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

二恶英类有机污染物持久存在于环境中， 在大多数个体的血液中可以检测到组织。接触这些污染物会导致糖尿病及其 肥胖症和心血管疾病的并发症。这些观察可能是 因为几项大型纵向流行病学研究表明， 这些污染物，例如多氯联苯（PCBs）， 2型糖尿病的治疗方法个体间对这些物质增加的身体负担反应的变异性 在这些流行病学研究中观察到的污染物可能是由以下因素的额外贡献所解释的： 遗传和其他环境风险因素，其中最强大的显然是饮食。这个目标 建议是为申请人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员， 人类疾病的决定因素。为了做到这一点，候选人将由一个互动小组指导， 在分析化学、多元统计学和 心血管和代谢疾病的临床前模型。培训将通过以下方式完成： 参与一项原创研究项目，研究饮食与接触二恶英之间的联系机制- 比如持久性有机污染物对心血管疾病风险的影响。增加循环水平的饮食来源 代谢产物，三甲胺N-氧化物（TMAO）与冠状动脉疾病和糖尿病风险相关， 人类TMAO的前体，三甲胺（TMA）是从饮食基质（胆碱）中产生的 含有脂质和肉毒碱）。TMA被肝脏中的黄素氧化成TMAO， 单加氧酶，主要是FMO 3同种型。我们发现，暴露于二恶英类多氯联苯强烈 在动物模型中增加肝脏中FMO 3的表达，以扩大饮食来源的TMAO形成 暴露于二恶英类污染物与循环中的TMAO水平呈正相关， 暴露的人群。这些观察使我们提出了我们的总体假设，即归纳法 FMO 3的表达是一种机制，将共面PCB暴露与心血管疾病的发展联系起来， 相关的代谢性疾病，循环TMAO水平是系统性二恶英类污染物的生物标志物 暴露在人体内。我们将在以下目标中检验这一假设。1：为了测试的假设，饮食高 在TMAO前体中，可加重体内二恶英诱导的心脏代谢疾病。2：检验假设 FMO 3和/或肠道微生物群是体内二恶英诱导的心脏代谢疾病所必需的。3为了测试 假设二恶英类污染物暴露个体中TMAO水平升高是由于FMO 3增加 活动/表情

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.