State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
Aquat Toxicol. 2020 Sep;226:105557. doi: 10.1016/j.aquatox.2020.105557. Epub 2020 Jun 30.
Extensive studies have shown that estrogenic endocrine-disrupting chemicals (EDCs) can disrupt testis differentiation and even cause feminization in vertebrates. However, little is known about the mechanisms by which estrogenic EDCs disrupt testis differentiation. Here, we employed Xenopus laevis, a model amphibian species sensitive to estrogenic EDCs, to explore the molecular and cellular events by which 17β-estradiol (E2) disrupts testis differentiation and causes feminization. Following waterborne exposure to E2 from stage 45/46, genetically male X. laevis were confirmed to undergo testis differentiation inhibition and ovary differentiation activation at stages 52 and 53, ultimately displaying gonadal feminization at stage 66. Using a time-course RNA sequencing approach, we then identified thousands of differentially expressed transcripts (DETs) in genetically male gonad-mesonephros complexes at stages 48, 50 and 52 (the window for testis differentiation) between E2 treatment and the control. Enrichment analysis suggests alterations in cell proliferation, extracellular matrix, and cell motility following E2 exposure. Further verification by multiple methods demonstrated that E2 inhibited cell proliferation, disrupted extracellular matrix, and altered cell motility in the genetically male gonads compared with controls, implying that these events together contributed to testis differentiation disruptions and feminization in X. laevis. This study for the first time uncovered some of the early molecular and cellular events by which estrogen disrupts testicular differentiation and causes feminization in X. laevis. These new findings improve our understanding of the mechanisms by which estrogenic EDCs disrupt testicular differentiation in vertebrates.
大量研究表明，雌激素类内分泌干扰化学物质（EDCs）可干扰睾丸分化，甚至导致脊椎动物雌性化。然而，对于雌激素类 EDC 干扰睾丸分化的机制知之甚少。在这里，我们采用爪蟾（Xenopus laevis）作为一种对雌激素类 EDC 敏感的模式两栖动物物种，来探索 17β-雌二醇（E2）干扰睾丸分化并导致雌性化的分子和细胞事件。在从第 45/46 期开始进行 E2 水暴露后，遗传上为雄性的爪蟾在第 52 和 53 期被证实经历了睾丸分化抑制和卵巢分化激活，最终在第 66 期表现出性腺雌性化。通过时间序列 RNA 测序方法，我们在 E2 处理和对照之间的第 48、50 和 52 期（睾丸分化的窗口期），在遗传上为雄性的性腺-中肾复合体中鉴定出数千个差异表达转录本（DETs）。富集分析表明，E2 暴露后细胞增殖、细胞外基质和细胞迁移发生改变。通过多种方法进一步验证表明，与对照相比，E2 抑制了遗传上为雄性的性腺中的细胞增殖、破坏了细胞外基质并改变了细胞迁移，这表明这些事件共同导致了爪蟾睾丸分化中断和雌性化。这项研究首次揭示了雌激素干扰睾丸分化并导致爪蟾雌性化的一些早期分子和细胞事件。这些新发现提高了我们对雌激素类 EDC 干扰脊椎动物睾丸分化的机制的理解。
