昼夜节律紊乱与环境污染物暴露在普通人群十分普遍，且在职业人群存在联合暴露，而非酒精因素引起的脂肪性肝病（NAFLD/NASH）发病率不断升高，病因未明。本项目从动物、人群和体外细胞三个层面研究昼夜节律紊乱和Cd、PCBs与NAFLD/NASH的因果关联。动物实验观察光照改变中枢节律、睡眠期饮食改变肝脏节律及Cd、PCBs经口暴露对小鼠肝脏一般毒性、糖脂代谢、炎症反应的影响以及核受体CAR及其靶基因的表达；人群研究包括以医院为基础的病例-对照研究和面向医护人员的横断面调查，用问卷收集轮班作业、昼夜作息制度以及饮食、运动、睡眠等混杂因素信息，采集尿样检测污染物水平，收集体检和疾病信息，分析轮班作业、作息类型及污染物暴露与NAFLD/NASH及相关代谢、炎症指标的关联性；体外细胞实验观察能够调节细胞节律的天然小分子物质咖啡因、蜜桔黄素和Cd、PCBs活化核受体CAR的方式及对CAR靶基因的调控。

Circadian misalignment or disorder and environmental pollutants, as potential risk factors for Non-alcoholic fatty liver disease/ Non-alcoholic steatohepatitis (NAFLD/ NASH) and related cardio-metabolic disorders show a high prevalence in general population, and the co-exposure is very common in some workplaces, e.g. doctors and nurses in hospitals, policemen, taxi drivers and industrial workers. The causal relationships between circadian disorder, environmental pollutants and NAFLD/NASH are not clear. We design animal tests, epidemiological studies and in vitro cell assays to assess the independent/synergistic effects of circadian misalignment and environmental pollutants on hepatotoxicity (NAFLD/NASH) and explore constitutive androstane receptor (CAR)-mediated mechanism..In animal (C57BL/6J mice) tests light/dark cycle is to be inverted once a week to change the central clock time , and shifting eating to the circadian rest phase changes the liver clocks. Both methods could induce circadian misalignment between central clock and liver clock. CdCl2 and PCBS (PCB126 and Aroclor 1260) as representative environmental pollutants will be used to induce toxicant-associated fatty liver disease (TAFLD) or more severe form toxicant-associated steatohepatitis (TASH). Liver gene transcripts, metabolites, and associated metabolic pathways and functions are assessed. The joint effects will be observed in orthogonal design tests for circadian misalignment and environmental pollutants exposure. To elucidate the role of nuclear receptor CAR in the above mentioned toxic effect, the mRNA accumulation of CAR target genes will be measured and CAR-/- mice will also be used. .We will design two epidemiological studies: a hospital-based case-control studies and a cross-sectional studies in nurses to explore the relationships between night shift work, chronotypes and environmental pollutants with NAFLD/NASH and its related metabolic disorders. In the case-control study, newly diagnosed NAFLD/NASH patients are selected as cases and hospital-based controls are selected. The total sample size is 1400 with equal cases and controls. In the cross-sectional study 1400 doctors and nurses are enrolled in hospitals. Questionnaires are used to collect information on shift work, chronotype and potential confounders, such as diet, sports and sleep. Urine samples are used to analyze Cd and PCBs. Annual physical examination results of the doctors and nurses including B-mode images of liver, liver function indexes, plasma lipids, glucose, insulin and inflammatory factors are collected and used as outcomes..In vitro cell studies will be performed to explore the activation mode of nuclear receptor CAR and its effects on CAR target genes induced by caffeine, nobiletin, Cd and PCBs (PCB126 and Aroclor 1260). Both caffeine and nobiletin are small molecules targeting the molecular oscillator in cells to enhance circadian rhythms.