MOLECULAR MECHANISMS OF ORGANOPHOSPHATE IMMUNOTOXICITY

免疫的物种和组织特异性及其分子机制 将研究有机磷杀虫剂马拉硫磷的调制作用。 小鼠急性口服非胆碱能低剂量马拉硫磷 剂量显示会导致腹膜和真皮肥大细胞脱颗粒。 并提高腹膜白细胞功能。在此基础上，三个 在这项赠款提案中，将继续进行调查。第一，学习 建议研究急性接触马拉硫磷对人体健康的影响 来自其他组织和不同组织的嗜碱性细胞脱颗粒 物种。给药途径对脱颗粒的影响 肥大细胞的特征也将被描述。此外，血液中的组胺 将测量水平，以可能建立用于研究的生物标记物 涉及职业性接触。二、对出资的审查 肥大细胞脱颗粒对增强免疫和白细胞的作用 提出了马拉硫磷给药后观察到的作用。 马拉硫磷对肥大细胞缺陷小鼠的治疗作用 肥大细胞成分的重建及免疫和免疫功能的评价 将进行白细胞功能检测。涉及的肥大细胞介体 巨噬细胞和免疫功能的增加将被评估 通过给药抑制介体合成或 活动。将检查的肥大细胞产品包括 组胺，血小板激活因子，花生四烯酸代谢物， 肿瘤坏死因子和5-羟色胺。此外，研究确定 马拉硫磷与肥大细胞的结合特性及对其的影响 代谢对马拉硫磷的活性和结合力也会产生影响 指挥。最后，亚急性和亚慢性给药的效果 马拉硫磷和其他有机磷的急性给药 杀虫剂，如对硫磷和敌敌畏，对肥大细胞脱颗粒 白细胞功能将会被测定。

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.