Biological Response Profiles of Selected Engineered Nanomaterials after Perinatal Exposure

项目总结 含有工程纳米材料(ENM)的产品的稳步增长速度已经超过了研究 确定它们对生物系统，最重要的是对人类健康的影响。我们在纳米材料领域的目标 健康影响研究(NHIR)联盟的提案是为了阐明 ENM及其分子相互作用影响暴露动物的免疫和激素状态。我们会 通过与NIEHS项目科学家和NHIR联盟成员合作来实现这一目标 ENM资源和协调核心(ERCC)首次使用一种新型的气-液体外提供ENM 接口系统，然后在体内使用肺毒素协议和开发中的ENM子集 毒理协议。每个方案都将采用仅经鼻子和全身吸入的暴露和一系列结果 评估身体状况、细胞毒性、炎症、氧化应激、基因表达、免疫的措施 调节、内分泌干扰和组织病理学。我们将在nhir内共享我们的数据和方法 财团和其他机构，从而有助于制定全面的生物应对措施 选定的ENM的概况，并确定那些对脆弱人群构成重大危险的ENM 包括孕妇和儿童。将处理三个具体目标：目标1：确定哪一个ERCC-- 特征性ENM最有可能在呼吸道引起细胞毒性、炎症或免疫调节 上皮细胞采用我们建立的体外气液界面模型系统。AIM2：角色化 孕妇亚慢性吸入暴露后对某些ENMS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ENMS，然后通过吸入和哺乳在出生后。这些目标将是 由一个在纳米材料吸入毒理学方面具有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。五个初选 假设将被检验：1)吸入研究中的ENM在 将所选剂量与对照组进行比较。H2)ENM暴露产生不良影响，具有明显的 取决于怀孕状态的生物反应配置文件。H3)母亲吸入来自 怀孕前分娩会对胎儿产生不利的发育反应。H4)幼崽有进一步的POST- 出生时暴露会产生在假暴露对照组或ENM暴露成人中看不到的毒理学反应。 H5)子宫内和出生后接触ENM后，成熟而不接触ENM与疾病有关 进步。本文提出的研究将大大促进对特定剂量的理解。 吸入ENMS的毒性和手术的AOPS，从而将建立一个框架，以提高安全性 介绍商业ENM，并指导其安全和可持续的使用。

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.