Date of Award

5-2011

Level of Access Assigned by Author

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

Julie A. Gosse

Second Committee Member

Robert Gundersen

Third Committee Member

Rebecca Van Beneden

Abstract

Arsenic exposure has been linked to many health conditions, including cancer, diabetes, and cognitive dysfunction. In addition to these, it has also been linked to endocrine disruption by interacting with steroid receptors. The steroid compound estradiol has recently been linked to exacerbation of mast cell degranulation in the presence of antigen stimulation. Because of the impact of arsenic on steroid receptors (including estrogen), and the effects of estrogen-like compounds on mast cell function, we have asked if arsenic has an effect on degranulation of mast cells. We have shown, utilizing rat basophilic leukemia cells, that arsenic does inhibit the antigen stimulated degranulation signal transduction cascade in a mast cell model and that this inhibition does not occur when the cells are stimulated with calcium ionophore. This points to an upstream site of effect on the signal transduction cascade for arsenic, and demonstrates the ability of arsenic to interfere in allergic signal transduction. Arsenic did not inhibit F-actin plasma membrane ruffling of mast cells either, an event which has been associated with degranulation. In combination with the lack of ionophore inhibition by arsenic, failure to inhibit F-actin membrane ruffling also points to an upstream target in the pathway by arsenic—a target which is not important for F-actin membrane ruffling. Another putative endocrine-disrupting compound, triclosan, which similarly inhibited antigen-stimulated degranulation of mast cells, was shown to inhibit both ionophore-simulated degranulation as well as F-actin membrane ruffling. Inhibition of both these pathways via triclosan indicates that while degranulation as a whole was still significantly decreased (and while both compounds are putative endocrine disruptors), the mechanism of action is diverse from that of arsenic. Data we have gathered point to a novel means of arsenic inhibition in allergic signal transduction which occurs early in the pathway following antigen stimulation of mast cells. Our data indicate that As may inhibit the ability of humans to fight off parasitic disease and also point to a potential drug target against asthma and allergy.

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