Medaka (Oryzias latipes) is a teleost fish with an XX/XY sex determination system, similar to that of mammals. However, under high temperature conditions, XX medaka is masculinised by elevation of cortisol, the major teleost glucocorticoid. in this study, to identify novel factors in the gonads acting downstream from cortisol during sexual differentiation, we performed RNA sequencing (RNA-seq) analysis using the gonadal regions of larvae reared at normal temperature with and without cortisol, and at high temperature. The RNA-seq and real-time PCR analyses showed that expression of some peroxisome proliferator-activated receptor α (PPARα) signalling-targeted genes was increased by cortisol. PPARα agonist treatment induced masculinisation of XX medaka in some cases, and co-treatment of the agonist with cortisol further induced masculinisation, whereas treatment of pparaa knockout medaka with cortisol or the agonist did not induce masculinisation. this study provides the first evidence that PPARα is involved in environmental sex determination in vertebrates. Many vertebrates have males and females that reproduce sexually. Sex is genotypically determined in many species, but sex determination is greatly affected by ambient temperature in poikilothermic vertebrates, including reptiles, amphibians, and fish 1. Furthermore, environmental factors, such as pH 2 , density 3 , and social factors 4 , are suggested to override genetic sex determination in some teleost fish. However, the molecular mechanisms of environmental sex determination in these species remain poorly understood. Medaka (Oryzias latipes) is a small teleost fish that offers many advantages, including the availability of many useful strains 5. Transgenic (Tg) techniques and the gene knockout systems using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), are established 6-8. Moreover, the sex-determining gene dmy (also known as dmrt1bY) on the Y chromosome has been identified in this fish 9. Therefore, medaka is a useful animal model for vertebrate genetic analysis of the sex determination and differentiation. The first appearance of morphological sex differentiation in medaka is the difference in the number of germ cells before hatching, as germ cells in genetic females (XX) undergo a rapid proliferation and subsequently initiate oogenesis while they remain quiescent in genetic males (XY) 10,11. High temperature (HT) treatment during the sex differentiation inhibits germ cell proliferation and oocyte development in XX medaka, and causes masculinisation 12-14. HT also causes masculinisation through elevating the levels of cortisol, the major teleost glucocorticoid 15. Furthermore, exposure of XX medaka to cortisol or HT increases expression of gonadal soma-derived growth factor (gsdf) and decreases expression of cytochrome P450 family 19 subfamily A member 1a (cyp19a1a) by 5 days post-hatching (dph) 16. However, it remains unclear how HT-elevated cortisol induces the masculinisation of XX medaka. Cortisol...
The heat shock response is important for the viability of all living organisms. It involves the induction of heat shock proteins whose expression is mainly regulated by heat shock factor 1 (HSF1). Medaka ( Oryzias latipes ) is a teleost fish with an XX/XY sex determination system. High water temperature (HT) inhibits the female-type proliferation of germ cells and induces the masculinisation of XX medaka in some cases during gonadal sex differentiation. Here, we investigated the roles of HSF1 on the proliferation of germ cells using HSF1 knockout medaka. Loss of HSF1 function under HT completely inhibited the female-type proliferation of germ cells, induced the expression of the anti-Mullerian hormone receptor type 2 ( amhr2 ) and apoptosis-related genes, and suppressed that of the dead end ( dnd ) and heat shock protein-related genes. Moreover, the loss of HSF1 and AMHR2 function under HT recovered female-type proliferation in germ cells, while loss of HSF1 function under HT induced gonadal somatic cell apoptosis during early sex differentiation. These results strongly suggest that HSF1 under the HT protects the female-type proliferation of germ cells by inhibiting amhr2 expression in gonadal somatic cells. These findings provide new insights into the molecular mechanisms underlying environmental sex determination.
The medaka Oryzias latipes is a teleost fish with an XX/XY sex determination system similar to that of mammals. However, under high-temperature conditions, XX medaka are masculinized by an elevation of the key teleost glucocorticoid, cortisol. Cortisol inhibits female-type proliferation of germ cells and induces masculinization of XX medaka during gonadal sex differentiation. To identify masculinization mechanisms downstream of cortisol, we analysed the functions of gonadal soma-derived growth factor (gsdf) and anti-Müllerian hormone receptor type 2 (amhr2); these genes are known to play important roles in the inhibition of germ cell proliferation and male differentiation. We investigated the impact of gsdf and amhr2 on the proliferation of germ cells using gsdf knockout (KO) and amhr2 KO medaka. At hatching stage, loss of gsdf or amhr2 function recovered female-type proliferation in germ cells under cortisol treatment. Moreover, cortisol treatment of gsdf KO or amhr2 KO medaka did not induce masculinization of XX medaka. These results suggest that cortisol inhibits female-type proliferation of germ cells and induces masculinization of XX medaka through GSDF and AMHR2. This study thereby provides the first evidence that GSDF and AMHR2 are involved in cortisol-induced masculinization.
Medaka (Oryzias latipes) is a teleost fish with an XX/XY sex determination system. Sex reversal from female-to-male (masculinization of XX fish) can be induced through cortisol elevation from exposure to environmental stress such as high temperature during sexual differentiation. However, the effects of oxidative stress, generated via metabolic reactions and biological defense mechanisms, on the sexual differentiation of medaka are unclear. Here, we investigated the effect of oxidative stress on medaka sexual differentiation using hydrogen peroxide (H2O2), which induces oxidative stress in vertebrates. H2O2 treatment from 0 to 5 days post-hatching induced masculinization of wild-type XX medaka, but not of gonadal soma-derived growth factor (gsdf) or peroxisome proliferator-activated receptor alpha-a (pparaa) knockout XX fish. Co-treatment with an oxidative stress inhibitor caused masculinization recovery but co-treatment with a cortisol synthesis inhibitor did not. H2O2 treatment significantly upregulated gsdf and pparaa expression in XX medaka. However, H2O2 did not elevate cortisol levels in medaka larvae during sexual differentiation. These results strongly indicate that oxidative stress induces masculinization of XX medaka without causing elevation of cortisol.
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