Systemic Health Implications of Occupational Nanomaterial Exposure

 描述（由申请人提供）：工程纳米材料（ENM）具有未知的潜在毒性，生物学效应与理化性质之间的关系仍不确定。我们的长期研究目标是对不同特征和暴露条件的ENM进行有效和准确的安全分析，以加强有关人类暴露风险的决策。我们在本申请中的目的是确定导致全身毒性（主要是血管和神经毒性）的肺ENM暴露引起的血清组成变化。我们提出了以下具体目标，将创新的离体生物活性输出与先进的高分辨率质谱组成分析配对。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改性循环成分的肺起源机制。有证据表明，循环因子可能与a）ENM和肺细胞/分子组分的直接反应或B）金属蛋白酶活性增加的降解副产物相关，并且循环组分通过内皮细胞表面模式识别受体起作用。在第二个目标中，我们将评估由肺部ENM诱导的血清组修饰引起的神经血管和中枢神经系统影响。在这里，我们将开发和优化基于序列标签的算法，以提高多壁碳纳米管（MWCNT）响应血清组内的内源性肽的识别，这将有助于评估ENM诱导的生物活化在血管系统和ENM响应血清组因子的扩散性跨越血脑屏障。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力。我们将根据内皮激活评估血清生物活性，并将其与元素碳的个人呼吸区测量结果联系起来，元素碳是碳纳米管/碳纳米管暴露的标志物。在这个项目完成后，我们希望已经确定了关键的生理和化学因素，影响血浆传播ENM毒性。这些研究的成功完成有望成为预防/减轻与环境纳米接触相关的不良健康影响的重要一步。一个额外的好处将是产生新的诊断技术和生物标志物，不仅可以加强，而且还可以加快ENM安全评估和暴露监测。研究结果将直接解决战略目标1，2，和2013-2016 NIOSH纳米技术研究和指导战略计划的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.