Department of Pharmacy, Peking University Third Hospital, Beijing, China.
Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China.
Cell Commun Signal. 2024 Jan 10;22(1):28. doi: 10.1186/s12964-023-01410-y.
Bisphenol A (BPA) levels are high in women with polycystic ovary syndrome (PCOS). The mechanism by which BPA induces abnormal glucose metabolism in PCOS patients is largely unknown.
Serum and urine samples were collected from women with and without PCOS (control) at the reproductive medicine center with informed consent. Non-PCOS patients who received in vitro fertilization were recruited for collection of ovarian follicular fluid and granular cells. Wild-type C57BL/6 and AhR mice were used to verify the effects of BPA on PCOS. Real-time PCR, western blotting, and ELISA were conducted to analyze the function of BPA. Chip-qPCR verified the role of AhR in GLUT4 transcription. Flow cytometry was performed to determine glucose uptake.
A positive correlation was observed between BPA concentration and serum BPA levels in PCOS patients. BPA aggravated the changes in PCOS with abnormal glucose metabolism, impaired fertility, and increased body fat. Mechanistically, we showed that BPA activated AhR and led to decreased glucose transport via GLUT4 downregulation in ovarian granular cells. Therefore, the use of inhibitors or knockout of AhR could effectively rescue BPA-induced metabolic disorders in PCOS mice.
Our results revealed that BPA suppressed GLUT4 expression and induced abnormal glucose metabolism by activating AhR, causing insulin resistance, and is thus a potential contributor to the development of PCOS. Therefore, AhR could be a potential new therapeutic target for PCOS. Video Abstract.
多囊卵巢综合征（PCOS）患者体内的双酚 A（BPA）水平较高。BPA 诱导 PCOS 患者葡萄糖代谢异常的机制在很大程度上尚不清楚。
在生殖医学中心，征得知情同意后，收集 PCOS 患者（病例组）和非 PCOS 患者（对照组）的血清和尿液样本。招募接受体外受精的非 PCOS 患者，以收集卵巢卵泡液和颗粒细胞。使用野生型 C57BL/6 和 AhR 小鼠验证 BPA 对 PCOS 的影响。实时 PCR、Western blot 和 ELISA 用于分析 BPA 的功能。芯片 qPCR 验证 AhR 在 GLUT4 转录中的作用。流式细胞术用于测定葡萄糖摄取。
病例组患者血清中 BPA 浓度与 BPA 水平呈正相关。BPA 加重了 PCOS 患者葡萄糖代谢异常、生育能力受损和体脂增加的变化。在机制上，我们发现 BPA 通过激活 AhR 导致 GLUT4 下调，从而减少卵巢颗粒细胞中的葡萄糖转运，从而加剧 PCOS 的发生。因此，使用 AhR 的抑制剂或敲除可以有效挽救 BPA 诱导的 PCOS 小鼠代谢紊乱。
我们的研究结果表明，BPA 通过激活 AhR 抑制 GLUT4 表达并诱导葡萄糖代谢异常，导致胰岛素抵抗，因此可能是 PCOS 发展的潜在因素。因此，AhR 可能是 PCOS 的一个潜在的新治疗靶点。视频摘要。
