新型酚类污染物通过ROS-NLRP3信号轴调控代谢性炎症的毒理机制研究

Diabetes and obesity are of increasing public health concern. Beyond the lifestyle and dietary factors, endocrine disruptors are closely related to the pathogenesis of metabolic diseases. Bisphenol pollutants may play an important role in the promotion of obesity, but their metabolic disruption effect and molecular mechanism are not completely clear. .The literature and our recent findings suggest that the oxidative stress and immune response induced by bisphenols exposure may play a key role in metabolic disorders. From the perspective of immune-metabolism crosstalk, macrophages were used as a tested model. Through the integrated application of cytokines profiling and mass spectrometry-based metabolomics, we found that, under the environmental-related concentrations, bisphenol exposure induces macrophage release of mitochondrial ROS and inflammatory cytokine of IL-1β significantly, suggesting that it may affects the occurrence and development of metabolic disease via the ROS-NLRP 3 inflammasome pathway..Based on these data, the underlying mechanism of bisphenol in metabolic inflammation will be further investigated through conducting mitochondrial disturbance assessment, preadipocytes differentiation, adipogenesis and macrophages phenotype polarization experiments. Toward elucidating the mechanisms of toxicity effects induced by bisphenols in adipose tissue microenvironment, this project may provide new clues and useful references for the analysis of environmental risk factors for metabolic diseases.

糖尿病肥胖等代谢性疾病的发病率逐年上升，严重威胁人类健康。除生活方式和膳食因素之外，内分泌干扰物与代谢性疾病的发病密切相关。双酚类污染物在肥胖发病过程中扮演着重要角色，但其代谢干扰效应和分子毒理机制尚不完全清楚。文献和我们最近的研究结果表明，双酚类物质诱导的氧化应激和免疫应答，在代谢紊乱中发挥着关键作用。从免疫-代谢对话切入，以巨噬细胞为受试模型，综合运用细胞因子表达谱和质谱代谢组学技术，我们发现在环境相关浓度下双酚类物质暴露能诱导巨噬细胞线粒体ROS和炎症因子IL-1β的显著释放，提示其可能通过ROS-炎症小体通路影响代谢性疾病的发生发展。本课题拟在此基础上，深入研究双酚类物质在代谢性炎症中的作用及机制，通过线粒体扰动、前脂肪细胞成脂分化和巨噬细胞表型极化等实验，阐明其影响脂肪组织微环境致代谢紊乱的毒性机制。上述研究将可能为代谢性疾病发病环境因素解析提供新线索和有益借鉴。

双酚类物质在环境和人体样本中普遍检出，流行病学调查显示双酚类物质暴露可能是糖尿病与肥胖等代谢性疾病频发的重要环境危害因素之一，但双酚类污染物诱发机体代谢功能紊乱的确切机制尚未完全明确。通过体外细胞实验和小鼠动物实验，本项目研究了双酚类污染物在环境相关浓度下暴露致巨噬细胞氧化应激和表型极化、小鼠糖脂代谢紊乱的毒理效应及作用机制，并运用代谢组学技术定量解析了小鼠在不同膳食营养（普通饮食ND和高脂饮食HFD）条件下低剂量双酚类污染物长期暴露后的肝脏代谢组特征。BPA和BPF均能诱导小鼠巨噬细胞向促炎性M1型表型极化，且BPF的极化效应更为显著。在环境相关浓度条件下BPA和BPF暴露后，胞内活性氧ROS和氧化应激指标MDA水平呈剂量依赖性地增高；而GSH-Px和SOD则剂量依赖性地受到抑制，证实了低剂量BPA和BPF会诱导氧化应激反应、破坏细胞氧化还原稳态。BPF会诱导促炎性细胞因子和抗炎性细胞因子分泌紊乱，表现为促炎性细胞因子TNF-α、IL-1β和IL-6水平显著升高，抗炎性细胞因子IL-10在mRNA水平和蛋白水平上均受到显著抑制。低剂量 BPA 长期暴露会造成ND条件下小鼠糖耐量受损和糖异生水平升高，而HFD条件下则显著增强糖耐量和抑制糖异生，且这两种效应均不依赖胰岛素信号通路，提示不同膳食模式下BPA可能通过不同机制干扰糖代谢稳态。低剂量BPF持续暴露则会增强HFD条件下的胰岛素敏感性和改善葡萄糖代谢。低剂量BPS慢性暴露呈现出预想之外的致低血糖效应，该作用部分归因于甲状腺信号通路。低剂量BPAF长期暴露血糖变化不明显。进一步研究了低剂量双酚类物质长期暴露对肝脏代谢组的影响，共性表现为肝脏脂肪酸和胆汁酸代谢变化显著。本项目发现环境相关浓度的双酚类物质可诱导免疫细胞向促炎性极化；不同膳食营养模式下，低剂量双酚类物质长期暴露能不依赖胰岛素信号通路干扰糖代谢稳态，这些发现加深了对双酚类物质代谢干扰效应的认识，为糖尿病肥胖等代谢性疾病发病的环境风险防控提供了基础数据和技术支撑。