MOLECULAR MECHANISMS OF ORGANOPHOSPHATE IMMUNOTOXICITY

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The species and tissue specificity and the molecular mechanism of immune modulation by the organophosphate pesticide, malathion, will be examined. Acute oral administration of malathion to mice at low, noncholinergic doses was shown to lead to peritoneal and dermal mast cell degranulation and increased peritoneal leukocyte function. Based upon this, three lines of inquiry will be pursued in this grant proposal. First, studies are proposed to examine the effect of acute exposure to malathion on the degranulation of basophilic cells from other tissues and from different species. The effect of the route of administration on the degranulation of mast cells will also be characterized. In addition, blood histamine levels will be measured to possibly establish a biomarker for studies involving occupational exposure. Second, examination of the contribution of mast cell degranulation to the enhancement of immune and leukocyte function that is observed after malathion administration is proposed. Administration of malathion to mast cell-deficient mice with and without reconstitution of the mast cell component and assessment of immune and leukocyte function will be conducted. The mast cell mediators involved in the increase in macrophage and immune function will be assessed through the administration of inhibitors of mediator synthesis or activity. The mast cell products that will be examined include histamine, platelet-activating factor, arachidonic acid metabolites, tumor necrosis factor and serotonin. In addition, studies to determine the binding characteristics of malathion to mast cells and the effect of metabolism on the activity and binding of malathion will also be conducted. Lastly, the effects of subacute and subchronic administration of malathion and acute administration of other organophosphate pesticides, such as parathion and dichlorovos, on mast cell degranulation and leukocyte function will be determined.