Biological Response Profiles of Selected Engineered Nanomaterials after Perinatal Exposure

项目概要 含有工程纳米材料 (ENM) 的产品的稳定增长已经超过了研究速度 确定它们对生物系统的影响，最重要的是对人类健康的影响。我们在纳米材料方面的目标 健康影响研究 (NHIR) 联盟提案旨在阐明 ENM 及其分子相互作用会影响暴露动物的免疫和激素状态。我们会 通过与 NIEHS 项目科学家和 NHIR 联盟成员合作进行测试来实现这一目标 ENM 资源和协调核心 (ERCC) 首次使用新型气液在体外提供 ENM 接口系统，然后使用肺毒性协议和发育性协议在体内进行 ENM 的子集 毒性协议。每个方案都将采用仅鼻子和全身吸入暴露以及一系列结果 评估身体状况、细胞毒性、炎症、氧化应激、基因表达、免疫的措施 调节、内分泌干扰和组织病理学。我们将在 NHIR 内分享我们的数据和方法 联盟及其他联盟，从而为综合生物反应的发展做出贡献 选定 ENM 的概况并确定那些对弱势群体构成重大危害的 ENM 包括孕妇和儿童。将解决三个具体目标： 目标 1：确定哪个 ERCC- 特征化的 ENM 最有可能在气道中诱导细胞毒性、炎症或免疫调节 使用我们建立的体外气液界面模型系统来观察上皮细胞。 AIM2：表征 孕妇亚慢性吸入暴露后对选定 ENM 的综合生物反应 与非怀孕小鼠相比。目标 3：阐明雄性和雌性后代的生物反应概况 在子宫内以及出生后通过吸入和哺乳接触 ENM 后。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、纳米气溶胶的产生和表征以及 ENM 蛋白质组学。五小学 将测试假设： H1) 吸入所研究的 ENM 会在以下条件下引起显着的生物反应： 将所选剂量与对照进行比较。 H2) ENM 暴露会产生明显的不利影响 取决于怀孕状态的生物反应特征。 H3) 母体 ENM 吸入暴露 怀孕前到分娩会对胎儿产生不良的发育反应。 H4) 幼犬有进一步的后处理 出生时暴露会产生毒理学反应，而在假暴露对照或 ENM 暴露成人中未见。 H5) 在子宫内和产后接触 ENM 后，未接触的成熟与疾病相关 进展。本文提出的研究将显着促进对剂量特异性的理解 吸入 ENM 和有效 AOP 的毒性，因此将建立一个提高安全性的框架 商业 ENM 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.