Evaluating environmental metals exposure on risk of LCH

项目摘要 朗格汉斯细胞组织细胞增生症（LCH）是一种炎性骨髓瘤， 化疗失败率为50%，导致疾病进展，导致相当大的短期 发病率和严重的迟发效应。LCH表现出广泛的症状，从自我解决 单器官病变到潜在致命的播散性多器官疾病。LCH发生在一生中，并且 诊断时的中位年龄为30个月，发病率为每100万名<15岁儿童4-8例。而 LCH的体细胞突变驱动因子已经阐明，与LCH易感性相关的风险因素尚未阐明， 很好理解。在我们的R 01中，我们正在研究LCH发病机制的遗传机制 并指出，拉美裔儿童（0-19岁）的LCH年龄标准化发病率较高 老年人）与非西班牙裔相比。我们还注意到SMAD 6的遗传变异可能有助于 观察到LCH发生率的种族差异。然而，我们不能排除环境的潜在作用。 西班牙裔人也不成比例地暴露于环境毒物。事实上， 有一些流行病学证据表明，暴露于某些环境因素，包括金属， 增加LCH的风险。几种金属，包括砷、镉、铬和镍，被归类为 国际癌症研究机构的致癌性。先前检查金属风险的研究 暴露和LCH是基于父母的职业暴露，这将错误地分类那些居住 暴露，并且没有指定暴露的时间（即，产前或产后）。为了克服这些 局限性，儿童白血病的研究已经将出生或诊断时的居住地址与 污染物和风险评估。然而，没有任何研究利用地理空间信息来评估 LCH豪华此外，自我报告或与地理空间数据联系的另一个局限性是， 特定金属的客观测量。乳牙或乳牙是一种新颖的，非侵入性的， 可获得的接触评估矩阵，可提供产前和产后的客观测量 此外，还没有在LCH的研究中采用。 此外，来自乳牙的数据还没有很好地表征与地理空间接近度的关系， 有毒物质的环境来源我们的总体目标是应用新颖的和未充分利用的曝光 评价方法的研究。我们资助的R 01的补充应用程序的目标是 进行一项试验性研究，以评估获取乳牙作为新型暴露评估矩阵的可行性 研究LCH和将地址与地理空间数据联系起来。我们假设乳牙会克服 暴露评估的局限性，并成为一个很好的暴露评估方法， 扩大到更大的研究调查LCH的环境风险因素。

PROJECT SUMMARY Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by an upfront chemotherapy failure rate of 50%, leading to disease progression that results in considerable short-term morbidity and significant late effects. LCH presents with a wide spectrum of symptoms, from self-resolving single-organ lesions to potentially fatal disseminated multi-organ disease. LCH occurs throughout life, with a median age at diagnosis of 30 months, and incidence of 4-8 cases per million children <15 years of age. While the somatic mutational drivers for LCH have been elucidated, risk factors related to LCH susceptibility are not well understood. In our R01, we are investigating the genetic mechanisms underlying the pathogenesis of LCH and noted that the age-standardized incidence rates for LCH is higher among Hispanic children (0-19 years old) compared to non-Hispanics. We also noted that genetic variation with SMAD6 may contribute to the observed ethnic disparity in incidence of LCH. However, we cannot rule out the potential role of environmental factors on susceptibility as Hispanics are also disproportionately exposed to environmental toxicants. In fact, there is some epidemiologic evidence that exposure to certain environmental factors, including metals, may contribute to risk of LCH. Several metals, including arsenic, cadmium, chromium, and nickel, are classified as carcinogenic by the International Agency for Research on Cancer. Prior studies examining risk of metal exposure and LCH were based on parental occupational exposure, which would misclassify those residentially exposed, and did not specify the timing of exposure (i.e., prenatal or postnatal). To overcome some of these limitations, studies of childhood leukemia have linked residential addresses at birth or diagnosis to sources of pollutants and evaluated risk. However, no studies have leveraged geospatial information in relation to risk of LCH. Furthermore, another limitation of self-reported or linkage to geospatial data is that the studies lack objective measurements of specific metals. Deciduous or primary teeth are a novel, non-invasive, and readily accessible exposure assessment matrix that can provide objective measurements on pre- and post-natal uptake of environmental toxicants, including metals, and have not been adopted in studies of LCH. Additionally, data from primary teeth have not been well characterized in relation to geospatial proximity to environmental sources of toxicants. Our overall objective is to apply novel and underutilized exposure assessment methods to our studies of LCH. The goal of this supplemental application to our funded R01 is to conduct a pilot study to assess the feasibility of obtaining primary teeth as novel exposure assessment matrix in studies of LCH and linking addresses to geospatial data. We hypothesize that primary teeth will overcome the exposure assessment limitations of prior studies and be an excellent exposure assessment method to expand to a larger study investigating environmental risk factors of LCH.