Evaluating environmental metals exposure on risk of LCH

评估环境金属暴露对 LCH 风险的影响

• 批准号: 10830151
• 负责人: THANH THIEN HOANG
• 金额: $ 10万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10830151
• 关键词: 15 year old; 19 year old; Address; Adopted; Age; Area; Arsenic; Biological Markers; Birth; Birth History; Cadmium; Chemical Exposure; Chemicals; Child; Childhood Leukemia; Chromium; Classification; Collection; Consent; Data; Development; Diagnosis; Disease; Disease Progression; Dose; Environmental Epidemiology; Environmental Risk Factor; Eosinophilic Granuloma; Epidemiology; Exposure to; Family; Funding; Genetic; Genetic Variation; Goals; Health Policy; Hispanic; Hispanic Populations; Histiocytosis; Histologic; Incidence; Inflammatory; International Agency for Research on Cancer; Late Effects; Learning; Lesion; Life; Link; Location; MADH6 gene; Measurement; Measures; Metal exposure; Metals; Methods; Morbidity - disease rate; Myelogenous; Neoplasms; Nickel; Not Hispanic or Latino; Occupational Exposure; Organ; Parents; Pathogenesis; Patient Self-Report; Patients; Pediatric Hospitals; Pediatric Oncology Group; Pilot Projects; Predisposition; Protocols documentation; Public Health; Questionnaires; Radial; Recycling; Risk; Risk Factors; Risk Reduction; Role; Sampling; Second Pregnancy Trimester; Somatic Mutation; Source; Standardization; Symptoms; Texas; Third Pregnancy Trimester; Tooth structure; Toxic Environmental Substances; Treatment Failure; Work; carcinogenicity; chemotherapy; deciduous tooth; driver mutation; early childhood; epidemiology study; ethnic disparity; follow-up; improved; novel; pollutant; postnatal; prenatal; programs; recruit; study population; toxicant; uptake

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.

项目摘要 Langerhans细胞组织细胞增多症（LCH）是一种炎性髓样肿瘤，其特征是前期 化学疗法衰竭率为50％，导致疾病进展，导致相当短的短期 发病率和明显的后期作用。 LCH呈现出广泛的症状，从自我分辨 单器官病变可能致命的散布多器官疾病。 LCH一生都发生， 诊断为30个月的中位年龄，每百万儿童的发生率为4-8例<15岁。尽管 LCH的躯体突变驱动因素已被阐明，与LCH敏感性有关的危险因素不是 理解。在我们的R01中，我们正在研究LCH发病机理的遗传机制 并指出，西班牙裔儿童的LCH年龄标准的发病率更高（0-19岁 与非西班牙裔相比。我们还注意到，使用SMAD6的遗传变异可能有助于 观察到LCH发生率的种族差异。但是，我们不能排除环境的潜在作用 易感性的因素也不成比例地暴露于环境毒性。实际上， 有一些流行病学的证据表明，暴露于某些环境因素（包括金属）可能 有助于LCH的风险。几种金属，包括砷，镉，铬和镍，被归类为 国际癌症研究机构致癌。先前研究金属风险的研究 曝光和LCH是基于父母职业曝光，这会误导他们的生活 暴露，并且没有指定暴露时间（即产前或产后）。克服其中一些 局限性，对儿童白血病的研究已将出生或诊断时的住宅地址联系起来 污染物和评估风险。但是，没有研究利用地理空间信息与 LCH。此外，自我报告或与地理空间数据联系的另一个局限性是研究缺乏 特定金属的客观测量。落叶或初级牙齿是一种新颖的，无创的，很容易 可访问的曝光评估矩阵，可以在产前和产后提供客观的测量 在LCH研究中尚未采用环境毒物，包括金属，尚未采用。 此外，与地理空间邻近性有关 有毒物质的环境来源。我们的总体目标是应用新颖和未充分利用的曝光 我们对LCH研究的评估方法。此补充应用于我们资助的R01的目标是 进行试点研究，以评估作为新型暴露评估矩阵获得原发牙的可行性 在LCH和链接地址与地理空间数据的研究中。我们假设主要牙齿将克服 先前研究的暴露评估局限性，是一种出色的暴露评估方法 扩展到一项更大的研究，研究了LCH的环境风险因素。