Date of Award

8-2013

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Julie A. Gosse

Second Committee Member

Adria Elskus

Third Committee Member

Robert E. Gundersen

Abstract

Endocrine disruptors are chemicals that alter normal hormone signaling by mimicking or antagonizing normal hormone signaling. As the result of exposure to these agents, which are commonly found in consumer products and the environment, a wide range of deleterious health effects have been documented. These effects include cancers in hormone-sensitive tissues, diabetes, and immune dysfunction. The steroid compound and endogenous estrogen estradiol has recently been associated with enhancement of mast cell signaling (degranulation). The degranulation function of mast cells contributes to allergic disease states such as allergies and asthma. Therefore, modulation of mast cell signaling by environmental estrogens may help to explain the rise in prevalence and morbidity of these diseases, which are nearly endemic to industrialized nations. By utilizing rat basophilic leukemia cells, we have shown that three putative environmental endocrine disruptors, 4-tert-octylphenol, arsenic, and triclosan, are able to interfere with antigen-stimulated allergic signal transduction. We have discovered that 4-tert- octylphenol exacerbates antigen-mediated mast cell degranulation in, likely, an estrogen- receptor dependent fashion. In the case of arsenic and triclosan, we have found that they inhibit antigen-stimulated degranulation of mast cells by two distinct mechanisms of action that are anti-inflammatory in nature. Using calcium ionophore stimulation to bypass early signaling events, we have found that arsenic’s suppressive effects disappear, while triclosan’s are actually enhanced. Moreover, in contrast to what is seen for triclosan, arsenic fails to inhibit F-actin membrane ruffling. Combined with the aforementioned and other data, an investigation of early tyrosine phosphorylation signaling suggests that arsenic’s targets in the degranulation pathway include the protein kinase Syk; triclosan’s target(s) appears to be downstream of calcium entry across the plasma membrane. An analysis of the human mast cell line HMC-1 was also performed, to examine its suitability as a model for these studies. Finally, this thesis describes experiments laying the groundwork for future zebrafish experiments to examine the effects of these chemicals on mast cell function in vivo.

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