related genes in the Western clawed metamorphosing frogs (Silurana tropicalis; Duarte-Guterman et al, 2009;Urbatzka et al, 2009;Langlois et al, 2011).…”

“…Aquatic amphibian species exposed to this 5a-reductase inhibitor also showed disrupted spermatogenesis, intersex animals, and a female biased sex ratio (Duarte-Guterman et al, 2009;Urbatzka et al, 2009). At the molecular level, gene expression endpoints have shown that finasteride alters the mRNA levels of gonadotropins-, androgen-, and thyroid hormone-related genes in the Western clawed metamorphosing frogs (Silurana tropicalis; Duarte-Guterman et al, 2009;Urbatzka et al, 2009;Langlois et al, 2011). Although it is established that finasteride induces sex reversal in amphibians, it is currently unknown which molecular signalling pathways are activated/inhibited by finasteride prior to morphological changes in the gonad.…”