PM2.5 from Fracking Operations Induces Microvascular and Mitochondrial Dysfunction

页岩气的生产，以及使用水平钻井和水力压裂的威尔斯井的开发 技术是美国经济的主要驱动力。准备井场至完成 工作创造了一个复杂的混合空气中的有毒物质，其中包括高浓度的颗粒垫， 三氧化二硫（PM）、柴油发动机排气（DEE）中的超细颗粒（UFP）、二氧化硅以及挥发性有机化合物。 磅（挥发性有机化合物）和多环芳烃的地质，地表和人为来源。去- 个人接触到的材料总量令联邦、州和地方政府机构感到震惊- 化。事实上，邻近非常规天然气开发（UNGD）井场的社区 与没有全球发展网的社区相比，对健康的影响更大。然而，我们不知道的是，究竟是如何-- 积极的联合国全球发展战略加速了这些健康影响。PM，特别是细PM（直径<2.5 µm，PM2.5）是已知的 心血管毒物几项研究表明，在血管和微血管中存在显著损伤， 血管功能结合起来，这些研究表明，即使在低环境下， 水平。此外，我们还发现了心肌线粒体损伤， 心脏衰竭的风险。然而，目前尚不清楚的是， 来源（源解析）或肺PM2.5暴露后心血管损伤的机制， 当然.长期目标是建立解释流行病学健康模式的生理机制， 在联合国全球发展战略期间举行。这项R15申请的目的是大幅推进科学理解- 将肺部UNGD PM2.5与远端组织功能障碍联系起来的机制。核心假设是 在水力压裂过程中，肺部暴露于现场收集的PM2.5， 和线粒体功能障碍，其特征在于支持正常小动脉连接的机制紊乱， 收缩、内皮依赖性舒张、线粒体功能和促凋亡蛋白表达导致 导致心脏功能下降这一假设将通过以下方式进行检验：1）确定MI中的机制性改变; 在UNGD的不同阶段期间的微血管和线粒体功能，2）识别心脏功能 微血管和线粒体功能障碍导致的衰退。这项工作的基本原理是，亲- 提出的研究将大大增加PM2.5诱导的微血管和线粒体的机制见解， 神经功能障碍，同时支持我们的使命，教育和准备学生。利用学生进行测试 这些目标将使学生获得显微镜知识，尸检，解剖学，生物化学， 微血管和心血管生理学。这项研究是创新的，因为它直接阻止了- 地雷的毒性，在联合国全球发展战略的三个阶段期间产生的全部有毒物质的矩阵。拟议的重新- 研究意义重大，因为它将评估钻井不同阶段的心血管毒性以及机械- 这将弥合基础科学与流行病学联合国全球治理司健康影响之间的差距。

The production of shale gas, and the development of wells using horizontal drilling and hydraulic fracturing technology, is a major driver of the U.S. economy. The process of preparing well pads to completion of the work creates a complex mixture of airborne toxicants that includes elevated concentrations of particulate mat- ter (PM), ultrafine particles (UFPs) from diesel engine exhaust (DEE), silica, as well as volatile organic com- pounds (VOCs) and polyaromatic hydrocarbons from geological, surface and anthropogenic sources. The to- tality of materials that the individuals are exposed to is alarming to federal, state and local governmental organ- izations. Indeed, communities that are proximal to unconventional natural gas development (UNGD) well sites have greater health effects compared to communities without UNGD. However, what is not known is how ac- tive UNGD precipitates these health effects. PM, specifically fine PM (<2.5 µm in diameter, PM2.5) is a known cardiovascular toxicant. Several studies have demonstrated a significant impairment in vascular, and micro- vascular function. Combined, these studies indicate significant cardiovascular health effects even at low ambi- ent levels. Moreover, we have shown cardiac mitochondrial impairment, a significant contributor to progression of heart failure, following ambient PM exposure. However, what is not known is the relative toxicity of specific sources (source apportionment) or the mechanisms of cardiovascular injury following pulmonary PM2.5 expo- sure. The long-term goal is to establish physiologic mechanisms that explain the epidemiological health pat- terns during UNGD. The objective for this R15 application is to substantially advance the scientific understand- ing of the mechanisms that link pulmonary UNGD PM2.5 to remote tissue dysfunction. The central hypothesis is that pulmonary exposure to PM2.5 collected on-site during hydraulic fracturing will have greater microvascular and mitochondrial dysfunction, characterized by disturbances in mechanisms supporting normal arteriolar con- striction, endothelium-dependent dilation, mitochondrial function, and pro-apoptotic protein expression leading to cardiac functional declines. This hypothesis will be tested by 1) identifying the mechanistic alterations in mi- crovascular and mitochondrial function during different stages of UNGD, 2) identifying the cardiac functional declines that result from microvascular and mitochondrial dysfunction. The rationale for this work is that pro- posed research will add substantially to the mechanistic insights of PM2.5-induced microvascular and mito- chondrial dysfunction, while supporting our mission to educate and prepare students. Utilizing students to test theses aims will allow the students to gain knowledge in microscopy, necropsy, anatomy, biochemistry, and microvascular and cardiovascular physiology. The research proposed is innovative because it directly deter- mines toxicity of the complete matrix of toxicants produced during three phases of UNGD. The proposed re- search is significant as it will assess cardiovascular toxicity during different phases of drilling as well as mech- anisms of dysfunction that will bridge the gap between basic science and epidemiological UNGD health effects.