Programming Effects of Flame Retardants on Lipid Metabolism in a Longitudinal Birth Cohort

阻燃剂对纵向出生队列中脂质代谢的编程效应

• 批准号: 9917775
• 负责人: Alexander Suvorov
• 金额: $ 17.87万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-17 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917775
• 关键词: 10 year old; Adult; Affect; Age; Atherosclerosis; Biological Assay; Birth; Blood; Blood specimen; Bromine; CD36 gene; Cardiovascular Diseases; Cessation of life; Chemicals; Child; Childhood; Childhood Injury; Chronic Kidney Failure; Cohort Studies; Consumption; Cytokeratin-18 Staining Method; Data; Deterioration; Development; Disease; Dose; Dyslipidemias; Environment; Environmental Exposure; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Equilibrium; Etiology; Evaluation; Exposure to; FRAP1 gene; Fatty Acids; Fetal Tissues; Flame Retardants; Follow-Up Studies; Funding; Future Generations; Gene Expression; Genes; Health; Hepatocyte; Human; Hyperlipidemia; Hypertension; Hypertriglyceridemia; Industry; Intervention; Laboratory Animals; Life; Lipids; Lipoproteins; Liver; Liver Cirrhosis; Malignant Epithelial Cell; Measures; Mediating; Mediation; Membrane; Morbidity - disease rate; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Placenta; Population; Pregnancy; Prevalence; Primary carcinoma of the liver cells; Protein Kinase; Public Health; Regulation; Research; Resources; Risk; Risk Factors; Role; Sampling; Series; Serum; Thyroid Gland; Thyroid Hormones; Toxic effect; Triglycerides; United States National Institutes of Health; Western Blotting; base; biobank; chronic liver disease; cohort; design; developmental toxicity; experimental study; fetal; high risk; human tissue; improved; in utero; lipid metabolism; lipid transport; liver injury; morphometry; mortality; mouse model; non-alcoholic fatty liver disease; novel; polybrominated diphenyl ether; prenatal; prenatal exposure; programs; prospective; receptor; translocase; uptake

Project Summary/Abstract Alterations in the balance of lipids between blood and liver in either direction results in higher risk of morbidity and mortality. Increased uptake of fatty acids results in accumulation of triglycerides in lipid droplets of hepatocytes and non-alcoholic fatty liver disease (NAFLD) development. NAFLD is estimated to have 33% to 88% prevalence and is known to increase the risk of type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease, chronic kidney disease, liver cirrhosis, hepatocellular carcinoma, and mortality. The etiology of NAFLD is poorly understood and treatment options have very limited efficacy. On the other hand, decreased uptake of fatty acids by liver may result in hyperlipidemia and atherosclerosis, - the primary risk factors for heart attack, with more than 700,000 deaths attributed to the disease in the US annually. Thus understanding of preventable causes of lipid imbalance may have tremendous consequences for public health. In our experiments with laboratory animals we discovered that developmental exposures to environmentally relevant doses of ubiquitous environmental flame retardants, polybrominated diphenyl ethers (PBDEs), result in permanent change in liver-blood balance of lipids associated with reprograming of fatty acid translocase CD36 expression in liver – a membrane receptor responsible for uptake of fatty acids. We have also found activation of mechanistic target of rapamycin (mTOR) in mouse livers and in human hepatocellular carcinoma cells by PBDE. Our recent experiments with genetically modified mice demonstrate that PBDE induced permanent changes in expression of many genes of lipid metabolism as well as permanent dyslipidemia are mTOR dependent. Base on this evidence we hypothesize that in utero exposure to PBDE and halogenated substitute flame retardants in human population is associated with altered mTOR activity in fetal tissues and affects lipid profile at later age. For the proposed study, we will leverage the established GESTE prospective birth cohort, designed to investigate developmental toxicity of flame retardants. GESTE has extensive data on prenatal and childhood exposures, morphometry, and a biobank of placenta and blood samples that we will use to achieve the study aims. In Aim 1 we will evaluate the associations of prenatal PBDE and halogenated substitute flame retardants in maternal blood (exposure data available) with mTOR protein kinase activity in fetal placentas. In Aim 2 we will evaluate the associations of prenatal serum PBDE and halogenated substitute flame retardant concentrations with lipid profiles and markers of liver injury in 8-10 years old children. For both aims we will use mediation analysis to evaluate mechanisms. Our results will identify new preventable developmental causes of lipid imbalance, and inform development of in utero and early life interventions to reduce morbidities and mortalities associated with lipid imbalance, such as NAFLD and heart attack. As such our research may have a tremendous impact on public health and public health spending.

项目总结/文摘

项目成果

In Utero Exposure to Persistent Organic Pollutants and Childhood Lipid Levels.

• DOI: 10.3390/metabo11100657
• 发表时间: 2021-09-28
• 期刊: Metabolites
• 影响因子: 4.1
• 作者: Boutot ME;Whitcomb BW;Abdelouahab N;Baccarelli AA;Boivin A;Caku A;Gillet V;Martinez G;Pasquier JC;Zhu J;Takser L;St-Cyr L;Suvorov A
• 通讯作者: Suvorov A

Modalities of aging in organisms with different strategies of resource allocation.

• DOI: 10.1016/j.arr.2022.101770
• 发表时间: 2022-12
• 期刊: Ageing research reviews
• 影响因子: 13.1