Biological Response Profiles of Selected Engineered Nanomaterials after Perinatal Exposure

选定的工程纳米材料在围产期暴露后的生物反应曲线

• 批准号: 9769736
• 负责人: Peter S Thorne
• 金额: $ 41.17万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769736
• 关键词: Address; Adult; Adult Children; Adverse effects; Affect; Air; Animals; Area; Binding; Biological; Biological Models; Birth; Cell Line; Cell Survival; Cell physiology; Child; Collaborations; Consultations; Copper; Couples; Data; Development; Disease Progression; Dose; Endocrine; Endocrine disruption; Engineering; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Female; Fetus; Gene Expression; Generations; Genes; Goals; Growth; Health; Histopathology; Hormonal; Human; Immune; Immune Response Genes; Immune Tolerance; Immune signaling; Immune system; Immunocompetence; Immunosuppression; In Vitro; Industrialization; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Inhalation Exposure; Inhalation Toxicology; Lactation; Life; Liquid substance; Lung; Medical; Methods; Modeling; Molecular; Mus; National Institute of Environmental Health Sciences; Nose; Organ; Outcome; Outcome Measure; Oxidative Stress; Pathology; Pathway interactions; Perinatal; Perinatal Exposure; Pregnancy; Pregnant Women; Production; Property; Proteomics; Protocols documentation; Reactive Oxygen Species; Research; Resources; Route; Safety; Scientist; Serum; Signal Pathway; Source; Spleen; Surface; System; Testing; Toxic effect; Toxicology; Up-Regulation; Vulnerable Populations; Weaning; Work; adverse outcome; aged; base; biological adaptation to stress; biological systems; body system; chemokine; consumer product; cytokine; cytotoxicity; data sharing; developmental toxicology; early life exposure; embryo/fetus antigen; experience; exposed human population; gene repression; hazard; immunoregulation; immunotoxicity; improved; in utero; in vivo; in vivo Model; innovation; insight; male; member; nanomaterials; nanoparticle; novel; offspring; postnatal; pregnant; prenatal; prenatal exposure; programs; pup; response; screening

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.

项目摘要 含有工程纳米材料（ENM）的产品的稳定增长超过了研究 确定它们对生物系统的影响，最重要的是人类健康。我们在这种纳米材料中的目标 健康影响研究（NHIR）联盟提案是为了阐明物理化学特性如何 ENM及其分子相互作用会影响暴露动物的免疫和激素状态。我们将 通过与NIEHS项目科学家和NHIR财团成员合作来实现这一目标 ENM资源和协调核心（ERCC）提供的ENM首先在体外使用新型的空气液体 接口系统，然后在体内使用肺托克斯协议和发育 托克斯协议。每种方案将采用仅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，内分泌破坏和组织病理学。我们将在NHIR中共享我们的数据和方法 财团及以后，从而有助于发展全面的生物学反应 选定的ENM的概况并确定那些对弱势群体造成重大危害的概况 包括孕妇和儿童。将解决三个具体目标：目标1：确定哪个ERCC- 表征ENM最有可能诱导气道中的细胞毒性，炎症或免疫调节 使用我们已建立的体外空气界面模型系统的上皮细胞。 AIM2：特征 孕妇亚基吸入暴露后，对选定的ENM的全面生物学反应 与非妊娠小鼠相比。 AIM 3：阐明男性和女性后代的生物反应谱 在子宫内接触ENM之后，然后在产后通过吸入和泌乳。这些目标将是 由经验丰富的研究团队完成的纳米材料吸入毒理学方面的专业知识， 发育毒理学，纳米毒素产生和表征以及ENM蛋白质组学。五个主要 将测试假设：H1）吸入研究中的ENM会引起大量的生物学反应 与对照组相比，选定的剂量。 H2）ENM暴露会产生不良反应 取决于怀孕状况的生物反应概况。 H3）孕产妇吸入暴露于 交货前的概念会产生胎儿的不良发育反应。 H4）幼崽有进一步的后 出生暴露会发展在假暴露对照或ENM暴露成年人中未见的毒理学反应。 H5）遵循子宫和产后ENM暴露，不暴露的成熟与疾病有关 进展。本文提出的研究将大大提高对剂量特异性的理解 吸入ENM和手术AOP的毒性将建立一个改善安全性的框架 商业ENM的概况并指导其安全和可持续的使用。