Mechanisms of Environmental-Mixture Induced Metabolic Disruption

点击翻译按钮获取中文摘要

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.