Chen Yingying, Zhang Jinjin, Zhang Tianyu, Wu Yaling, Xi Yueyue, Wu Tong, Li Mo, Li Yan, Zhou Su, Wu Mingfu, Wang Shixuan
Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Research (Wash D C). 2024 Dec 5;7:0538. doi: 10.34133/research.0538. eCollection 2024.
Exposure to airborne fine particulate matter (PM) is strongly associated with poor fertility and ovarian damage. However, the mechanism underlying this remains largely unclear. Here, we found that PM markedly impaired murine ovarian reserve, decreased hormone levels, and aggravated ovarian inflammation. Circulating interleukin-6 (IL-6) was elevated in PM-exposed mice and was further confirmed to mediate this damage by IL-6 recombinant protein intervention. PM exposure led to increased alveolar macrophage infiltration in the lungs. However, alveolar macrophage clearance with clodronate liposomes could not fully reverse the elevated IL-6 levels and ovarian injury, suggesting that alveolar macrophages were probably not the only source of circulating IL-6. Further experiments indicated that IL-6 mainly targeted ovarian theca-interstitial cells and impaired testosterone synthesis via suppressing the peroxisome proliferator-activated receptor γ (PPARγ) pathway. In addition, apoptosis of granulosa cells and restriction of follicular growth were observed in co-cultures with IL-6-treated theca-interstitial cells, which could be further reversed by the PPARγ agonist. Moreover, IL-6-neutralizing antibodies ameliorated PM-induced ovarian damage. Notably, increased levels of circulating IL-6 were observed in premature ovarian aging patients and were inversely associated with their ovarian function. In summary, our findings offer a mechanistic explanation for PM-induced ovarian dysfunction and verify IL-6 as a biomarker and potential therapeutic target.
暴露于空气中的细颗粒物（PM）与生育能力低下和卵巢损伤密切相关。然而，其潜在机制在很大程度上仍不清楚。在此，我们发现PM显著损害小鼠的卵巢储备，降低激素水平，并加重卵巢炎症。暴露于PM的小鼠循环白细胞介素-6（IL-6）水平升高，通过IL-6重组蛋白干预进一步证实其介导了这种损伤。PM暴露导致肺中肺泡巨噬细胞浸润增加。然而，用氯膦酸脂质体清除肺泡巨噬细胞并不能完全逆转升高的IL-6水平和卵巢损伤，这表明肺泡巨噬细胞可能不是循环IL-6的唯一来源。进一步的实验表明，IL-6主要作用于卵巢膜间质细胞，并通过抑制过氧化物酶体增殖物激活受体γ（PPARγ）途径损害睾酮合成。此外，在与经IL-6处理的膜间质细胞共培养中观察到颗粒细胞凋亡和卵泡生长受限，而PPARγ激动剂可进一步逆转这种情况。此外，IL-6中和抗体改善了PM诱导的卵巢损伤。值得注意的是，在卵巢早衰患者中观察到循环IL-6水平升高，且与卵巢功能呈负相关。总之，我们的研究结果为PM诱导的卵巢功能障碍提供了机制解释，并验证了IL-6作为生物标志物和潜在治疗靶点。
