基于代谢组学的环境镉暴露健康危害早期生物标志物及代谢机制研究

Studies on human health risk assessment of environmental exposure to cadmium in previously has been concentrated on target organs such as the kidney toxicity rather than on identification of biomarkers for disease prevention or revealing of pathological mechanisms. Our preliminary studies showed that there were certain specific metabolites appeared in human biofluids asthe result of exposure to cadmium, specifically, various endogenous metabolites already showed changes before organ injury. This approach therefore offers opportunity for idenitication of useful and sensitive biomarkers for prevention and for discovery of pathogenic mechanisms. In this proposed research, we will use multiple techniques which include MS, metabolomics and environmental-epidemiologic investigation to study the variation of endogenous small molecule metabolite shifts in blood, urine and saliva for humans exposed to different concentrations of cadmium in different periods. This new systematic risk assessment platform should provide a better understanding on cadmium intake from environmental source. In order to investigate the pathogenic mechanisms, reveal the principles of metabolomic shift at the systematic biology level and provide a scientific basis for risk assessment of environmental exposure to cadmium, we will select most specific metabolites as the new sensitive biomarkers of environmental exposure to cadmium. The selection will be based on early exposure to low concentrations of cadmium. This research is novel and innovatve for risk assessment for human exposure to metal and has obvious scientific significance in the development of management standards and policies.

既往环境镉污染健康效应标志物研究主要集中在肾脏等靶器官，从代谢组学角度探索新的早期敏感生物标志物与健康危害代谢机制罕见。我们的前期研究提示环境镉暴露人群存在特异性代谢产物，推测镉暴露后可能存在早期敏感生物标志物。本研究拟应用基于质谱（MS）的代谢组学技术并结合环境流行病学调查，分析环境镉暴露不同时期人群生物材料（血、尿和唾液）中内源性小分子代谢产物的变化规律，探索其动态代谢途径，建立环境镉暴露人群的代谢谱并筛选出一种或数种环境镉暴露的特异性代谢产物作为新的敏感生物标志物，目的在于从系统生物学水平揭示环境镉暴露对机体代谢组的影响规律，探讨镉引发健康危害的代谢机制，重点甄选早期暴露的敏感生物标志物，为深入了解环境镉污染健康危害的代谢机制、新的早期敏感生物标志物应用于镉污染健康风险评估、继而制定相关管理标准与政策提供科学依据。

环境镉污染引起的健康效应研究一直是备受关注的公共卫生热点问题。本研究从系统生物学角度出发，研究环境镉污染地区人群暴露与肾损伤效应关系，采用代谢组学方法，探讨镉引发健康危害的代谢机制。①通过开展环境镉长期暴露人群的现场流行病学调查，获得调查对象的人口学特征、主要食物及饮用水镉污染状况、机体镉负荷水平和人群肾损伤效应生物标志物等信息，构建了样本量900人以上的流行病学信息数据库；②以国际评估方法对环境镉污染地区人群开展膳食暴露健康风险评估，为进一步评价国家食品安全标准的适用性和科学性提供参考依据；③基于质谱分析技术，分别建立了适用于环境镉暴露人群血液和尿液的气相色谱-质谱联用（GC-MS）和超高效液相色谱-飞行时间质谱（UPLC/Q-TOF-MS）的代谢组学分析方法，灵敏度高、高通量、稳定性好、重现性好；④分别对不同环境镉暴露人群的尿液和血液开展GC-MS和UPLC-Q-TOF-MS非靶向性代谢组学分析，各鉴定出46个和33个具有显著性差异的小分子代谢物；绘制了环境镉暴露影响机体代谢异常的代谢通路图，镉暴露可能通过影响机体糖代谢、氨基酸代谢、能量代谢、类固醇代谢、嘌呤代谢等过程，进而引起机体的一系列生化功能转变；尿L-谷氨酰胺、血清肌醇、尿N-甲基-L-组氨醇的含量随着尿镉含量的变化呈现一定的变化趋势，有望通过进一步研究发展为环境镉暴露人群的潜在生物标志物。本研究为深入了解环境镉污染健康危害效应的代谢机制、筛选特异性的早期敏感生物标志物，并应用于镉污染健康风险评估及制定相关标准与管理政策提供了科学依据。