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Mechanisms of Environmental-Mixture Induced Metabolic Disruption

Award Number: R00ES030405
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/23/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Mechanisms of Environmental-Mixture Induced Metabolic Disruption - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	5	1/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $246,625 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	5	8/4/2022	NON-COMPETING CONTINUATION	$246,625
														Subtotal = $246,625

Issue Date FY: 2021 ( Subtotal = $322,387 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	001	4	7/20/2021	NON-COMPETING CONTINUATION	$248,348
2021	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	3	4/13/2021	EXTENSION WITH OR WITHOUT FUNDS	$74,039
														Subtotal = $322,387

Issue Date FY: 2020 ( Subtotal = $249,000 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	3	9/23/2020	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $818,012

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Mechanisms of Environmental-Mixture Induced Metabolic Disruption

Award Number: R00ES030405

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/23/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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