Wu Hao, Xu Tong, Chen Ting, Liu Jing, Xu Shiwen
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
State Key Lab of Inorganic Synthesis and Preparative Chemistry, Jilin University, Changchun 130012, PR China.
Sci Total Environ. 2022 Sep 10;838(Pt 2):155825. doi: 10.1016/j.scitotenv.2022.155825. Epub 2022 May 18.
Microplastics (MPs), as a new environmental pollutant, have received widespread attention worldwide. Uterine fibrosis is one of the main factors of female reproductive disorders. However, it is unclear whether the female reproductive disorders caused by MPs are related to uterine fibrosis. Therefore, in this study, we constructed female mouse models exposed to polystyrene microplastics (PS-MPs). We found that PS-MP exposure resulted in endometrial thinning and severe collagen fibre deposition in female mice. Further mechanistic studies found that PS-MP exposure increased the expression of high mobility group Box 1 (HMGB1) and acetyl-HMGB1, further activating the Toll-like receptor 4/NADPH oxidase 2 (TLR4/NOX2) signalling axis and eventually causing oxidative stress. Afterwards, oxidative stress elicited the activation of Notch and the transforming growth factor β (TGF-β) signalling pathway, leading to increased levels of fibrotic proteins and collagen. Correspondingly, PS-MP treatment upregulated the expression of TLR4 and NOX2 and the level of reactive oxygen species (ROS) and increased the levels of fibrotic protein and collagen in mouse endometrial epithelial cells cultured in vitro. Conversely, inhibition of the TLR4/NOX2 signalling pathway effectively reduced the level of ROS in cells, weakened the upregulation of Notch and TGF-β signalling by PS-MPs, and efficiently reduced the expression of fibrotic and collagen genes. In summary, we demonstrated a new mechanism by which MPs induce uterine fibrosis in mice, that is, by inducing oxidative stress to activate the Notch and TGF-β signalling pathways by triggering the TLR4/NOX2 signalling axis. Targeting TLR4/NOX2 signalling may consequently prove to be an innovative therapeutic option that is effective in alleviating the reproductive toxicity of PS-MPs. Our study sheds new light on the reproductive toxicity of MPs and provides suggestions and references for comparative medicine and clinical medicine.
微塑料（MPs）作为一种新型环境污染物，已在全球范围内受到广泛关注。子宫纤维化是女性生殖系统紊乱的主要因素之一。然而，MPs导致的女性生殖系统紊乱是否与子宫纤维化有关尚不清楚。因此，在本研究中，我们构建了暴露于聚苯乙烯微塑料（PS-MPs）的雌性小鼠模型。我们发现，暴露于PS-MP会导致雌性小鼠子宫内膜变薄和严重的胶原纤维沉积。进一步的机制研究发现，暴露于PS-MP会增加高迁移率族蛋白B1（HMGB1）和乙酰化HMGB1的表达，进一步激活Toll样受体4/烟酰胺腺嘌呤二核苷酸磷酸氧化酶2（TLR4/NOX2）信号轴，并最终导致氧化应激。之后，氧化应激引发Notch和转化生长因子β（TGF-β）信号通路的激活，导致纤维化蛋白和胶原蛋白水平升高。相应地，PS-MP处理上调了TLR4和NOX2的表达以及活性氧（ROS）水平，并增加了体外培养的小鼠子宫内膜上皮细胞中纤维化蛋白和胶原蛋白的水平。相反，抑制TLR4/NOX2信号通路可有效降低细胞内ROS水平，减弱PS-MPs对Notch和TGF-β信号的上调作用，并有效降低纤维化和胶原基因的表达。总之，我们证明了MPs诱导小鼠子宫纤维化的一种新机制，即通过诱导氧化应激，触发TLR4/NOX2信号轴来激活Notch和TGF-β信号通路。因此，靶向TLR4/NOX2信号可能被证明是一种创新的治疗选择，可有效减轻PS-MPs的生殖毒性。我们的研究为MPs的生殖毒性提供了新的见解，并为比较医学和临床医学提供了建议和参考。
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