The Cortisol and Androgen Pathways Cross Talk in High Temperature-Induced Masculinization: The 11β-Hydroxysteroid Dehydrogenase as a Key Enzyme

Abstract

In many ectotherm species the gonadal fate is modulated by temperature early in life [temperature-dependent sex determination (TSD)] but the transducer mechanism between temperature and gonadal differentiation is still elusive. We have recently shown that cortisol, the glucocorticoid stress-related hormone in vertebrates, is involved in the TSD process of pejerrey, Odontesthes bonariensis. Particularly, all larvae exposed to a male-producing temperature (MPT, 29 C) after hatching showed increased whole-body cortisol and 11-ketotestosterone (11-KT; the main bioactive androgen in fish) levels and developed as males. Moreover, cortisol administration at an intermediate, mixed sex-producing temperature (MixPT, 24 C) caused increases in 11-KT and in the frequency of males, suggesting a relation between this glucocorticoid and androgens during the masculinization process. In order to clarify the link between stress and masculinization, the expression of hydroxysteroid dehydrogenase (hsd)11b2, glucocorticoid receptors gr1 and gr2, and androgen receptors ar1 and ar2 was analyzed by quantitative real time PCR and in situ hybridization in larvae reared at MPT, MixPT, and female-producing temperature (FPT, 17 C) during the sex determination period. We also analyzed the effects of cortisol treatment in larvae reared at MixPT and in adult testicular explants incubated in vitro. MPT and cortisol treatment produced significant increases in hsd11b2 mRNA expression. Also, gonadal explants incubated in the presence of cortisol showed increases of 11-KT levels in the medium. Taken together these results suggest that cortisol promotes 11-KT production during high temperature-induced masculinization by modulation of hsd11b2 expression and thus drives the morphogenesis of the testes.

On the proper rearing density in domesticated zebrafish to avoid unwanted masculinization. Links with the stress response

“…In the pejerrey, cortisol interacts with the glucocorticoid response element in the promoter of the 11β-hydroxysteroid dehydrogenase type 2 (hsd11β2) gene, a key enzyme that is shared between the glucocorticoid and androgen pathways, increasing its expression. This led Fernandino et al, (2012Fernandino et al, ( , 2013 to suggest that while increased hsd11β2 expression contributes to the degradation of cortisol to cortisone, it also helps to convert 11β-hydroxyandrogens into 11-ketotestosreone, the typical teleost androgen, with more masculinizing potency than testosterone (Piferrer et al, 1993). In contrast, in the Japanese flounder, it was suggested that cortisol suppressed gonadal aromatase (cyp19a1a) expression by blocking the cAMP response element located in the cyp19a1a promoter .…”

Demonstration of viability and fertility and development of a molecular tool to identify YY supermales in a fish with both genotypic and environmental sex determination

“…We also noted while performing artificial fertilization that all 1‐year‐old YY males ( n  = 11) had abundant milt production compared to 36.4% (eight of 22) in XY males (unpublished observations), suggesting that the former may attain sexual maturation earlier than the latter. Studies including mRNA quantification of genes involved in amh signaling (such as amhy , amha , and amhr2 ) and measurement of androgens and stress hormones, which are related to sex determination in pejerrey (Fernandino, Hattori, Kishi, Strüssmann, & Somoza, 2012; Hattori, Fernandino, et al., 2009), will be conducted for comparison of thermal sensitivity between XY and YY fish. Similar studies should examine whether amhy has any role in the onset of puberty in this species that could explain the early maturation observed in YY fish.…”

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…In fish, 11␤-HSD2 is also important in testicular androgen activation and sex determination (197) by catalyzing conversion of 11␤-hydroxytestosterone to active 11-keto-testosterone (470).…”

“…Both 11␤-HSD1 and 11␤-HSD2 are expressed in the adult male reproductive tract, although there are substantial species differences (4,369). In fish testis, 11␤-HSD2 plays a glucocorticoid-independent role, converting 11␤-hydroxytestosterone to 11-ketotestosterone, a major fish androgen important in fertility and sex determination (197,324,573). 11␤-HSD2 is absent from the chicken testis (351).…”