TMAO is a biomarker of dioxin-like pollutant exposure and cardiometabolic disease

TMAO 是二恶英类污染物暴露和心脏代谢疾病的生物标志物

• 批准号: 10226231
• 负责人: Michael Curtis Petriello
• 金额: $ 24.9万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226231
• 关键词: Adipose tissue; Analytical Chemistry; Animal Model; Antibiotics; Atherosclerosis; Biological Markers; Blood; Body Burden; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Carnitine; Choline; Chronic Disease; Coronary Arteriosclerosis; Dairy Products; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Diet and Nutrition; Dietary Factors; Dioxins; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Exposure to; FMO3; Functional disorder; Future; Genes; Genetic; Goals; Hepatic; Human; Individual; Inflammation; Intervention; Investigation; Knockout Mice; Lead; Levocarnitine; Link; Lipids; Liver; Mass Spectrum Analysis; Meat Products; Medicine; Mentors; Metabolic Diseases; Modeling; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxides; Pharmacology; Plasma; Polychlorinated Biphenyls; Pre-Clinical Model; Process; Protein Isoforms; Public Health; Publishing; Research Personnel; Research Project Grants; Research Support; Risk; Risk Assessment; Role; Serum; Source; Testing; Toxicant exposure; Training; Translating; Work; bioaccumulation; cardiometabolism; cardiovascular disorder risk; career; design; diabetes risk; dietary; dietary control; disorder risk; epidemiology study; exposed human population; flavin-containing monooxygenase; gut microbiota; human disease; in vivo; individual response; insulin sensitivity; inter-individual variation; lipid metabolism; metabolomics; mouse model; novel marker; persistent organic pollutants; pollutant; prevent; statistics; toxicant; trimethylamine; trimethyloxamine

Dioxin-like organic pollutants persist in the environment and, because of their bioaccumulation in adipose tissue can be detected in the blood of most individuals. Exposure to these pollutants causes diabetes and its complications of obesity and cardiovascular disease in animal models. These observations can likely be translated to humans because several large longitudinal epidemiological studies have associated serum levels of these pollutants, for example polychlorinated biphenyls (PCBs) with an increased risk of cardiovascular disease and type 2 diabetes. The variability in inter-individual responses to increased body burdens of these pollutants observed in these epidemiological studies can likely be explained by the additional contributions of genetic and other environmental risk factors, the most powerful of which is clearly the diet. The goal of this proposal is to provide the applicant with mentored training and early career research support to become an independent investigator studying interactions between diet, nutrition and environmental exposures as determinants of human disease. To accomplish this the candidate will be mentored by an interactive group of established investigators with complementary expertise in analytical chemistry, multivariate statistics, and preclinical models of cardiovascular and metabolic disease. This training will be accomplished through participation in an original research project studying a mechanism that could link diet and exposure to dioxin- like persistent organic pollutants to cardiovascular disease risk. Increased circulating levels of a diet derived metabolite, trimethylamine N-oxide (TMAO) are associated with coronary artery disease and diabetes risk in humans. The precursor of TMAO, trimethylamine (TMA) is generated from dietary substrates (choline containing lipids and carnitines) by the gut microbiota. TMA is oxidized to TMAO by hepatic Flavin-containing monooxygenases, predominantly the FMO3 isoform. We have found that exposure to dioxin-like PCBs strongly increases FMO3 expression in the liver to amplify formation of TMAO from dietary sources in animal models and that exposure to dioxin like pollutants positively associates with circulating TMAO levels in a highly exposed human population. These observations lead us to propose our overarching hypothesis that induction of FMO3 expression is a mechanism linking coplanar PCB exposure to the development of cardiovascular and related metabolic diseases and that circulating TMAO levels are a biomarker of systemic dioxin-like pollutant exposure in humans. We will test this hypothesis in the following aims. 1: To test the hypothesis that a diet high in TMAO precursors can exacerbate dioxin-induced cardiometabolic disease in vivo. 2: To test the hypothesis that FMO3 and/or gut microbiota are required for dioxin-induced cardiometabolic disease in vivo. 3 To test the hypothesis that elevated TMAO levels in dioxin-like pollutant-exposed individuals result from increased FMO3 activity/expression.

二恶英类有机污染物持续存在于环境中，由于它们在脂肪中的生物积累 在大多数人的血液中都可以检测到组织。暴露在这些污染物中会导致糖尿病及其 动物模型中肥胖和心血管疾病的并发症。这些观察结果很可能是 因为几项大型纵向流行病学研究都有相关的血清水平 在这些污染物中，例如，多氯联苯(PCbs)会增加心血管风险 疾病和2型糖尿病。这些人对增加的身体负担的个体间反应的变异性 在这些流行病学研究中观察到的污染物很可能可以通过以下额外的贡献来解释 基因和其他环境风险因素，其中最强大的显然是饮食。这样做的目的是 建议为申请者提供指导培训和早期职业研究支持，使其成为 研究饮食、营养和环境暴露之间相互作用的独立调查者 人类疾病的决定因素。为了实现这一点，候选人将由一个互动小组进行指导 在分析化学、多元统计方面具有互补专业知识的资深研究人员，以及 心血管和代谢性疾病的临床前模型。这项培训将通过以下方式完成 参与了一项原创研究项目，研究一种可能将饮食与接触二恶英联系起来的机制-- 像持久性有机污染物会增加心血管疾病的风险。增加循环水平的饮食来源 代谢产物三甲胺氮氧化物(TMAO)与冠心病和糖尿病风险有关 人类。TMAO的前体三甲胺(TMA)是从饮食底物(胆碱)中产生的 含有脂类和肉碱)的肠道微生物群。TMA被含黄素的肝脏氧化成TMAO 单加氧酶，主要是FMO3亚型。我们发现，暴露在类似二恶英的多氯联苯中 在动物模型中增加肝脏中FMO3的表达以放大饮食来源的TMAO的形成 接触二恶英类污染物与循环中的TMAO水平呈高度正相关 暴露在人群中。这些观察结果使我们提出了我们的总体假设，即归纳 FMO3的表达是一种将共面印刷电路板暴露与心血管疾病的发展联系起来的机制 相关代谢性疾病和循环TMAO水平是全身性二恶英类污染物的生物标志物 在人类身上暴露。我们将在以下目标中检验这一假设。1：为了验证这样一种假设：高饮食 在TMAO中，前体可以在体内加重二恶英诱导的心脏代谢性疾病。2：检验假设 体内二恶英诱导的心脏代谢性疾病需要FMO3和/或肠道微生物区系。3来测试 二恶英类污染物暴露人群中TMAO水平升高是由于FMO3增加的假说 活动/表情。