Reproductive Science Group, School of Environmental and Life Sciences.
Toxicol Sci. 2011 Oct;123(2):563-75. doi: 10.1093/toxsci/kfr195. Epub 2011 Jul 23.
7,12-Dimethylbenz-[a]anthracene (DMBA) is an environmental carcinogen which has a potent ovotoxic affect on rat and mouse ovaries, causing complete follicular depletion resulting in premature ovarian failure. Although the overall effects of DMBA on ovarian folliculogenesis are well known, little is known about the exact molecular mechanisms behind its ovotoxicity. In this study, we characterized the mechanisms behind DMBA-induced ovotoxicity in immature follicles. Microarray analysis of neonatal mouse ovaries exposed to DMBA in vitro revealed a multilayered mechanism of DMBA-induced neonatal ovotoxicity involving a distinct cohort of genes and ovarian signaling pathways primarily associated with follicular atresia, tumorigenesis, and follicular growth. Histomorphological and immunohistological analysis supported the microarray data, showing evidence of primordial follicle activation and preantral follicle atresia both in vitro and in vivo. Further immunohistological analysis identified increased Akt1 phosphorylation, mTOR activation, and decreased FOXO3a expression in DMBA-treated primordial oocytes. Our results reveal a novel mechanism of DMBA-induced preantral ovotoxicity involving selective immature follicle destruction and primordial follicle activation involving downstream members of the PI3K/Akt and mTOR signaling pathways.
7,12-二甲基苯并[a]蒽（DMBA）是一种环境致癌物，对大鼠和小鼠的卵巢具有强烈的卵毒性作用，导致完全卵泡耗竭，从而导致卵巢早衰。尽管 DMBA 对卵巢卵泡发生的总体影响众所周知，但对其卵毒性的确切分子机制知之甚少。在这项研究中，我们描述了 DMBA 诱导未成熟卵泡卵毒性的机制。体外暴露于 DMBA 的新生小鼠卵巢的微阵列分析揭示了 DMBA 诱导的新生卵毒性的多层次机制，涉及一组独特的基因和卵巢信号通路，主要与卵泡闭锁、肿瘤发生和卵泡生长有关。组织形态学和免疫组织化学分析支持微阵列数据，显示体外和体内均存在原始卵泡激活和初级卵泡闭锁的证据。进一步的免疫组织化学分析表明，DMBA 处理的原始卵母细胞中 Akt1 磷酸化、mTOR 激活和 FOXO3a 表达减少。我们的结果揭示了一种新的 DMBA 诱导的前腔卵毒性机制，涉及选择性的未成熟卵泡破坏和原始卵泡激活，涉及 PI3K/Akt 和 mTOR 信号通路的下游成员。
