生命早期镉暴露协同维生素D缺乏引发个体肠道菌群紊乱导致代谢异常的机制及干预研究

Low-dose and long-term toxicological effects assessment and combined exposure of multiple pollutants are the urgent scientific needs and hot spots in modern toxicology. Environmental exposure to heavy metals such as Cadmium and malnutrition such as vitamin D deficiency pose severe public health problems in China. It is highly significant and important to determine their long-term, combined effects of these exposures in the early stage of life. This proposed project will employ various early-life mouse models with cadmium exposure and vitamin D deficiency, investigate the health effects of cadmium exposure/vitamin D deficiency and the underlying mechanisms of action from the perspective of intestinal flora, and validate the findings in exposed populations. Three specific aims are proposed: 1) Determine the synergistic effects of cadmium exposure and vitamin D deficiency in the early stage of life on the intestinal microbiota, inflammation, and metabolism; 2) Elucidate the role of intestinal microbiota in cadmium exposure and vitamin D deficiency induced long-term health effects; and 3) Explore the potential protective effects of vitamin D supplements or intestinal probiotics on cadmium exposure/vitamin D deficiency caused toxicity. Upon the completion of the project, we will be able to provide rational approaches to reduce the health impairments of cadmium pollution and the vitamin D deficiency in our country, including new intervention strategies in early stage of life.

长期低剂量毒性健康效应评估和多因素联合暴露是现代毒理学亟待解决的科学问题和关注热点。镉污染和维生素D缺乏是严重影响我国人口健康的环境和营养因素，阐明二者在生命早期联合暴露对个体长期健康的影响及机制，对于有效防控我国慢病发生具有重要的现实意义。本项目将通过建立生命早期镉暴露/维生素D缺乏模型，从肠道菌群的角度阐明其毒性作用机制以及协同影响代谢异常的长期生物学效应，并在暴露人群中进行验证。通过本项目研究，拟解决以下3个关键科学问题：1）生命早期不同阶段镉暴露/维生素D缺乏对肠道菌群稳态、机体炎症和代谢的协同影响；2）肠道菌群对镉暴露/维生素D缺乏的长期生物学效应的介导作用；3）补充维生素D或肠道菌群策略可预防和降低镉暴露/维生素D缺乏导致的代谢异常。本项目的开展将为降低我国镉污染和维生素D缺乏引起的健康危害，发展新的干预策略和制定公共卫生政策提供科学支持和理论依据。

长期低剂量毒性健康效应评估和多因素联合暴露是现代毒理学亟待解决的科学问题和关注热点。镉污染和维生素D缺乏是严重影响我国人口健康的环境和营养因素，阐明二者在生命早期联合暴露对个体长期健康的影响及机制，对于有效防控我国慢病发生具有重要的现实意义。本项目通过建立生命早期低剂量长期镉暴露模型，从肠道菌群的角度阐明其毒性作用机制以及协同维生素D缺乏影响代谢异常的长期生物学效应，发现：1）镉暴露/维生素D缺乏能协同促进机体脂肪的积累，诱导胰岛素抵抗等代谢异常症状；2）长期低剂量镉暴露能降低肠道屏障的完整性加剧慢性肠炎水平，并能促进从细胞损伤、炎性平衡到肿瘤发生发展等慢病发生发展全过程；3）肠道菌群稳态失衡及异常代谢物在长期低剂量镉暴露/维生素D缺乏诱导的糖脂代谢改变过程中发挥关键介导作用；4）补充维生素D或特定益生菌策略可预防和降低镉暴露/维生素D缺乏导致的健康危害。本项目的开展为降低我国镉污染和维生素D缺乏引起的健康危害，发展新的干预策略和制定公共卫生政策提供科学支持和理论依据。