tretinoin and Disorders-of-Sex-Development

Meiosis is a process unique to the differentiation of germ cells. Retinoic acid (RA) is the key factor controlling the sex-specific timing of meiotic initiation in tetrapods; however, the role of RA in meiotic initiation in teleosts has remained unclear. In this study, the genes encoding RA synthase aldh1a2, and catabolic enzyme cyp26a1 were isolated from Nile tilapia (Oreochromis niloticus), a species without stra8. The expression of aldh1a2 was up-regulated and expression of cyp26a1 was down-regulated before the meiotic initiation in ovaries and in testes. Treatment with RA synthase inhibitor or disruption of Aldh1a2 by CRISPR/Cas9 resulted in delayed meiotic initiation, with simultaneous down-regulation of cyp26a1 and up-regulation of sycp3. By contrast, treatment with an inhibitor of RA catabolic enzyme and disruption of cyp26a1 resulted in earlier meiotic initiation, with increased expression of aldh1a2 and sycp3. Additionally, treatment of XY fish with estrogen (E2) and XX fish with fadrozole led to sex reversal and reversion of meiotic initiation. These results indicate that RA is indispensable for meiotic initiation in teleosts via a stra8 independent signaling pathway where both aldh1a2 and cyp26a1 are critical. In contrast to mammals, E2 is a major regulator of sex determination and meiotic initiation in teleosts.

Topics: Animals; Cell Differentiation; Cichlids; Cytochrome P-450 Enzyme System; Disorders of Sex Development; Estrogens; Fadrozole; Gene Expression Regulation, Developmental; Meiosis; Retinal Dehydrogenase; Retinoic Acid 4-Hydroxylase; Sex Determination Processes; Synaptonemal Complex; Tretinoin

To clarify how tributyltin (TBT) and triphenyltin (TPT) interact with the retinoid X receptor (RXR) to induce growth of male sex organs in female gastropods, we treated female rock shells (Thais clavigera) with three different concentrations (0.1, 1, or 5 microg/g wet wt) of 9-cis-retinoic acid (9CRA) or with a single concentration (1 microg/g wet wt) of TBT, TPT, or fetal bovine serum (as a control). The effects of each treatment were measured as the incidence of imposex, the length of the penis-like structure, and the vas deferens sequence (VDS) index. 9CRA induced imposex in a dose-dependent manner; imposex incidence was significantly higher in the rock shells that received 1 (P < 0.05) or 5 microg (P < 0.001) 9CRA than in the controls. After 1 month, the rock shells treated with 5 microg 9CRA exhibited substantial growth of the penis-like structure that was not as evident in the other treated shells. The length of the structure differed between the 0.1- and 5-microg 9CRA treatment groups (P < 0.05) but not between the 1- and 5-microg 9CRA treatment groups (P > 0.05). Compared with the control, the VDS index increased significantly in the 1- (P < 0.05) and 5-microg (P < 0.001) 9CRA groups. The penis-like structures behind the right tentacle in female rock shells treated with 5 microg 9CRA were essentially the same as the penises and vasa deferentia of normal males and of TBT-treated or TPT-treated imposexed females. These results further support the hypothesis that imposex in gastropods could be mediated by RXR.

Topics: Alitretinoin; Animals; Disorders of Sex Development; Environmental Exposure; Female; Gastropoda; Male; Organotin Compounds; Penis; Tretinoin; Trialkyltin Compounds; Vas Deferens