The past several decades have witnessed a dramatic expansion in the rates of metabolic disease, most prominently the obesity and diabetes epidemics. While metabolic disease is undoubtedly driven by increased caloric intake and decreased physical activity, exposure to endocrine disrupting chemicals (EDCs) has been implicated as a causal factor in the development of metabolic disease. EDCs are exogenous compounds capable of modulating endogenous hormonal axes, with some compounds capable of interfering with metabolic pathways. Prior work identified the fungicide and booster biocide tolylfluanid (TF) as a potent EDC with the capacity to induce adipocyte differentiation and impair adipocyte insulin signaling through stimulation of the glucocorticoid receptor (GR). The present studies seek to expand upon these data by investigating the outcomes of dietary exposure to TF across the lifespan, with the hypothesis that TF disrupts energy metabolism through aberrant stimulation of the GR, and that disruptions in global metabolic homeostasis are driven by modulation of adipose physiology. When male mice were provided a diet supplemented with 100ppm TF, they exhibited several metabolic changes that mirror the metabolic syndrome, including augmented visceral adiposity, glucose intolerance, global and cellular insulin resistance, and disruptions in circadian rhythms. Importantly, gene set enrichment analysis identified an enrichment of GR-dependent genes in the adipose tissue of exposed mice. Next, investigating the interaction of TF with diet identified novel differences in the outcomes of exposure depending on the background macronutrient content of the diet. Finally, developmental exposure to TF during prenatal and early postnatal life was found to modulate insulin-glucose homeostasis in adult life, in a sex-dependent manner. Taken together, these findings identify TF as a novel metabolic disruptor in vivo, and support prior studies identifying TF as a potent environmental glucocorticoid.
|Advisor:||Sargis, Robert M.|
|Commitee:||Brady, Matthew, Cohen, Ronald, Schwartz, Nancy|
|School:||The University of Chicago|
|Department:||Molecular Metabolism and Nutrition|
|School Location:||United States -- Illinois|
|Source:||DAI-B 76/12(E), Dissertation Abstracts International|
|Subjects:||Endocrinology, Environmental Health, Physiology|
|Keywords:||Diabetes, Endocrine disruption, Glucocorticoid, Insulin resistance, Obesity, Tolylfluanid|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be