Department of Critical Medicine, The First Affiliated Hospital of Hunan Normal University (The People's Hospital of Hunan Province), Changsha, 410002, PR China.
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Medical School, Hunan Normal University, Changsha, 410013, PR China; Department of Sanitation Monitoring, Hanzhong Center for Disease Control and Prevention, Hanzhong City, 723000, PR China.
Toxicology. 2021 Aug;460:152842. doi: 10.1016/j.tox.2021.152842. Epub 2021 Jun 26.
Vinclozolin (VCZ) is a fungicide with antiandrogen activity. Exposure to VCZ in maternal uterus may cause uterine, ovarian and testicular damage, hypospadias and prostate abnormality in the offspring. Hippo pathway, which is highly conservative and may be activated by miR132 and miR195a, can control organ size and tissue regeneration, and participate in injury and deformity. In the present study, VCZ was found to have caused penile malformation in the male offspring and also induced "small testis" when it was administered to the pregnant mice orally at a dose of 400 mg kg day on Days 12-18 of gestation. At 1, 3 and 7 weeks of age, VCZ could increase miR132, Mst1, Sav1, phosphorylated Yes-associated protein (pYap) and pLats, and decrease Yap in offspring penises and testes. Besides, it could also raise miR195a both in the testes of 1, 7-week and in the penises of all the three ages. In addition, we found the levels of some cyclin (Ccn) genes elevated in the testes, the expression of the androgen receptor (Ar) gene dereased and Jnks changed in the penises of offspring aged 1, 3 and 7 weeks. The results suggest that that gestational VCZ exposure could not only increase miR132 and miR195a in penises and testes of the offspring, but also activate Hippo pathway and down-regulate Ar. These may directly inhibit cell proliferation, accelerate cell death by up-regulating the expression of some Ccns, and ultimately lead to penile and testicular damage and malformations in the offspring.
萎锈灵（VCZ）是一种具有抗雄激素活性的杀菌剂。母体子宫内接触 VCZ 可能导致后代子宫、卵巢和睾丸损伤、尿道下裂和前列腺异常。Hippo 通路高度保守，可能被 miR132 和 miR195a 激活，可控制器官大小和组织再生，并参与损伤和畸形。本研究发现，VCZ 可导致雄性后代阴茎畸形，并在妊娠 12-18 天经口给予孕鼠 400mg/kg/d 剂量时引起“小睾丸”。在 1、3 和 7 周龄时，VCZ 可增加 miR132、Mst1、Sav1、磷酸化 Yes 相关蛋白（pYap）和 pLats，并降低后代阴茎和睾丸中的 Yap。此外，它还可以提高 1、7 周龄睾丸和所有三个年龄段阴茎中的 miR195a。此外，我们发现一些细胞周期蛋白（Ccn）基因在睾丸中的水平升高，雄激素受体（Ar）基因在 1、3 和 7 周龄后代阴茎中的表达减少，Jnks 发生变化。结果表明，妊娠期 VCZ 暴露不仅可增加后代阴茎和睾丸中的 miR132 和 miR195a，还可激活 Hippo 通路并下调 Ar。这可能直接抑制细胞增殖，通过上调某些 Ccns 的表达加速细胞死亡，最终导致后代阴茎和睾丸损伤和畸形。
