Project 3: Arsenic Biomarker Epidemiology

项目3：砷生物标志物流行病学。砷在超级基金优先项目中排名第一 有害物质清单。在过去的五年里，我们发现早期接触砷 导致30-49岁的年轻人肺癌和支气管扩张症的死亡率大幅增加， 心肌梗塞、肾癌和膀胱癌。我们对智利的研究最近发现， 更多的死亡原因与砷有关，并表明死亡率峰值风险远大于那些 从世界上任何地方的任何其他环境暴露。我们计划继续调查 1950年至2000年智利北方砷暴露和死亡率，目前正在评估 肺结核，慢性肾衰竭，以及我们新发现的死亡率增加的证据 喉癌、阴茎癌、宫颈癌和甲状腺癌。我们还将跟踪一组独特的儿童 在孟加拉国，妇女在子宫内和幼儿期高度接触砷， 肺功能，评估慢性呼吸道疾病和上呼吸道感染的发病率， 测量血压，血糖和; ff 2-微球蛋白，肾小球减少的标志物 过滤速率我们将从孟加拉国和我们正在进行的 北方智利早期生活暴露研究，分析表观遗传改变和蛋白质组生物标志物， 砷暴露、易感性和疾病。我们将使用北方智利的口腔和尿液样本， 评估高血压几十年后对成人肺功能和呼吸道症状的影响 exposure.我们将进行体外研究，以确定参与的机制和下游效应。 有毒砷代谢物MMA 3持续下调HBD 1基因表达。我们将 也可以在靶器官细胞系中敲低HBD 1基因表达，以确定受影响的基因 通过HBD 1下调，总之，我们提出了一个综合研究策略， 人口研究中砷暴露的多种结果，重点关注早期生活的影响 暴露，沿着寻找有关作用机制的证据。

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.