Preclinical Indicators & Biomarkers of Cardiovascular Effects of Arsenic Exposure

描述(由申请人提供) 心血管疾病(CVD)是世界范围内发病率和死亡率的主要原因，有证据表明，暴露于环境毒物会增加CVD的风险。最近，高水平的砷(As)，一种主要的环境污染物，已经被认为与心血管疾病的发病率、死亡率、血压和全身炎症的增加有关。砷在较低暴露水平下的影响尚不确定，研究也有限，但在这种低水平暴露下，暴露可能比之前认为的更广泛，因为数据表明，水和饮食来源可能对成人和儿童的总体砷暴露有贡献。在这项研究中，候选人建议采用生命周期方法来检查更广泛的砷暴露水平对成人和儿童心血管疾病风险的影响，并确定临床前指标和心血管疾病易感性的生物标志物。在K99指导阶段，使用两个成年人群暴露水平不等的现有数据，候选人将探索AS暴露与心血管疾病风险的生物标志物之间的关系，同时获得分子流行病学方面的专业知识。这位候选人将测试美国人群的血液和尿液样本，以检查低水平的砷暴露与全身炎症、氧化应激和内皮功能的标记物之间的关系，这些指标与成年人高水平的砷暴露有关。在暴露程度较高的孟加拉人群中，候选人将分析一组与暴露于砷有关的潜在遗传易感基因，以及它们随着时间的推移对血压测量的影响。她还将通过正式的课程作业、研讨会和由受人尊敬的研究人员组成的多样化咨询委员会的指导，来增进她对分子和心血管疾病流行病学的知识。在R00独立阶段，她将应用她的发现来启动一系列新的调查测试，无论是在子宫和/或早期生命中，因为接触会影响早期的指标 两类儿童的心血管疾病风险，因为怀孕和儿童早期是特别脆弱的时期，环境侮辱可能会影响发育，从而影响后来的疾病风险。与孟加拉国砷对健康的影响纵向研究和新汉普郡出生队列研究相结合，候选人将对暴露于砷的5岁儿童的心血管疾病风险早期指标进行两项平行调查。她将测试血管内皮细胞功能的非侵入性测量是否与这两个人群中不同水平的宫内和/或儿童早期AS暴露有关，因为AS对心血管疾病风险的亚临床效应可能远远早于临床表现。深入了解AS相关心血管疾病的潜在机制，并确定与AS暴露相关的生命阶段心血管疾病风险的生物标记物，将有助于确定环境因素对疾病从发病到临床表现的不同阶段的影响。通过这项拟议的研究，候选人将利用现有的资源，以开发独立但互补的项目，旨在帮助填补我们对一系列AS暴露水平对终身心血管健康影响的理解方面的关键空白。

DESCRIPTION (provided by applicant) Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and evidence has suggested that exposure to environmental toxicants can increase CVD risk. Recently, high levels of arsenic (As), a leading environmental contaminant of concern have been associated with increases in CVD incidence, mortality, blood pressure, and systemic inflammation. Arsenic's effects at lower exposure levels are uncertain and studies are limited, but exposure at these low levels may be more widespread than previously thought, as data suggest that both water and dietary sources may contribute to overall As exposure in adults and children. In this study, the candidate proposes to take a lifecourse approach to examining the effects of a wider range of As exposure levels on CVD risk in both adults and children and identify preclinical indicators and biomarkers of susceptibility for CVD. In the K99 mentored phase, using existing data from two adult populations ranging in levels of As exposure, the candidate will explore the relationship between As exposure and biomarkers of CVD risk, while gaining expertise in molecular epidemiology. The candidate will test archived blood and urine samples from a U.S. population to examine the relationship between low level As exposure and markers of systemic inflammation, oxidative stress and endothelial function, which have been related to high levels of As exposure among adults. In a more highly exposed Bangladeshi population, the candidate will analyze a set of potential genetic susceptibility loci in relation t As exposure and their impact on blood pressure measurements over time. She will also advance her knowledge of molecular and cardiovascular disease epidemiology through formal coursework, workshops and guidance from a diverse advisory committee of respected researchers. In the R00 independent phase, she will apply her findings to initiate a new line of investigation testing whether in utero and/or early life As exposure influences early indicators of CVD risk in two populations of children, as pregnancy and early childhood are particularly vulnerable periods when environmental insults may impact development and thus later risk of disease. In conjunction with the Health Effects of Arsenic Longitudinal Study in Bangladesh and the New Hampshire Birth Cohort Study, the candidate will implement two parallel investigations of early indicators of CVD risk among five-year-old children exposed to As. She will test whether non-invasive measures of endothelial function are associated with varying levels of in utero and/or early childhood As exposure in these two populations, as subclinical effects of As on CVD risk may occur far in advance of clinical presentation. Developing insight into the mechanisms underlying As-related CVD and identifying biomarkers of CVD risk across life stages as they relate to As exposure, will help to define the contribution of environmental As exposure to different phases of disease, from initiation to clinical presentation. With this proposed study, the candidate is positioned to take advantage of existing resources to in order to develop independent, yet complementary projects, designed to help to fill critical gaps in our understanding of the lifelong cardiovascular health impacts of a range of As exposures levels.