Project 2: Development of biomarkers of autoimmunity in 3 tribal communities exposed to mixed metal contaminants

摘要-研究项目2 废弃矿山废物的高度集中和部落社区的农村性质往往带来 社区成员直接和频繁地接触来自未经修复和 废弃矿场，导致潜在的有毒物质暴露，通过吸入、饮用水和 摄入直接或间接受到废物污染的食物来源。的目标是 研究项目2(RP2)是评估金属暴露的关系(通过生物监测确定 血液和尿样)与来自部落社区的个人的免疫学结果 靠近遗留的矿山废料。这一目标直接回应了部落社区的关切 长期接触金属和类金属混合物会影响免疫反应，并有助于发生 疾病。我们最重要的假设是，由于环境原因，人体内的金属负担增加了。 暴露在部落社区内的混合金属污染物中，这种暴露导致免疫 调节失调和自身免疫反应。我们将决定是接触金属还是接触金属 混合物(通过生物监测测量)会增加抗核抗体(ANA)和/或 来自我们三个受影响部落社区的个体的淋巴细胞凋亡。2)确定是否 暴露在金属或金属混合物中与细胞因子谱或T和B的可预测变化有关 来自我们三个部落群体的个体的细胞表型和3)决定金属混合物的效果 与我们关于自身免疫性疾病恶化或诱发的三个参与部落社区有关，以及 活体动物模型中饮用水暴露引起的免疫失调。一个根本问题 这些研究解决的问题是，环境金属的某些组合是否具有独立性， 相加的，甚至协同的毒性作用。部落社区不成比例地接触到各种 重金属和类金属，但没有基于人群的研究调查混合金属的影响 暴露在免疫反应上，特别是在暴露于 环境金属。我们有独特的机会在三个不同的领域使用相同的研究方法 美洲原住民部落人口清楚地识别接触和不同接触和 暴露结果。本研究的一个主要目标和创新点是开发一个通用的数据库，该数据库具有 来自三个部落社区的数据(计划扩大到其他社区)，关于接触和结果 从未汇编过的免疫学参数。这些数据将是确定 这些社区在暴露和健康结果方面的共性和重叠，对这些社区来说， 健康差距是存在的。

Summary-Research Project 2 The high concentration of abandoned mine waste and rural nature of Tribal communities often brings community members into direct and frequent contact with low-level metal mixtures from un-remediated and abandoned mine sites, resulting in potentially toxic exposures occurring via inhalation, drinking water, and ingestion of food sources that are either directly or indirectly contaminated by wastes. The objective of research project 2 (RP2) is to assess the relationship of metal exposures (determined through biomonitoring of blood and urine samples) with immunologic outcomes in individuals from Tribal communities who live in proximity to legacy mine waste. This objective responds directly to concerns of the Tribal communities that chronic exposure to metal and metalloid mixtures affects immune responses and contributes to development of disease. Our overarching hypothesis is that there is an increased body burden of metals due to environmental exposure to mixed metal contaminants within the Tribal communities, and that this exposure results in immune dysregulation and autoimmune responses. We will 1) Determine whether exposure to metals or metal mixtures (measured through biomonitoring) increases the prevalence of anti-nuclear antibodies (ANA) and/or lymphocyte apoptosis in individuals from our three affected Tribal communities. 2) Determine whether exposure to metals or metals mixtures are associated with predictable changes in cytokine profiles or T and B cell phenotypes in individuals from our three Tribal populations and 3) Determine the effect of metal mixtures relevant to our three participating Tribal communities on exacerbation or induction of autoimmune disease and immune dysregulation via a drinking water exposure in in vivo animal models. A fundamental question addressed by these studies is whether certain combinations of environmental metal have independent, additive, or even synergistic toxic effects. Tribal communities are disproportionately exposed to a variety of heavy metals and metalloids, yet there are no population-based studies investigating the effect of mixed metals exposure on immune responses, especially across different Tribal communities with exposures to environmental metals. We have the unique opportunity to use the same research approaches on three different Native American Tribal populations to clearly identify commonalities and differences in exposures and exposure outcomes. A major goal and innovation of this study is the development of a common database with data from three Tribal communities (with planned expansion to other communities) on exposure and resulting immunologic parameters that have never been compiled. This data will be crucial to establishing commonalities and overlaps in exposures and health outcomes in these communities for which such significant health disparities exist.