地屈孕酮导致的雄性偏向斑马鱼性别分化和代谢组学特征变化。
Male-biased zebrafish sex differentiation and metabolomics profile changes caused by dydrogesterone.
机构信息
State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China; SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; University of Chinese Academy of Sciences, Beijing 100049, China.
SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China.
出版信息
Aquat Toxicol. 2019 Sep;214:105242. doi: 10.1016/j.aquatox.2019.105242. Epub 2019 Jul 11.
Some progestins, including the widely used dydrogesterone (DDG), have been shown to cause male-biased sex ratio in teleost. However, there is a gap to fully understand the mechanisms of the sex differentiation disturbance by progestins, particularly from the metabolic aspect. We thus aimed to examine the sex changes by exposing zebrafish embryos to 4.4 (L), 44 (M) and 440 (H) ng/L DDG for up to 140 days, and investigated metabolomic profile changes during the critical period of sex differentiation at fry stage (35 dpf). DDG increased the percentage of male zebrafish in a dose-dependent manner, with 98% male fish in the high concentration group. In zebrafish fry, DDG increased the levels of some free fatty acids, monoglycerides, acylcarnitines, organic acids, free amino acids, while decreased lysophospholipids, uric acid and bile acids. DDG exposure also decreased the nucleoside monophosphates and UDP-sugars while increased nucleosides and their bases. These metabolite changes, namely increase in n-3 PUFAs (polyunsaturated fatty acids), myo-inositol, taurine, palmitoleic acid, oleic acid, lactic acid, fumaric acid, and uracil, and decrease in uric acid and bile acids, might account for the male-biased sex ratio in zebrafish. It appears that many of these metabolites could inhibit several pathways that regulate zebrafish gonad differentiation, including NF-κB/COX-2 and Wnt/β-catenin pathways, and activate p53 pathway. Thus we proposed a hypothesis that DDG might induce oocytes apoptosis through the above pathways and finally lead to female-to-male sex reversal. The results from this study suggest that DDG at environmentally relevant concentrations could affect zebrafish metabolomic profiles and finally disturb fish sex differentiation.
一些孕激素，包括广泛使用的地屈孕酮（DDG），已被证明会导致鱼类雄性偏性性别比。然而，对于孕激素引起的性别分化干扰机制，特别是从代谢方面，我们仍缺乏全面的了解。因此，我们旨在通过将斑马鱼胚胎暴露于 4.4（L）、44（M）和 440（H）ng/L 的 DDG 中长达 140 天，来研究性别变化，并在幼鱼阶段（35 dpf）的性别分化关键时期研究代谢组学特征的变化。DDG 以剂量依赖的方式增加了雄性斑马鱼的比例，高浓度组中 98%的鱼为雄性。在斑马鱼幼鱼中，DDG 增加了一些游离脂肪酸、单甘油酯、酰基肉碱、有机酸、游离氨基酸的水平，而降低了溶血磷脂、尿酸和胆汁酸的水平。DDG 暴露还降低了核苷一磷酸和 UDP-糖的水平，同时增加了核苷及其碱基的水平。这些代谢物的变化，即 n-3PUFAs（多不饱和脂肪酸）、肌醇、牛磺酸、棕榈油酸、油酸、乳酸、富马酸和尿嘧啶的增加，以及尿酸和胆汁酸的减少，可能是导致斑马鱼雄性偏性性别比的原因。似乎这些代谢物中的许多可以抑制调节鱼类性腺分化的几种途径，包括 NF-κB/COX-2 和 Wnt/β-catenin 途径，并激活 p53 途径。因此，我们提出了一个假设，即 DDG 可能通过上述途径诱导卵母细胞凋亡，最终导致雌性到雄性的性别逆转。本研究结果表明，DDG 在环境相关浓度下可能会影响斑马鱼的代谢组学特征，并最终干扰鱼类的性别分化。
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