Olmstead Allen W, Kosian Patricia A, Korte Joseph J, Holcombe Gary W, Woodis Kacie K, Degitz Sigmund J
U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Boulevard, Duluth, MN, USA.
Aquat Toxicol. 2009 Jan 31;91(2):143-50. doi: 10.1016/j.aquatox.2008.07.018. Epub 2008 Aug 15.
Aromatase is a steroidogenic enzyme that catalyzes the conversion of androgens to estrogens in vertebrates. Modulation of this enzyme's activity by xenobiotic exposure has been shown to adversely affect gonad differentiation in a number of diverse species. We hypothesized that exposure to the aromatase inhibitor, fadrozole, during the larval development of the tropical clawed frog, Xenopus tropicalis, would result in masculinization of the developing female gonad. Tadpoles were exposed to fadrozole at nominal concentrations from 1 to 64 microg/L in a flow-through system from < 24 h post-fertilization (Nieuwkoop Faber (NF) stage 15-20) to metamorphosis (NF stage 66). At metamorphosis, morphologically examined gonads indicated complete masculinization of all tadpoles at concentrations of 16 microg/L and above and a significant bias in sex ratio towards males at concentrations of 1 microg/L and above. No effects on time to metamorphosis, body mass, or body length were observed. A random subsample of frogs was raised to reproductive maturity (39 weeks post-fertilization) in control water. All frogs exposed as tadpoles to 16 microg/L fadrozole or greater possessed testes at sexual maturity. Intersexed gonads characterized by the presence of both testicular and ovarian tissue were observed in 12% of frogs in the 4 microg/L treatment. No differences in estradiol, testosterone, or vitellogenin plasma concentrations were observed in exposed males or females compared to controls. Females in the 4 microg/L treatment possessed a significantly greater percentage of pre-vitellogenic oocytes than controls and were significantly smaller in body mass. No differences in sperm counts were observed in exposed males compared to controls. Results from this study demonstrate that larval exposure to an aromatase inhibitor can result in the complete masculinization of female gonads. These masculinized females are phenotypically indistinguishable from normal males at adulthood. Lower levels of aromatase inhibition resulted in intersexed gonads and possible female reproductive impairment at adulthood. These results indicate that exposure of amphibians to xenobiotics capable of inhibiting aromatase would result in adverse reproductive consequences.
芳香化酶是一种类固醇生成酶，可催化脊椎动物体内雄激素向雌激素的转化。已表明，外源性物质暴露对该酶活性的调节会对许多不同物种的性腺分化产生不利影响。我们推测，在热带爪蟾（非洲爪蟾）幼体发育期间暴露于芳香化酶抑制剂法倔唑会导致发育中的雌性性腺雄性化。在受精后不到24小时（纽科普-法伯（NF）15-20期）至变态期（NF 66期）的流水系统中，将蝌蚪暴露于名义浓度为1至64微克/升的法倔唑中。在变态期，形态学检查的性腺表明，浓度为16微克/升及以上时，所有蝌蚪完全雄性化；浓度为1微克/升及以上时，性别比例显著偏向雄性。未观察到对变态时间、体重或体长的影响。将一组随机抽取的青蛙在对照水中饲养至生殖成熟（受精后39周）。所有在幼体期暴露于16微克/升或更高浓度法倔唑的青蛙在性成熟时都拥有睾丸。在4微克/升处理组中，12%的青蛙性腺呈现雌雄同体特征，即同时存在睾丸和卵巢组织。与对照组相比，并暴露的雄性或雌性青蛙的雌二醇、睾酮或卵黄蛋白原血浆浓度均未观察到差异；4微克/升处理组中的雌性青蛙，其未成熟卵母细胞的比例显著高于对照组，且体重显著更小。与对照组相比，暴露的雄性青蛙的精子数量未观察到差异。本研究结果表明，幼体暴露于芳香化酶抑制剂可导致雌性性腺完全雄性化。这些雄性化的雌性在成年期在表型上与正常雄性无法区分。较低水平的芳香化酶抑制导致雌雄同体性腺，并可能在成年期导致雌性生殖功能受损。这些结果表明，两栖动物暴露于能够抑制芳香化酶的外源性物质会导致不良的生殖后果。
