Date of Award

2017

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Demetri D. Spyropoulos

Second Advisor

John A. Bowden

Third Advisor

Benjamin P. Parrott

Fourth Advisor

Louis M. Luttrell

Fifth Advisor

Andrew M. Shedlock

Abstract

The National obesity epidemic has reached a point where 36.5% of the adults are obese. While diet, exercise and genetics are major factors driving obesity, recent studies also implicate environmental chemical agents known as ‘Obesogens’. Research efforts have begun to identify obesogens, which promote obesity and metabolic syndrome and are especially potent during fetal and childhood development. The research presented herein provides a logical framework for the identification, characterization and validation of obesogens in environmental samples. This framework was developed based on potential obesogens present in crude oil (MC252 oil) and dispersant (Corexit) from the Deepwater Horizon oil spill given the magnitude of the spill and cleanup efforts and that components of oil have been previously implicated as obesogens. Receptor transactivation assays for nuclear receptors that regulate metabolic pathways previously implicated were used to identify obesogenic activities. Corexit components were identified to have obesogenic activities, including dioctyl sodium sulfosuccinate (DOSS), Span 80 and Tween 80. These candidate obesogens were then validated in vitro using adipogenic differentiation assays. DOSS increased adipogenesis in both mouse and human pre-adipocytes and stem cells. DOSS is a ubiquitous chemical used as a food additive and stool softener often prescribed to pregnant women. As such, DOSS was evaluated in vivo using mice in a scenario imitating human pregnancy-associated exposure. Significantly, DOSS exposure to pregnant dams produced increased weight gain and adiposity, glucose intolerance, decreased bone area, altered adipokine production, a proinflammatory state and dyslipidemia in the male F1 population. Together, these studies provide a framework for investigation of obesogens. Furthermore, the data suggest that DOSS can act as an obesogen in vivo at physiologically relevant doses and prompt further research into the safe use of DOSS during pregnancy.

Rights

All rights reserved. Copyright is held by the author.

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