Autoimmune toxicity of chlorinated compounds

氯化化合物的自身免疫毒性

• 批准号: 6580398
• 负责人: JOEL SCHIFFENBAUER
• 金额: $ 13.16万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580398
• 关键词: autoimmune disorder; chlorohydrocarbon; chlorohydrocarbon insecticide; dichlorodiphenyltrichloroethane; environmental health; environmental toxicology; estrogen analog; hazardous substances; hormone regulation /control mechanism; laboratory mouse; systemic lupus erythematosus

It is estimated that upwards of 10 million Americans have some form of autoimmune disorder. It is clear that for most of these disorders both genetic and environmental factors contribute to the development and progression of disease. In specific disorders such as systemic lupus erythematosis, women of childbearing age are affected at a rate 9-10 times that of men, and data both from human and animal studies suggest that estrogens can have an adverse impact on the course of the autoimmune process. Recently considerable interest has focused on possible environmental factors that may contribute to the development of autoimmune disorders in general, and lupus in particular. Several chemicals have been shown to have estrogen-like effects, and one mechanism by which environmental toxicants might influence the appearance of severity of autoimmune diseases is by mimicking the effects of estrogen. Preliminary studies in our laboratory have found that three chlorinated pesticides (o,p'-DDT, chlordecone, and methoxychlor) previously shown to have estrogenic effects in vivo significantly accelerate the development of autoimmune disease in a lupus model, (NZB x NZW)F1 (or BW1) mice. A proposed series of experiments 3will extend these observations by establishing dose-response relationships for this effect for each of the three toxicants and determining on-effect levels. To facilitate extrapolation to other species including humans, body burdens in key tissues corresponding to these dosages will be determined. A related objective will be to determine whether autoimmune effects can be elicited by these agents following fetal and neonatal exposure or in a mouse strain that does not normally develop spontaneous lupus. The hypothesis that effects are due to estrogenic activity will be tested in mice administered an estrogen antagonist, and a potential mechanism will be examined. Using o,p'-DDT, methoxychlor, and chlordecone as prototype environment estrogenic autoimmune disease, as well as provide important information regarding mechanisms through which immune function is altered by these agents.

据估计，超过 1000 万美国人患有某种形式的自身免疫性疾病。显然，对于大多数这些疾病，遗传和环境因素都会导致疾病的发生和进展。在系统性红斑狼疮等特定疾病中，育龄女性受影响的几率是男性的 9-10 倍，来自人类和动物研究的数据表明雌激素会对自身免疫过程产生不利影响。最近，人们对可能导致自身免疫性疾病（特别是狼疮）发展的环境因素产生了极大的兴趣。几种化学物质已被证明具有类似雌激素的作用，环境毒物可能影响自身免疫性疾病严重程度的一种机制是模仿雌激素的作用。我们实验室的初步研究发现，先前证明具有体内雌激素作用的三种氯化农药（邻滴滴涕、十氯酮和甲氧滴滴涕）可显着加速狼疮模型（NZB x NZW）F1（或BW1）小鼠自身免疫性疾病的发展。拟议的一系列实验3将通过建立三种毒物中每种毒物的剂量反应关系并确定有效水平来扩展这些观察结果。为了便于外推到包括人类在内的其他物种，将确定与这些剂量相对应的关键组织的身体负担。一个相关的目标是确定这些药物在胎儿和新生儿接触后是否会引起自身免疫效应，或者在通常不会发展为自发性狼疮的小鼠品系中是否会引起自身免疫效应。将在给予雌激素拮抗剂的小鼠中测试效应是由于雌激素活性引起的假设，并检查潜在的机制。使用邻滴滴涕、甲氧滴滴涕和十氯酮作为雌激素性自身免疫性疾病的原型环境，并提供有关这些药物改变免疫功能的机制的重要信息。