Biological Response Profiles of Selected Engineered Nanomaterials after Perinatal Exposure

项目摘要 含有工程纳米材料（ENM）的产品的稳定增长已经超过了研究， 确定它们对生物系统的影响，最重要的是人类健康。我们在纳米材料领域的目标 健康影响研究（NHIR）联盟的建议是阐明 ENM及其分子相互作用影响暴露动物的免疫和激素状态。我们将 通过与NIEHS项目科学家和NHIR联盟成员合作， 由ENM资源和协调核心（ERCC）提供的ENM首次在体外使用新型气液 接口系统，然后在体内使用肺毒性方案和发育毒性方案， 毒性实验。每个方案将采用仅鼻和全身吸入暴露和一系列结果 评估身体状况、细胞毒性、炎症、氧化应激、基因表达、免疫 调节、内分泌干扰和组织病理学。我们将在NHIR内部分享我们的数据和方法 联合会及其他组织，从而促进制定全面的生物应对措施 选定的环境营养物质的概况，并查明对脆弱人口构成重大危害的环境营养物质 包括孕妇和儿童。将讨论三个具体目标：目标1：确定哪个ERCC- 表征的ENM最有可能在气道中诱导细胞毒性、炎症或免疫调节， 上皮细胞使用我们建立的体外气液界面模型系统。目标2：表征 孕妇亚慢性吸入暴露后对选定ENM的综合生物学反应 与未怀孕的小鼠相比。目的3：阐明雄性和雌性后代的生物学反应特征 在子宫内暴露于ENM，然后在出生后通过吸入和哺乳暴露于ENM。这些目标将是 由具有纳米材料吸入毒理学专业知识的经验丰富的研究团队完成， 发育毒理学、纳米气溶胶生成和表征以及ENM蛋白质组学。五个主要 将检验假设：H1）吸入研究中的ENM诱导显著的生物反应， 与对照组相比，选择的剂量。H2）ENM暴露产生的不良影响具有明显的 取决于妊娠状态的生物学反应特征。H3）母体吸入ENM， 怀孕前到分娩在胎儿中产生不利的发育反应。H4）具有进一步后- 纳塔尔时接触会产生在假接触对照组或接触ENM的成年人中未见的毒理学反应。 H5）子宫内和出生后ENM暴露后，未暴露的成熟与疾病相关 进展本文提出的研究将大大促进对剂量特异性的理解。 吸入ENM和手术AOP的毒性，因此，将建立一个框架，以提高安全性 商业环境营养物质的概况，并指导其安全和可持续使用。

PROJECT SUMMARY The steady growth of products containing engineered nanomaterials (ENMs) has outpaced research to determine their impact on biological systems, most importantly human health. Our goal in this Nanomaterials Health Implications Research (NHIR) Consortium proposal is to elucidate how physicochemical properties of ENMs and their molecular interactions affect the immune and hormonal status of exposed animals. We will accomplish this goal by collaborating with NIEHS project scientists and NHIR Consortium members to test ENMs provided by the ENM Resource and Coordination Core (ERCC) first in vitro using a novel air-liquid interface system, and then in vivo for a subset of ENMs using a Pulmonary Tox Protocol and a Developmental Tox Protocol. Each protocol will employ nose-only and whole-body inhalation exposure and a host of outcome measures to assess body condition, cytotoxicity, inflammation, oxidative stress, gene expression, immune modulation, endocrine disruption, and histopathology. We will share our data and methods within the NHIR Consortium and beyond, thereby contributing to the development of comprehensive biological response profiles of selected ENMs and identifying those that pose significant hazards for vulnerable populations including pregnant women and children. Three specific aims will be addressed: AIM 1: Identify which ERCC- characterized ENMs are most likely to induce cytotoxicity, inflammation, or immunomodulation in airway epithelial cells using our established in vitro air-liquid interface model system. AIM2: Characterize comprehensive biological responses to selected ENMs following subchronic inhalation exposure in pregnant compared to non-pregnant mice. AIM 3: Elucidate biological response profiles in male and female offspring following exposure to ENMs in utero and then postnatally by inhalation and lactation. These aims will be accomplished by an experienced research team with expertise in inhalation toxicology of nanomaterials, developmental toxicology, nanoaerosol generation and characterization, and ENM proteomics. Five primary hypotheses will be tested: H1) Inhalation of the ENM under study induces significant biological responses at the selected dose compared with controls. H2) ENM exposure produces adverse effects with a distinct biological response profile that is dependent on pregnancy status. H3) Maternal ENM inhalation exposure from pre-conception to delivery produces adverse developmental responses in fetuses. H4) Pups with further post- natal exposure develop toxicological responses not seen in sham-exposed controls or in ENM-exposed adults. H5) Following in utero and post-natal ENM exposure, maturation without exposure is associated with disease progression. The research proposed herein will significantly advance understanding of the dose-specific toxicity of inhaled ENMs and the operative AOPs and thus, will establish a framework for improving the safety profile of commercial ENMs and guide their safe and sustainable use.