Autoimmune toxicity of chlorinated compounds

据估计，超过1000万的美国人患有某种形式的自身免疫性疾病。很明显，对于大多数这些疾病，遗传和环境因素都有助于疾病的发展和进展。在某些特定疾病中，如系统性红斑狼疮病，育龄妇女的发病率是男性的9-10倍，来自人类和动物研究的数据表明，雌激素可对自身免疫过程的进程产生不利影响。最近相当大的兴趣集中在可能的环境因素，可能有助于自身免疫性疾病的发展，特别是狼疮。一些化学物质已被证明具有类似雌激素的作用，其中一种机制是环境毒物可能通过模仿雌激素的作用来影响自身免疫性疾病的严重程度。我们实验室的初步研究发现，三种氯化农药（o,p'-DDT，十氯酮和甲氧基氯）先前在体内显示出雌激素效应，显著加速狼疮模型（NZB x NZW）F1（或BW1）小鼠自身免疫性疾病的发展。提出的一系列实验将通过建立三种毒物的剂量-反应关系和确定非效应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中的身体负荷。一个相关的目的是确定这些药物是否可以在胎儿和新生儿暴露后或在正常情况下不会发生自发性狼疮的小鼠品系中引起自身免疫效应。这种效应是由于雌激素活性的假设将在给予雌激素拮抗剂的小鼠中进行测试，并检查潜在的机制。使用o，p'-滴滴涕，甲氧基氯和十氯酮作为环境雌激素性自身免疫性疾病的原型，并提供有关这些药物改变免疫功能的机制的重要信息。

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.