Roles of estrogens in fish sexual plasticity and sex differentiation.

Fish sex could be reversed at the undifferentiated stage of gonad by administration of exogenous estrogen (E2) or blockade of endogenous estrogen synthesis with aromatase inhibitors, which is designated as primary sex reversal (PSR). Recent studies have well demonstrated that gonochoristic fish maintain their sexual plasticity after sex determination/differentiation. The differentiated ovary could be transdifferentiated into functional testis, and vice versa, the differentiated testis could be transdifferentiated into ovary. By analyzing these two secondary sex reversal (SSR) models, it was found that induction of male-to-female sex reversal initiates from dorsal (near the blood vessel) to the ventral, while induction of female-to-male sex reversal initiates from the ventral to dorsal. Down regulation of endogenous estrogen is the prerequisite for the ovarian transdifferentiation. However, exogenous estrogen alone is not sufficient for inducing differentiated testis to ovary. Administration of E2 and simultaneous blockage of androgen synthesis could induce testicular transdifferentiation. Therefore, endogenous estrogen is critical for the ovarian differentiation/maintenance and androgen is critical for testicular maintenance. Recently, genetic studies with genome editing technologies also showed that disruption of Cyp19a1a induced testicular development, indicating that cyp19a1a is the key gene essential for estrogen synthesis and ovary differentiation/maintenance. Knockout of male pathway genes or overexpression of female pathway genes could up-regulate cyp19a1a expression and increase estrogen level so as to promote ovary. Conversely, knockout of female pathway genes or overexpression of male pathway genes could down-regulate cyp19a1a expression and decrease estrogen level so as to promote testis (transgenic or knockout sex reversal, TSR). Epigenetic regulation of cyp19a1a play a critical role in natural sex reversal (NSR), but its relation with PSR, SSR and TSR needs further detailed investigations. In all, these studies further highlighted the important roles of endogenous estrogens in fish sex differentiation/maintenance.