In poikilothermic vertebrates, sex determination is sometimes influenced by environmental factors such as temperature. However, little is known about the molecular mechanisms underlying environmental sex determination. The medaka (Oryzias latipes) is a teleost fish with an XX/XY sex determination system. Recently, it was reported that XX medaka can be sex-reversed into phenotypic males by high water temperature (HT; 32-34 degrees C) treatment during the sex differentiation period. Here we report that cortisol caused female-to-male sex reversal and that metyrapone (an inhibitor of cortisol synthesis) inhibited HT-induced masculinization of XX medaka. HT treatment caused elevation of whole-body levels of cortisol, while metyrapone suppressed the elevation by HT treatment during sexual differentiation. Moreover, cortisol and 33 degrees C treatments inhibited female-type proliferation of germ cells as well as expression of follicle-stimulating hormone receptor (fshr) mRNA in XX medaka during sexual differentiation. These results strongly suggest that HT induces masculinization of XX medaka by elevation of cortisol level, which, in turn, causes suppression of germ cell proliferation and of fshr mRNA expression.
Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. We evaluated the in vivo pharmacological profile of a potent and selective PDE10A inhibitor, TAK-063 (1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one). TAK-063 at 0.3 and 1 mg/kg p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP-and cGMPdependent protein kinases. TAK-063 at 0.3 and 1 mg/kg p.o.,-imine]-induced hyperlocomotion, which is often used as a predictive model for antipsychotic-like activity in rodents. Upregulation of striatal cAMP/cGMP levels and the antipsychotic-like effect of TAK-063 were not attenuated after 15 days of pretreatment with TAK-063 in mice. The potential side effect profile of TAK-063 was assessed in rats using the clinical antipsychotics haloperidol, olanzapine, and aripiprazole as controls. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg p.o. At 3 mg/kg p.o., TAK-063 elicited a weak cataleptic response compared with haloperidol and olanzapine. Evaluation of pathway-specific markers (substance P mRNA for the direct pathway and enkephalin mRNA for the indirect pathway) revealed that TAK-063 activated both the direct and indirect pathways of MSNs. These findings suggest that TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles.
Medaka (Oryzias latipes) is a teleost fish with an XX/XY sex determination system. Recently, it was reported that XX medaka can be sex-reversed into phenotypic males by exposure to high water temperature (HT) during gonadal sex differentiation, possibly by elevation of cortisol, the major glucocorticoid produced by the interrenal cells in teleosts. Yet, it remains unclear how the elevation of cortisol levels by HT causes female-to-male sex reversal. This paper reports that exposure to cortisol or HT after hatching inhibited both the proliferation of female-type germ cells and the expression of ovarian-type aromatase (cyp19a1), which encodes a steroidogenic enzyme responsible for the conversion of androgens to estrogens, and induced the expression of gonadal soma-derived growth factor (gsdf) in XX gonads during gonadal sex differentiation. In contrast, exposure to either cortisol or HT in combination with 17β-estradiol (E2) did not produce these effects. Moreover, E2 completely rescued cortisol- and HT-induced masculinization of XX medaka. These results strongly suggest that cortisol and HT cause female-to-male sex reversal in medaka by suppression of cyp19a1 expression, with a resultant inhibition of estrogen biosynthesis. This mechanism may be common among animals with temperature-dependent sex determination.
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