Project 3: Arsenic Biomarker Epidemiology

项目3：砷生物标志物流行病学。砷在超级基金优先级中排名第一 《危险物质清单》。在过去的五年里，我们发现早期接触砷 结果在30-49岁的年轻人中，肺癌和支气管扩张导致的死亡率大幅上升， 心肌梗塞、肾癌和膀胱癌。我们的智利研究最近发现，甚至 更多的死因与砷有关，并表明峰值死亡风险远远大于 免受世界上任何地方任何其他环境的影响。我们计划继续调查 智利北部1950至2000年的砷暴露和死亡率，目前正在评估 肺结核，慢性肾功能衰竭，以及我们新发现的死亡率增加的证据 喉癌、阴茎癌、子宫颈癌和甲状腺癌。我们还将关注一群独特的儿童 在孟加拉国，在宫内和儿童早期高度暴露于砷的人，包括测量 肺功能，评估慢性呼吸道疾病和上呼吸道感染的发生率， 测量血压、血糖和肾小球减少的标志物；FF2-微球蛋白 滤过率。我们将从孟加拉和我们正在进行的 智利北部早期生命暴露研究，以分析表观遗传学改变和蛋白质组生物标志物 砷暴露、易感性和疾病。我们将使用智利北部的口腔和尿液样本 评估高脂饮食后数十年对成人肺功能和呼吸道症状的影响 曝光。我们将进行体外研究，以确定涉及到的机制和下游影响 毒性砷代谢产物MMA3持续下调HBd1基因表达。我们会 还下调了目标器官细胞系中HBD1基因的表达，以确定受影响的基因 总而言之，通过下调HBD，我们提出了一种综合研究战略评估 人群研究中砷暴露的多种结果，重点是早期生活的影响 暴露，同时寻找有关行动机制的证据。

Project 3: Arsenic Biomarker Epidemiology. Arsenic is ranked number one on the Superfund Priority List of Hazardous Substances. During the last five years, we have found that early life exposure to arsenic results in major mortality increases among young adults aged 30-49 from lung cancer and bronchiectasis, myocardial infarction, kidney cancer, and bladder cancer. Our Chile studies have recently identified even more causes of death related to arsenic, and show that peak mortality risks are much greater than those from any other environmental exposure anywhere in the worid. We plan to continue our investigation of arsenic exposure and mortality in northern Chile for the years 1950 to 2000, now assessing mortality due to pulmonary tuberculosis, chronic renal failure, and our newly discovered evidence of increased mortality from cancers of the larynx, penis, cervix and thyroid gland. We will also follow a unique cohort of children in Bangladesh who were highly exposed to arsenic in utero and in early childhood, including measuring lung function, assessing the incidence of chronic respiratory disease and upper respiratory tract infections, measuring blood pressure, blood glucose and ;ff2-microglobulin, a marker of reduced kidney glomerular filtration rate. We will collect urine samples and buccal cells from Bangladesh and from our ongoing northern Chile eariy life exposure study, to analyze epigenetic alterations and proteomic biomarkers of arsenic exposure, susceptibility, and disease. We will use the northern Chile buccal and urine samples to assess the impact on pulmonary function and respiratory symptoms in adults, decades after high exposure. We will conduct in vitro studies to determine the mechanism and downstream effects involved in the persistent down-regulation of HBDl gene expression by the toxic arsenic metabolite, MMA3. We will also knock down HBDl gene expression in target organ cell lines to detennine the genes that are affected by HBDl down-regulation, in summary, we are proposing an integrated research strategy assessing multiple outcomes from arsenic exposure in population studies, focusing on effects from eariy life exposure, along with pursuing evidence concerning mechanisms of action.