Evaluating environmental metals exposure on risk of LCH

项目总结 朗格汉斯细胞组织细胞增生症(LCH)是一种炎症性髓系肿瘤，其特征是 化疗失败率为50%，导致疾病进展，导致相当短的时间内 发病率和明显的后遗症。LCH表现出一系列症状，从自我解决 从单一器官损害到潜在的致命性播散性多器官疾病。LCH发生在一生中，伴随着 确诊时的中位年龄为30个月，发病率为每百万儿童和15岁儿童中有4-8例。而当 LCH的体细胞突变驱动因素已被阐明，与LCH易感性相关的危险因素尚未阐明 很好理解。在我们的R01中，我们正在研究LCH发病的遗传机制 并指出，在西班牙裔儿童(0-19岁)中，LCH的年龄标化发病率较高 与非西班牙裔美国人相比。我们还注意到，SMAD6的遗传变异可能有助于 观察到LCH发病率的种族差异。然而，我们不能排除环境的潜在作用。 西班牙裔美国人的易感性因素也不成比例地暴露在环境毒物中。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，可能会 增加LCH的风险。几种金属，包括砷、镉、铬和镍，被归类为 致癌物质，由国际癌症研究机构提供。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，这会在居住上对这些人进行错误分类 暴露的时间，没有具体说明暴露的时间(即产前或出生后)。要克服其中的一些困难 局限性，对儿童白血病的研究将出生或诊断时的住址与疾病的来源联系起来 污染物和评估的风险。然而，还没有研究利用地理空间信息来研究 啊哈。此外，自我报告或与地理空间数据关联的另一个限制是研究缺乏 对特定金属的客观测量。乳牙或乳牙是一种新的、非侵入性的、容易接受的 可访问的暴露评估矩阵，可提供产前和产后的客观测量 对包括金属在内的环境毒物的吸收，并未被用于对LCH的研究。 此外，来自乳牙的数据还没有很好地描述与地理空间接近的关系 毒物的环境来源。我们的总体目标是应用新的和未充分利用的曝光 对我国LCH研究的评价方法。对我们资助的R01的这一补充申请的目标是 进行一项初步研究，以评估获取乳牙作为新暴露评估矩阵的可行性 在研究LCH和将地址链接到地理空间数据中。我们假设乳牙会克服 暴露评估先前研究的局限性，是一种很好的暴露评估方法 扩展到一项更大规模的研究，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.