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Endocrinology. 2015 May;156(5):1887-99. doi: 10.1210/en.2014-1852. Epub 2015 Feb 25.

Estrogen receptor 1 (ESR1; ERα), not ESR2 (ERβ), modulates estrogen-induced sex reversal in the American alligator, a species with temperature-dependent sex determination.

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Department of Obstetrics and Gynecology (S.K., J.Z., T.A.B., L.J.G.), Medical University of South Carolina, Charleston, South Carolina 29425; Marine Biomedicine and Environmental Science Center (S.K., M.C.B., T.A.B., B.M.D., L.J.G.), Hollings Marine Laboratory, Charleston, South Carolina 29412; Graduate Program in Marine Biology at the College of Charleston (M.C.B.), Charleston, South Carolina 29412; Graduate School of Life Science and Department of Biological Sciences (Y.K.), Hokkaido University, Sapporo, 060-0808 Japan; Department of Biology (T.A.B.), University of Florida, Gainesville, Florida 32611; Okazaki Institute for Integrative Bioscience (T.I.), National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, 444-8585 Japan; and Department of Basic Biology (T.I.), The Graduate University for Advanced Studies (SOKENDAI), Okazaki, 444-8585 Japan.


All crocodilians and many turtles exhibit temperature-dependent sex determination where the temperature of the incubated egg, during a thermo-sensitive period (TSP), determines the sex of the offspring. Estrogens play a critical role in sex determination in crocodilians and turtles, as it likely does in most nonmammalian vertebrates. Indeed, administration of estrogens during the TSP induces male to female sex reversal at a male-producing temperature (MPT). However, it is not clear how estrogens override the influence of temperature during sex determination in these species. Most vertebrates have 2 forms of nuclear estrogen receptor (ESR): ESR1 (ERα) and ESR2 (ERβ). However, there is no direct evidence concerning which ESR is involved in sex determination, because a specific agonist or antagonist for each ESR has not been tested in nonmammalian species. We identified specific pharmaceutical agonists for each ESR using an in vitro transactivation assay employing American alligator ESR1 and ESR2; these were 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY 200070), respectively. Alligator eggs were exposed to PPT or WAY 200070 at a MPT just before the TSP, and their sex was examined at the last stage of embryonic development. Estradiol-17β and PPT, but not WAY 200070, induced sex reversal at a MPT. PPT-exposed embryos exposed to the highest dose (5.0 μg/g egg weight) exhibited enlargement and advanced differentiation of the Müllerian duct. These results indicate that ESR1 is likely the principal ESR involved in sex reversal as well as embryonic Müllerian duct survival and growth in American alligators.

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