Biomarkers for Arsenic Toxicity: Genetics, Epigenetics and Folate

砷毒性的生物标志物：遗传学、表观遗传学和叶酸

• 批准号: 8391762
• 负责人: Mary Gamble
• 金额: $ 42.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391762
• 关键词: Accounting; Adult; Affect; Age; Arsenic; Bangladesh; Biological; Biological Markers; Blood; Cacodylic Acid; Candidate Disease Gene; Carbon; Cardiovascular Diseases; Chronic; Clinical; Clinical Trials; Consensus; Controlled Clinical Trials; Country; Cystathionine; DNA; DNA Methylation; Development; Diagnostic; Disease; Disease Outcome; Drug Metabolic Detoxication; Epidemiology; Epigenetic Process; Evaluation; Exposure to; Folate; Folic Acid; Gender; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Guidelines; Half-Life; Hand; Health; High Prevalence; Human; Hyperhomocysteinemia; In Vitro; Individual; Intervention; Laboratory Animals; Leukocytes; Malignant Neoplasms; Measures; Metabolism; Methionine; Methylation; Methylenetetrahydrofolate reductase (NADPH); Methyltransferase; Mono-S; Nested Case-Control Study; Nutritional; Nutritional status; Outcome; Pathology; Pathway interactions; Population; Predisposition; Premalignant; Regulation; Risk; Role; Seminal; Single Nucleotide Polymorphism; Specimen; Supplementation; Testing; Therapeutic; Time; Toxic effect; Urine; Work; World Health Organization; cost; disorder risk; drinking water; follow-up; high risk; interest; methionine synthase reductase; monomethylarsonic acid; nutrition related genetics; programs; skin lesion; urinary

DESCRIPTION (provided by applicant): Current estimates indicate that as many as 100 million people in over 70 countries are drinking water with arsenic (As) concentrations up to 100 times the World Health Organization (WHO) guideline of 10 ug per liter. There is significant variability in progression from As exposure to clinical manifestations of disease, and it is thought that genetic and nutritional factors may together account for a substantial portion of this variability. Thus, this proposal seeks to develop biomarkers that predict risk for the development of arsenicosis. Ingested inorganic As (InAs) is methylated to methylarsonic (MMA) and dimethylarsinic (DMA) acids via folate- dependent one-carbon metabolism. A reduced capacity to fully methylate As to DMA is associated with reduced urinary elimination of As. DMAV is less toxic and has a much shorter circulating half-live than InAs, and it is rapidly excreted in urine. There is great inter-individual variability in As methylation capacity, and epidemiological evidence, including our own, suggests that people who are "good methylators" are at reduced risk for As-induced skin lesions, cancers and cardiovascular disease. However, a growing body of evidence from in vitro and laboratory animal studies indicates that the trivalent form of MMA, a requisite intermediate in the pathway toward DMA synthesis, is extremely toxic. Our work over the past several years in Bangladesh has made seminal findings regarding the strong impact of nutritional regulation of one-carbon metabolism on the inter-individual variability in As methylation, blood As levels, and risk for arsenic-induced skin lesions, e.g., our clinical trial demonstrated that folic acid supplementation lowered blood As and blood MMA concentrations. Our 1st aim is to conduct a nested case-control study of 1,000 incident premalignant skin lesion cases and 1,000 controls to test the hypotheses that the capacity to methylate As is influenced by As methyltransferase (AS3MT) genotypes and that AS3MT genotypes and As methylation are associated with risk for skin lesions. Our 2nd aim will examine whether polymorphisms in one-carbon metabolism candidate genes are associated with hyperhomocysteinemia (which is very common in this population, and is associated with reduced capacity to methylate As to DMA), with methylation of As, methylation of leukocyte DNA, and with risk for skin lesions. We will also examine whether these associations are influenced by folate status. Collectively, these aims will allow us to identify of a set of biomarkers (As metabolites, leukocyte DNA methylation, folate, B12, Hcys, and SNPs) to identify sub-groups of individuals who may be at increased risk for As-induced pathology utilizing biological specimens that are already in hand. These studies will also resolve the critical issue of whether or not a higher capacity to methylate As is beneficial. Results of these studies will create opportunities for evaluation of interventions among high risk groups. They will also result in the identification of biomarkers to facilitate targeted therapies that exploit the mechanisms involved in susceptibility, resulting in low-risk, low-cost therapeutic strategies that could potentially reduce disease risk for hundreds of thousands of people.

描述（由申请人提供）：目前估计表明，70 多个国家有多达 1 亿人正在饮用砷 (As) 浓度高达世界卫生组织 (WHO) 指导标准（每升 10 微克）100 倍的水。从砷暴露到疾病临床表现的进展存在显着的变异性，并且人们认为遗传和营养因素可能共同解释了这种变异性的很大一部分。因此，该提案旨在开发预测砷中毒发生风险的生物标志物。摄入的无机砷 (InAs) 通过叶酸依赖性一碳代谢被甲基化为甲基胂 (MMA) 和二甲基胂 (DMA) 酸。 As 完全甲基化至 DMA 的能力降低与尿液中 As 消除的减少有关。 DMAV 的毒性较低，循环半衰期比 InAs 短得多，并且可迅速从尿液中排出。 As 甲基化能力存在很大的个体差异，流行病学证据（包括我们自己的证据）表明，“良好甲基化者”患 As 引起的皮肤损伤、癌症和心血管疾病的风险较低。然而，越来越多的体外和实验动物研究证据表明，三价形式的 MMA（DMA 合成途径中必需的中间体）具有极高的毒性。我们过去几年在孟加拉国的工作取得了开创性的发现，涉及一碳代谢的营养调节对个体间砷甲基化、血液砷水平和砷引起的皮肤损伤风险的强烈影响，例如，我们的临床试验表明，补充叶酸可降低血液 As 和血液 MMA 浓度。我们的第一个目标是对 1,000 例癌前皮肤病变病例和 1,000 例对照进行巢式病例对照研究，以测试 As 甲基化能力受 As 甲基转移酶 (AS3MT) 基因型影响以及 AS3MT 基因型和 As 甲基化相关的假设有皮肤损伤的风险。我们的第二个目标是检查一碳代谢候选基因的多态性是否与高同型半胱氨酸血症（这在该人群中很常见，并且与 DMA 甲基化能力降低有关）、As 甲基化、白细胞 DNA 甲基化、并有皮肤损伤的风险。我们还将研究这些关联是否受到叶酸状况的影响。总的来说，这些目标将使我们能够识别一组生物标志物（砷代谢物、白细胞 DNA 甲基化、叶酸、B12、Hcys 和 SNP），以识别可能面临砷诱发病理风险增加的个体亚组已经在手的生物标本。这些研究还将解决较高的砷甲基化能力是否有益的关键问题。这些研究的结果将为评估高危人群的干预措施创造机会。它们还将导致生物标志物的鉴定，以促进利用易感性机制的靶向治疗，从而产生低风险、低成本的治疗策略，有可能降低数十万人的疾病风险。