短链氯化石蜡的代谢过程及其毒性效应的代谢组学评价

Short chain chlorinated paraffins (SCCPs) have been listed as the candidate of persistent organic pollutants (POPs) due to their potential for the persistence in the environment, bioaccumulation, long-range transport, and the high toxicity to aquatic organisms; meanwhile they exist at higher levels in the Environments of China. However, only a limited number of studies focused on their toxic mechanisms, ecological risk and human health risk. In this project, metabolomic approach will be adopted for studying the toxic effects of SCCPs. Zebra fish, rainbow trout, mice, human hepatoma cells and human adult stem cells will be selected as model organisms to conduct the SCCPs exposure tests. Using chromatography-mass spectrometry combined technique, the responses of biological metabolism to the SCCPs stress will be demonstrated, and the biomarkers for SCCPs stress will be identified. Furthermore, metabolic flux analysis method will be used to indicate the influence of SCCPs on the metabolic pathways in human cells, in order to get better understanding for the types of toxicity mechanism. Moreover, the metabolic kinetics of SCCPs in model animals will be tested, and the main metabolic products will be identified; and thereafter the mechanisms of toxicity will be deduced through comparing the toxic effects of SCCPs and their main metabolic products. This research will indicate the toxic effects and toxicity mechanisms of SCCPs from the aspect of metabolism, provide the evidences for the diagnose and treatment of SCCPs poisoning, and give a guide for the assessments of ecological and human health risks.

短链氯化石蜡（SCCPs）具有环境持久性和生物累积性，可长距离迁移，对水生动物有较高毒性，已被列为持久性有机污染物（POPs）的候选者；并且在国的环境介质中存量较高。但有关其毒理机制、生态风险和人体健康风险的研究仍十分有限。本项目将代谢组学研究方法引入到SCCPs的毒性效应研究，通过鱼类（斑马鱼和虹鳟鱼）、大鼠和人体细胞（肝癌细胞和成体干细胞）暴露试验，借助色质联用分析技术，研究生物体代谢对SCCPs的应答，鉴定生物标志物；并通过代谢流量分析的方法，研究SCCPs对人体细胞主要代谢通路的影响，揭示其毒性作用方式。同时，通过模式动物暴露试验，测试SCCPs毒代动力学，鉴定主要代谢降解产物；并比较其与母体化合物的毒性效应差别，推断SCCPs毒性作用机制。研究的开展可在代谢组研究层次上认识SCCPs的毒性效应和毒性机制，为其中毒症状的诊断和治疗提供依据，并为其生态和人体健康风险评估提供科学基础。

短链氯化石蜡（SCCPs）的毒性效应及代谢动力学研究十分有限，限制了对其进行生态风险和人体健康风险评估。本项目以人体肝癌细胞HepG2、雄性SD大鼠和斑马鱼幼体为模式生物，基于发展的靶向分析和拟靶向分析代谢组学研究策略，研究了SCCPs暴露所引起的生物代谢改变，同时，测试了SCCPs在大鼠体内的代谢动力学。结果表明，SCCPs对生物代谢的影响程度（以代谢影响水平指数为评价指标）随着暴露剂量的增加而增加，即使环境相关剂量的SCCPs也会引起生物代谢的显著改变。SCCPs暴露可引起HepG2细胞活性降低、大鼠体重下降、斑马鱼幼体存活率下降。一次喂饲暴露后，SCCPs在大鼠体内的毒代动力学过程符合有滞后时间的开放二室模型，血液中SCCPs的最高峰出现在2.8天，吸收半衰期为1天，消除半衰期为6.6天。SCCPs对生物代谢的影响程度明显高于多环芳烃（PAHs），且两者联合暴露对脂类代谢的影响表现为协同效应。SCCPs最显著的代谢毒性是使脂肪酸代谢上调，尤其是脂肪酸的β氧化过程。脂肪酸代谢的上调引起了磷脂代谢的紊乱。同时，SCCPs暴露可抑制氧化磷酸化过程，并明显干扰氨基酸代谢、核苷酸代谢、糖酵解过程和尿素循环。生物体内游离脂肪酸的含量、长链脂酰CoA脱氢酶活性和长链脂酰CoA合成酶活性可作为SCCPs暴露的生物标志物。SCCPs最主要的毒性作用方式的促进过氧化酶体增殖，引起脂肪代谢紊乱。