Developmental programming of TCE induced autoimmune disease

描述（由申请人提供）：自身免疫性疾病是一种普遍的人类健康问题。由于我们对自身免疫性疾病病因学的了解有限，目前无法预防这些无法治愈的疾病。有证据表明，暴露于某些环境污染物（如溶剂三氯乙烯（TCE））可引发特发性自身免疫疾病。我们已经证明，暴露于低水平TCE的成年MRL+/+小鼠发生自身免疫性疾病，沿着与DNA甲基化相关的CD 4 + T细胞功能的“遗传性”改变。 虽然只有成人暴露于TCE会引发自身免疫性疾病，但有证据表明，发育中的免疫系统对化学毒性比成人免疫系统更敏感。因此，发育期接触三氯乙烯可能会增强成人接触三氯乙烯的自身免疫促进作用。预计这种效应将通过CD 4 + T细胞中特定效应基因的DNA甲基化变化介导。如果这些预测得到证实，它将支持这样一个概念，即以前认为安全的化学物质的发育暴露可以促进成人自身免疫性疾病的发展。这些预测和相关的作用机制将在3个目标中进行测试。目标1。确定发育期TCE暴露对成人自身免疫性疾病的影响。我们将测试如果TCE暴露开始于妊娠期而不是成年期，自身免疫性疾病病理学和相关的CD 4 + T细胞改变是否更稳健。目标2.定义TCE诱导的CD 4 + T细胞表观遗传学改变。新的基因组规模的DNA甲基化谱将确定TCE处理小鼠的CD 4 + T细胞中的时间和浓度依赖性基因改变。目标3.表征TCE处理小鼠的CD 4 + T细胞的自身反应性。将检测TCE处理的MRL+/+小鼠的CD 4 + T细胞过继转移至淋巴细胞缺陷型（Rag敲除）MRL+/+小鼠后产生自身免疫性疾病的能力。该过继转移实验将比较从供体TCE暴露的两个窗口（发育和仅成人）产生的CD 4 + T细胞的自身反应性。

DESCRIPTION (provided by applicant): Autoimmune diseases are a widespread human health problem. Preventing these incurable disorders is currently impossible due to our limited knowledge of autoimmune disease etiology. There is evidence that idiopathic autoimmune disease can be triggered by exposure to certain environmental pollutants such as the solvent trichloroethylene (TCE). We have shown that adult MRL+/+ mice exposed to low-level TCE developed autoimmune disease along with "heritable" alterations in CD4+ T cell function associated with DNA methylation. Although adult-only exposure to TCE triggered autoimmune disease, there is evidence that the developing immune system is even more sensitive than the adult immune system to chemical toxicity. Thus, developmental exposure to TCE is likely to augment the autoimmune-promoting effects of adult exposure. It is expected that this effect will be mediated by changes in the DNA methylation of specific effector genes in CD4+ T cells. If these predictions are confirmed it would support the concept that developmental exposure to chemicals at levels previously thought safe can promote autoimmune disease development in adults. These predictions and associated mechanism of action will be tested here in 3 Aims. Aim 1. Determine impact of developmental TCE exposure on adult autoimmune disease. We will test whether autoimmune disease pathology and associated CD4+ T cell alterations are more robust if TCE exposure begins at gestation rather than as an adult. Aim 2. Define TCE-induced epigenetic alterations in CD4+ T cells. Novel genome-scale DNA methylation profiles will identify time- and concentration-dependent gene alterations in CD4+ T cells from the TCE-treated mice. Aim 3. Characterize autoreactivity of CD4+ T cells from TCE-treated mice. CD4+ T cells from TCE-treated MRL+/+ mice will be tested for their ability to generate autoimmune disease following adoptive transfer into lymphocyte-deficient (Rag knockout) MRL+/+ mice. This adoptive transfer experiment will compare the autoreactivity of CD4+ T cells generated from two windows of donor TCE exposure (developmental and adult- only).