Mechanisms of Environmental-Mixture Induced Metabolic Disruption

环境混合物引起的代谢紊乱的机制

基本信息

批准号：
10454401
负责人：
Christopher Dennis Kassotis
金额：
$ 24.66万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454401
关键词：
3T3-L1 Cells Address Adipocytes Adolescent Adult Affect Affinity Alcohols Analytical Chemistry Animal Model Attention Automobile Driving Award Behavior Biological Assay Biological Models CRISPR/Cas technology Cell model Cells Chemicals Child Cholesterol Chronic Complex Complex Mixtures Coupled Data Detergents Development Diabetes Mellitus Diagnosis Diet Endocrine Endocrine Disruptors Environmental Impact Environmental Pollution Exhibits Exposure to Fellowship Fertilization Fishes Gases Genetic Glucose Goals Hand Health Health Care Costs Health Sciences Health trends Healthcare Healthcare Systems High Fat Diet Homeostasis Hormonal House Dust Human In Vitro Intervention Knock-out Laboratories Leptin Ligand Binding Domain Ligands Lipids Liquid substance Mass Spectrum Analysis Measures Mentors Mentorship Metabolic Metabolic Diseases Metabolic dysfunction Modeling Molecular Molecular Target Municipalities Mus National Research Service Awards North Carolina Obesity Obesity Epidemic Oils Oral cavity PPAR gamma Paint Pathway interactions Phase Prevalence Public Health Publishing Reporter Genes Reporting Research Research Personnel Research Training Resolution Sampling Societies Speed Surface Techniques Technology Testing Thyroid Gland Toxic effect Toxicology Training Triglycerides Universities Vertebrates Weight Gain Zebrafish adipocyte differentiation adult obesity antagonist base bioaccumulation career cost drinking water environmental justice experience experimental study exposed human population exposure pathway hydraulic fracturing in vitro Model in vitro testing in vivo in vivo Model indoor exposure lipid biosynthesis novel obesogen public health relevance receptor receptor binding response skills surfactant wastewater samples

项目摘要

Project Summary/Abstract Recent research has demonstrated that factors generally associated with obesity such as activity level, genetics, and diet, are insufficient to account for the magnitude and speed of the worsening obesity epidemic. Increasing research to evaluate other causative factors has focused on environmental contaminants that have been demonstrated to impact metabolic health. Many chemicals have been demonstrated to promote adipocyte commitment from multipotent precursors or promote triglyceride accumulation and/or pre-adipocyte proliferation in vitro, while some have been further demonstrated to directly increase weight gain and/or metabolic dysfunction in vivo. Alkylphenol and alcohol polyethoxylated surfactants are found at high levels in unconventional oil and gas wastewater, indoor house dust extracts, and wastewater effluent, and have been recently demonstrated to promote potent and efficacious lipid accumulation and pre-adipocyte proliferation in the 3T3-L1 mouse pre-adipocyte cell model. Interestingly, they appear to exert this activity through a mechanism other than peroxisome proliferator-activated receptor-gamma (PPARγ), often considered the master regulator of fat cell development. This proposal aims to interrogate the potential for in vivo metabolic disruption by these ubiquitous environmental contaminants through a mentored training aim (K99 phase). This aim will provide crucial experience utilizing zebrafish as a model organism to bridge in vitro and mammalian in vivo research, gaining skills in targeted molecular interrogation techniques, and culminating in a mentored exposure experiment assessing the impact of select alkylphenol and alcohol polyethoxylates on metabolic health of zebrafish. The independent aims of this fellowship (R00 phase) include a comparison of metabolic mechanism interrogation, comparing zebrafish and human receptor pathways utilizing in vitro model systems to elucidate mechanisms through which these contaminants might affect human health and how these may differ from those of a common endocrine in vivo model. Further, this fellowship will use technology applied in the previous NRSA fellowship, utilizing modified, non-immobilized receptor ligand binding domains and high resolution mass spectrometry of complex environmental samples known to contain alkylphenol and alcohol polyethoxylates: hydraulic fracturing wastewater, indoor house dust, and wastewater effluent. We will quantitate polyethoxylates and determine their relative contribution to the adipogenic activity induced by these environmental mixtures to assess their relative influence on environmental metabolic disruption. These skills will prove critical to my career goals of becoming an independent health-science researcher in an academic setting by establishing a comprehensive pipeline from in vitro testing of emerging contaminants and mixtures to assessing putative impacts on human health. Coupled with skills with high resolution mass spectrometry gained under the NRSA fellowship, I will be uniquely placed to assess and characterize complex environmental mixtures of contaminants and emerging contaminants from in vitro to robust in vivo models.

项目摘要/摘要最近的研究表明，通常与肥胖相关的因素，例如活动水平，遗传学和饮食不足以说明恶性肥胖肥胖症的幅度和速度。越来越多的研究以评估其他严重性因素已集中在具有的环境污染物上我们被证明会影响代谢健康。已经证明许多化学物质可以促进来自多元前体的脂肪细胞承诺或促进甘油三酸酯的积累和/或前脂肪细胞在体外增殖，而有些则进一步证明是直接增加体重增加和/或体内代谢功能障碍。在高水平的高水平中，烷基苯酚和酒精聚甲氧基化表面活性剂在非常规的石油和天然气废水，室内房屋灰尘提取物和废水废水，一直存在最近被证明是为了促进有效，有效的脂质积累和前脂肪细胞增殖 3T3-L1小鼠前脂肪细胞模型。有趣的是，他们似乎通过除过氧化物组增殖物激活受体伽马（PPARγ）以外的机制，通常认为脂肪细胞发育的主要调节剂。该建议旨在审问体内代谢的潜力这些无处不在的环境污染物通过指导的培训目标（K99阶段）造成了破坏。这 AIM将利用斑马鱼作为模型有机体提供至关重要的经验体内研究，获得针对性分子询问技术的技能，并在某个问题上达到顶点暴露实验评估精选的醇和酒精聚甲氧基对代谢的影响斑马鱼的健康。该奖学金的独立目标（R00阶段）包括代谢的比较机理审讯，比较利用体外模型系统的斑马鱼和人体受体途径阐明这些污染物可能影响人类健康的机制以及这些污染物如何可能影响人类健康与常见内分泌模型的不同。此外，该奖学金将使用应用的技术先前的NRSA奖学金，使用改良的，非弹性的受体配体结合域和高复杂环境样品的分辨率质谱法已知包含酒精苯酚和酒精聚甲氧基：水解压裂废水，室内房屋灰尘和废水废水。我们将定量聚甲氧基并确定其对这些诱导的掺杂活性的相对贡献环境混合物评估其对环境代谢破坏的相对影响。这些技能在学术中成为一名独立的健康科学研究人员的职业目标至关重要通过建立从新兴污染物和混合物的体外测试到的全面管道来设置评估对人类健康的推定影响。结合具有高分辨率质谱的技能在NRSA奖学金下获得的，我将独特地评估和表征复杂环境污染物和新兴污染物的混合物从体外到强大的体内模型的混合物。