College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan 430065, China; State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
Comp Biochem Physiol C Toxicol Pharmacol. 2022 Jul;257:109332. doi: 10.1016/j.cbpc.2022.109332. Epub 2022 Mar 26.
Progestins are worldwide environmental contaminants, however, their ecotoxicological risks and underlying molecular mechanisms of effects are not fully understood. In this study, newly hatched rare minnow (Gobiocypris rarus) larvae were exposed to environmentally realistic concentrations (1 and 10 ng/L) of levonorgestrel (LNG) for 6 months. The sex ratios were not affected by LNG at both concentrations, but the growth was significantly inhibited at 10 ng/L while promoted at 1 ng/L. Histological analysis revealed impaired gonadal development. Plasma concentrations of estradiol in females and testosterone in both sexes were significantly induced after exposure to 1 ng/L LNG; plasma concentrations of 11-ketotestosterone were markedly increased in females exposed to 10 ng/L LNG and in males exposed to both concentrations of LNG. The transcription of cyp19a1a was significantly up-regulated in ovaries exposed to LNG at both concentrations, while cyp17a1 was down-regulated in testes exposed to 10 ng/L LNG. The global DNA methylation level was significantly decreased in testes exposed to 10 ng/L LNG, which might be associated with inhibited spermatogenesis. Gender-specific changes in CpG methylation patterns were induced by LNG in the 5' flanking region of cyp19a1a, with hypomethylation in ovaries but hypermethylation in testes, which was linked to the regulation of cyp19a1a transcription. The results suggest that LNG could induce endocrine disrupting effects in fish at environmentally realistic concentrations, which may be linked to altered DNA methylation. This study indicates potentially high ecological risk of LNG to fish populations, and warrants researches on regulatory mechanisms of epigenetic modifications in progestin-induced effects.
孕激素是全球性的环境污染物，但它们的生态毒理学风险及其作用的潜在分子机制尚未完全阐明。在本研究中，将刚孵化的稀有鲫（Gobiocypris rarus）幼鱼暴露于环境现实浓度（1 和 10 ng/L）的左炔诺孕酮（LNG）中 6 个月。在这两种浓度下，LNG 对性别比例均无影响，但在 10 ng/L 时生长受到显著抑制，而在 1 ng/L 时生长受到促进。组织学分析显示性腺发育受损。暴露于 1 ng/L LNG 后，雌性血浆中雌二醇和两种性别中睾丸酮的浓度均显著升高；暴露于 10 ng/L LNG 的雌性和两种浓度暴露的雄性血浆中 11-酮睾丸酮浓度明显升高。两种浓度的 LNG 暴露均导致卵巢中 cyp19a1a 的转录显著上调，而 10 ng/L LNG 暴露导致睾丸中 cyp17a1 下调。10 ng/L LNG 暴露导致睾丸中的总 DNA 甲基化水平显著降低，这可能与精子发生抑制有关。LNG 在 cyp19a1a 的 5'侧翼区诱导了性别特异性的 CpG 甲基化模式变化，在卵巢中呈低甲基化，而在睾丸中呈高甲基化，这与 cyp19a1a 转录的调节有关。结果表明，LNG 可以在环境现实浓度下诱导鱼类内分泌干扰效应，这可能与改变 DNA 甲基化有关。本研究表明 LNG 对鱼类种群可能具有潜在的高生态风险，需要研究孕激素诱导效应中表观遗传修饰的调节机制。
