Drareg
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It seems the researchers are making big assumptions here,it's still a good read.
The Cortisol and Androgen Pathways Cross Talk in High Temperature-Induced Masculinization: The 11β-Hydroxysteroid Dehydrogenase as a Key Enzyme
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.
Sex steroids have been considered to play critical roles during sex determination in nonmammalian vertebrates (1). Although they are not considered as initiators of gonadal sex differentiation, their timely appearance and maintenance are fundamental for the subsequent development of ovaries and testes. In teleost fishes, for example, larvae are highly sensitive to sex steroids, and the administration of estrogens or androgens during the critical period of gonadal sex differentiation often leads to a functional sex inversion (2–4). It is currently believed that whereas estrogens are essential for female sex differentiation, androgens, on the other hand, are the product or a consequence of differentiation along the male pathway (2, 5–8). In contrast, high levels of 11-oxygenated androgens or the expression of enzymes involved in their synthesis during the critical period of sex determination/differentiation have been detected in some teleosts (9–11). These differences make the involvement of 11-oxygenated androgens in sex determination/differentiation a fact that remains unsolved.
The enzymes involved in steroid synthesis and metabolism are important for regulating tissue-specific steroid action (12). In particular, the 11β-hydroxysteroid dehydrogenase (11β-HSD) plays a key role in the synthesis of 11-oxygenated androgens, and it is also known to be involved in the metabolism of glucocorticoids (GCs) (13, 14). In mammals, two types of 11β-HSD have been found: 11β-HSD1, which acts as an 11-oxo-reductase reduced nicotinamide adenine dinucleotide phosphate-dependent enzyme converting cortisone to cortisol, and 11β-HSD2, which acts as an oxidase nicotinamide adenine dinucleotide-dependent enzyme that converts the active ligand cortisol to cortisone, an inactive form unable to bind to GC receptors (GRs) (15). In fish, only one 11β-HSD has been described so far, and it is considered to be the homolog of the mammalian 11β-HSD2 (12). The importance of 11β-hsd2 for glucocorticoid metabolism in fish is still not clear, but it seems to be important for the final step of the major fish androgen biosynthesis, the 11-ketotestosterone (11-KT). Based on this pathway, testosterone (T) is hydroxylated by 11β-hydroxylase (cyp11β) to 11β-hydroxytestosterone (11β-OHT), which comprises a substrate for 11β-hsd2 to produce 11-KT (16). Although the biosynthesis and bioactivity of 11-KT was reported to be conserved also in mammals, the physiological role(s) of this androgen might not, as suggested by studies in mice (17, 18).
It is known that the activity or synthesis of many steroidogenic enzymes, including those related to androgens, can be affected by the stress axis during the process of gamete maturation (19). The stress axis is activated quite early during development in teleost fish (20), and recent studies have shown that GCs can also play important roles on gonadal fate, particularly during high temperature-induced testicular differentiation, a form of environmental sex determination (10, 21, 22). Elevated cortisol levels were observed during the critical period of sex determination at male-producing temperatures (MPT), and the administration of cortisol to larvae during this period produced a significant increase in the percentage of males in the progeny (10, 21). During the cortisol-induced masculinization, the expression of gonadal aromatase cyp19a1a, the inhibition of which is known to be tightly associated with masculinization in fish (2), was repressed. Interestingly, T and 11-KT levels began to rise before the inhibition of gonadal aromatase in pejerrey, and they were positively correlated with cortisol body levels (10, 21). This suggests an interaction between androgens and the stress axis on the masculinization process before the inhibition of the aromatase expression. However, the details of this cross talk and the possible involvement of 11β-hsd2 are still not known.
In vertebrates, cortisol actions are mediated by the glucocorticoid receptors (Grs) and, as with other steroid receptors, they act as ligand-dependent transcription factors on transactivation or repression of glucocorticoid-responsive genes (23). With the exception of zebrafish (24), two paralog grs (gr1 and gr2) have been described in teleosts (14, 25), and their expression was shown to be modulated by cortisol in some species (26–29). Androgen actions are also mediated by specific receptors, known as androgen receptors (Ars). Once more, with the exception of zebrafish (30), two androgen receptors [ar1 (also referred to as ara) and ar2 (or arb)] have been described in teleosts (31–34). Teleost Ars preferentially bind 11-KT over T (30, 35, 36) and, therefore, the regulation of Ar expression is important to address androgen actions during the sex determination and differentiation periods.
In this conceptual framework, we investigated the expression patterns of hsd11b2, both grs, and ars during sex determination of pejerrey fish Odontesthes bonariensis, a species in which temperature alone can produce all-female or all-male populations (37, 38), to clarify the interactions and effects of temperature, cortisol, and androgens in the mechanism of high temperature-induced masculinization of this species. Given the dual function of 11β-hsd2 in the inactivation of glucocorticoids and the biosynthesis of 11-oxygenated androgens previously mentioned, we also examined the in vitro androgen production under cortisol administration.
- See more at: http://press.endocrine.org/doi/10.1210/en.2012-1517#sthash.MZytrQJ7.dpuf
http://press.endocrine.org/doi/10.1210/en.2012-1517
The Cortisol and Androgen Pathways Cross Talk in High Temperature-Induced Masculinization: The 11β-Hydroxysteroid Dehydrogenase as a Key Enzyme
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.
Sex steroids have been considered to play critical roles during sex determination in nonmammalian vertebrates (1). Although they are not considered as initiators of gonadal sex differentiation, their timely appearance and maintenance are fundamental for the subsequent development of ovaries and testes. In teleost fishes, for example, larvae are highly sensitive to sex steroids, and the administration of estrogens or androgens during the critical period of gonadal sex differentiation often leads to a functional sex inversion (2–4). It is currently believed that whereas estrogens are essential for female sex differentiation, androgens, on the other hand, are the product or a consequence of differentiation along the male pathway (2, 5–8). In contrast, high levels of 11-oxygenated androgens or the expression of enzymes involved in their synthesis during the critical period of sex determination/differentiation have been detected in some teleosts (9–11). These differences make the involvement of 11-oxygenated androgens in sex determination/differentiation a fact that remains unsolved.
The enzymes involved in steroid synthesis and metabolism are important for regulating tissue-specific steroid action (12). In particular, the 11β-hydroxysteroid dehydrogenase (11β-HSD) plays a key role in the synthesis of 11-oxygenated androgens, and it is also known to be involved in the metabolism of glucocorticoids (GCs) (13, 14). In mammals, two types of 11β-HSD have been found: 11β-HSD1, which acts as an 11-oxo-reductase reduced nicotinamide adenine dinucleotide phosphate-dependent enzyme converting cortisone to cortisol, and 11β-HSD2, which acts as an oxidase nicotinamide adenine dinucleotide-dependent enzyme that converts the active ligand cortisol to cortisone, an inactive form unable to bind to GC receptors (GRs) (15). In fish, only one 11β-HSD has been described so far, and it is considered to be the homolog of the mammalian 11β-HSD2 (12). The importance of 11β-hsd2 for glucocorticoid metabolism in fish is still not clear, but it seems to be important for the final step of the major fish androgen biosynthesis, the 11-ketotestosterone (11-KT). Based on this pathway, testosterone (T) is hydroxylated by 11β-hydroxylase (cyp11β) to 11β-hydroxytestosterone (11β-OHT), which comprises a substrate for 11β-hsd2 to produce 11-KT (16). Although the biosynthesis and bioactivity of 11-KT was reported to be conserved also in mammals, the physiological role(s) of this androgen might not, as suggested by studies in mice (17, 18).
It is known that the activity or synthesis of many steroidogenic enzymes, including those related to androgens, can be affected by the stress axis during the process of gamete maturation (19). The stress axis is activated quite early during development in teleost fish (20), and recent studies have shown that GCs can also play important roles on gonadal fate, particularly during high temperature-induced testicular differentiation, a form of environmental sex determination (10, 21, 22). Elevated cortisol levels were observed during the critical period of sex determination at male-producing temperatures (MPT), and the administration of cortisol to larvae during this period produced a significant increase in the percentage of males in the progeny (10, 21). During the cortisol-induced masculinization, the expression of gonadal aromatase cyp19a1a, the inhibition of which is known to be tightly associated with masculinization in fish (2), was repressed. Interestingly, T and 11-KT levels began to rise before the inhibition of gonadal aromatase in pejerrey, and they were positively correlated with cortisol body levels (10, 21). This suggests an interaction between androgens and the stress axis on the masculinization process before the inhibition of the aromatase expression. However, the details of this cross talk and the possible involvement of 11β-hsd2 are still not known.
In vertebrates, cortisol actions are mediated by the glucocorticoid receptors (Grs) and, as with other steroid receptors, they act as ligand-dependent transcription factors on transactivation or repression of glucocorticoid-responsive genes (23). With the exception of zebrafish (24), two paralog grs (gr1 and gr2) have been described in teleosts (14, 25), and their expression was shown to be modulated by cortisol in some species (26–29). Androgen actions are also mediated by specific receptors, known as androgen receptors (Ars). Once more, with the exception of zebrafish (30), two androgen receptors [ar1 (also referred to as ara) and ar2 (or arb)] have been described in teleosts (31–34). Teleost Ars preferentially bind 11-KT over T (30, 35, 36) and, therefore, the regulation of Ar expression is important to address androgen actions during the sex determination and differentiation periods.
In this conceptual framework, we investigated the expression patterns of hsd11b2, both grs, and ars during sex determination of pejerrey fish Odontesthes bonariensis, a species in which temperature alone can produce all-female or all-male populations (37, 38), to clarify the interactions and effects of temperature, cortisol, and androgens in the mechanism of high temperature-induced masculinization of this species. Given the dual function of 11β-hsd2 in the inactivation of glucocorticoids and the biosynthesis of 11-oxygenated androgens previously mentioned, we also examined the in vitro androgen production under cortisol administration.
- See more at: http://press.endocrine.org/doi/10.1210/en.2012-1517#sthash.MZytrQJ7.dpuf
http://press.endocrine.org/doi/10.1210/en.2012-1517
