Autoimmune toxicity of chlorinated compounds

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，对于这些疾病中的大多数，遗传和环境因素都有助于疾病的发展和进展。在系统性红斑狼疮等特定疾病中，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，雌激素可能会对自身免疫过程产生不利影响。最近，相当大的兴趣集中在可能的环境因素上，这些因素可能有助于自身免疫性疾病的发展，特别是狼疮。几种化学物质已被证明具有雌激素样作用，环境毒物可能影响自身免疫性疾病严重程度的一个机制是通过模仿雌激素的作用。我们实验室的初步研究发现，三种先前被证明在体内具有雌激素样作用的氯化农药(o，p‘-DDT，十氯酮和甲氧氯胺)显著加速了狼疮模型(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将通过为三种毒物中的每一种建立这种影响的剂量-反应关系并确定影响程度来扩展这些观察。为了便于推算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。一个相关的目标将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展为自发性狼疮的小鼠品系中引发自身免疫效应。将在给予雌激素拮抗剂的小鼠身上测试作用源于雌激素活性的假设，并将检验潜在的机制。利用o，p‘-DDT、甲氧氯胺和十氯酮作为环境雌激素样自身免疫性疾病的原型，并提供关于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.