Document Type

Honors Thesis

Publication Date

5-2013

Abstract

Exposure to arsenic (As) is a global health concern, according to the World Health Organization and Agency for Toxic Substances and Disease Registry. Prolonged exposure to this naturally occurring chemical has been linked to hyperkeratosis, type II diabetes, developmental abnormalities, and cancer. Some of the adverse health effects of As may be linked to its ability to alter cellular signal transduction. Recently, published work from the Gosse laboratory has shown that inorganic arsenite inhibits the signaling cascade leading to mast cell degranulation, a vital immune function, through an as-yet unknown mechanism.
Further work in the Gosse lab has suggested that arsenic’s effect occurs early in the degranulation signaling pathway, between receptor aggregation and calcium influx. Alternate FcεRI cross-linking methods produced similar As inhibition patterns, suggesting an As effect downstream of receptor aggregation. Calcium ionophore and compound 48/80-mediated degranulation responses were not inhibited by As-- evidence that arsenic’s effect occurs upstream of calcium influx as well. This thesis will concentrate on testing the hypothesis that As disrupts antigen-stimulated tyrosine phosphorylation of Syk kinase, a signaling molecule functioning between receptor aggregation and calcium influx in mast cells. Using a piceatannol-arsenic combination assay it was found that Syk and piceatannol, a competitive inhibitor of Syk, cause an additive inhibitory effect on degranulation. Preliminary Phospho-Syk ELISA data provides evidence that arsenic may be interfering with the phosphorylation of Syk, a vital process during the development of hypersensitivity. Taken together, these data provide insight into possible mechanisms of toxicity of arsenic as well as a possible drug target in the treatment and prevention of asthma and allergy.

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Biochemistry Commons

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