Interrogation of molecular mechanisms involved in driving adipogenesis in environmental mixtures and novel analytical techniques for identifying putative causative chemicals

点击翻译按钮获取中文摘要

Project Summary/Abstract Endocrine disrupting chemicals (EDCs) include 1,000 or more synthetic or naturally occurring chemicals or mixtures that can interfere with hormone action; some, termed “obesogens”, have been shown to directly increase weight gain and/or lipid accumulation in vivo. The prevalence of metabolic disorders, such as obesity, is currently of great societal concern. Obese individuals contribute to an estimated $215 billion in annual US health care costs due to medical care and lost productivity, and also exhibit increased risks of type II diabetes, cardiovascular disease, hypertension, and other adverse health effects. Despite increased attention and interventions, rates of US occurrence remain high: 9% of infants/toddlers, 17% of 2-19 year olds, and 38% of adults aged 20 and older are obese. Our laboratory has demonstrated that more than half of house dust samples, a ubiquitous EDC exposure source, exhibit agonist activity for peroxisome proliferator-activated receptor-gamma (PPARγ) and/or antagonist activity for thyroid receptor-beta (TRβ). Both of these receptors play critical roles in adipogenesis and triglyceride accumulation, and EDCs that interact with these receptors are commonly detected in extracts of house dust, an environmentally relevant mixture. We have also demonstrated that house dust extracts can promote triglyceride accumulation in 3T3-L1 cells, suggesting that disruption of these receptors may contribute to the observed activity. However, many other receptors can contribute to adipogenesis, and ligands for some of these receptors have been frequently detected in house dust. This proposal aims to interrogate the main signaling pathways driving triglyceride accumulation in house dust extracts via in vitro co-treatment experiments and gene expression analyses. Further, this fellowship will utilize modified, non-immobilized receptor ligand binding domains for PPARγ and TRβ to isolate ligands from dust sample extracts that may be responsible for the adipogenic activity observed in 3T3-L1 cells. The proposed NRSA postdoctoral fellowship will 1) provide additional training in molecular mechanism characterization through gene expression and mixture analyses and 2) provide competency in applying analytical isolation and mass spectrometry techniques to identify and quantitate both known and unknown EDCs present in environmental mixtures. These skills are essential to my immediate goals of developing a working knowledge of analytical chemical isolation and detection methods that can be used to identify and quantify causative EDCs in complex environmental mixtures. Furthermore, this will support my long-term goals of becoming an independent health-science researcher in an academic setting able to couple these skills to identify previously unreported environmental EDCs and characterize their potential health impacts. This research program, supported by a successful mentorship team at Duke University, will foster my career development, address critical needs in chemical mixture assessments, and will help develop and assess better tools to identify environmental EDCs in order to allow for more directed mixture assessments in the future.