Systemic Health Implications of Occupational Nanomaterial Exposure

 描述(由申请人提供)：工程纳米材料(ENM)具有未知的毒性潜力，其生物效应和物理化学特性之间的关系仍不确定。我们的长期研究目标是实现对不同暴露特征和条件的ENM进行高效和准确的安全分析，以加强对人类暴露风险的决策。我们在这项应用中的目标是确定肺部ENM暴露导致的导致全身毒性(主要是血管和神经毒性)的血清成分变化。我们提出了以下具体目标，将创新的体外生物活性输出与先进的高分辨率质谱仪组成分析配对。在第一个目标中，我们将确定与金属蛋白酶活性和炎症相关的修饰循环成分的肺起源机制。有证据表明，循环因子可能与a)ENM与肺细胞/分子成分的直接反应或b)金属蛋白酶活性增加的降解副产物有关，循环成分通过内皮细胞表面模式识别受体发挥作用。在第二个目标中，我们将评估肺ENM诱导的血清组修饰对神经血管和中枢神经系统的影响。在这里，我们将开发和优化一种基于序列标签的算法来增强多壁碳纳米管(MWCNT)响应血清组中内源性多肽的识别，这将有助于评估ENM诱导的脑血管生物激活和ENM响应血清组因子跨血脑屏障的扩散性。最后，在第三个目标中，我们将评估来自职业暴露队列的样本中MWCNT相关的循环特征和炎症潜能。我们将根据内皮激活和个人呼吸区元素碳的测量来评估血清的生物活性，元素碳是碳纳米管/纳米纤维暴露的标志。在这个项目完成后，我们预计将确定影响等离子体传播的ENM毒性的关键生理和化学因素。这些研究的成功完成预计将成为预防/减轻与ENM接触有关的不良健康影响的重要一步。一个额外的好处将是新诊断技术和生物标志物的产生，这些技术和生物标志物不仅可以加强，而且可以加快ENM安全评估和暴露监测。研究成果将直接针对2013-2016年NIOSH纳米技术研究和指导战略计划的战略目标1、2和4。

 DESCRIPTION (provided by applicant): Engineered nanomaterials (ENMs) have an unknown toxic potential and the relationship between the biological effects and the physicochemical properties remains uncertain. Our long-term research goal is to enable an efficient and accurate safety profiling of ENM of varying characteristics and conditions of exposure that would enhance decision-making regarding human exposure risks. Our objective in this application is to determine serum compositional changes resulting from pulmonary ENM exposure that lead to systemic toxicity (vascular and neural, primarily). We propose the following specific aims, which will pair innovative ex vivo bioactivity outputs with advanced high-resolution mass spec compositional analysis. In the first Aim, we will ascertain mechanisms of pulmonary origin of modified circulatory components related to metalloproteinase activity and inflammation. Evidence suggests that circulating factors may be related to a) direct reactions of ENMs and pulmonary cellular/molecular components or b) degradation by-products of increased metalloproteinase activity and that the circulating components act through endothelial cell surface pattern recognition receptors. In the second Aim, we will assess neurovascular and central nervous system impacts arising from pulmonary ENM- induced serome modifications. Here, we will develop and optimize a sequence tag-based algorithm to enhance the identification of endogenous peptides within the multi-walled carbon nanotube (MWCNT)-responsive serome, which will facilitate evaluation of the ENM-induced bioactivation in the cerebrovasculature and the diffusivity of ENM-responsive serome factors across the blood brain barrier. Lastly, in the third Aim, we will assess MWCNT-associated circulatory characteristics and inflammatory potential in samples derived from an occupationally-exposed cohort. We will assess the serum bioactivity in terms of endothelial activation and link to personal breathing zone measurements of elemental carbon, a marker of carbon nanotube/nanofiber exposure. At the completion of this project, we expect to have identified key physiological and chemical factors that influence plasma-borne ENM toxicity. The successful completion of these studies is expected to constitute an important step towards preventing / attenuating adverse health effects associated with ENM exposure. An added benefit will be the generation of novel diagnostic technologies and biomarkers that can not only strengthen, but also expedite ENM safety assessments and exposure monitoring. The research results will directly address Strategic Goals 1, 2, and 4 of the 2013-2016 NIOSH Nanotechnology Research and Guidance Strategic Plan.