Mitochondrial Mechanisms, Microvascular Function, and Gestational Nanotoxicology

线粒体机制、微血管功能和妊娠纳米毒理学

• 批准号: 8804356
• 负责人: Phoebe Stapleton
• 金额: $ 8.62万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804356
• 关键词: Adult; Adult Children; Adverse effects; Affect; Biological Availability; Blood Vessels; Breathing; Cardiovascular Diseases; Cardiovascular system; Consumption; Coronary; Coupled; Data; Development; Dimensions; Disease; Drug or chemical Tissue Distribution; Endothelial Cells; Engineering; Environment; Environmental Exposure; Etiology; Evaluation; Exposure to; Fetal Development; Fetus; Functional disorder; Future Generations; Goals; Health; Homeostasis; Human; Impairment; Inhalation Exposure; Laboratories; Lead; Link; Malnutrition; Mentors; Metabolic Diseases; Microvascular Dysfunction; Mitochondria; Mothers; Nanotechnology; Nitric Oxide; Nutrient; Occupational; Oxidative Stress; Perinatal Exposure; Physiological; Policies; Predisposition; Pregnancy; Prevention strategy; Production; Rattus; Regulation; Research; Research Personnel; Risk; Smooth Muscle Myocytes; Testing; Thinking; Time; Toxic effect; Toxicant exposure; Toxicokinetics; Vascular Diseases; Woman; Work; base; career; ceric oxide; child bearing; consumer product; dosage; evidence base; evidence based guidelines; fetal; fetal programming; in utero; innovation; insight; male; mitochondrial dysfunction; multi walled carbon nanotube; nanomaterials; nanoparticle; nanotoxicology; nitrosative stress; pregnant; public health relevance; response; safety engineering; screening; skills; stem; titanium dioxide; wasting

 DESCRIPTION (provided by applicant): Maternal homeostasis and the fetal milieu are highly susceptible to a variety of external or environmental exposures during gestation (e.g. malnutrition, toxicant exposure). Any dysfunction within the coordinated exchange of nutrients and waste during gestation could create a hostile gestational environment (HGE), leading to devastating fetal consequences. It has been hypothesized that fetal development within a HGE could be an underappreciated etiology for adult disease and/or sensitivity. Mitochondrial inefficiency has been theorized as one mechanistic link between development within a HGE and the development of adult disease. The continued development of engineered nanomaterials (ENM) (<100 nm in one dimension) coupled with their increasing use in biomedical and commercial products have given rise to concerns over potential exposure and resulting human health effects. Recent evidence from this laboratory suggests that inhalation of titanium dioxide nanoparticles (TiO2) by pregnant rats can lead to the development of a HGE, impairing maternal and fetal microvascular function. Existing evidence from this laboratory indicates that inhaled ENM (multi-walled carbon nanotubes (MWCNT), TiO2, and CeO2) can impair coronary microvascular function in healthy male rats associated with decreased nitric oxide (NO) bioavailability. Further, recent preliminary findings from the Candidate provide evidence of mitochondrial inefficiencies and fetal microvascular dysfunction that persist systemically into adulthood. The present study proposes exposing pregnant rats to MWCNT via inhalation in order to: (1) identify mitochondrial health as a high throughput predictive screening test, (2) ascertain the toxicokinetic "critical windows" of exposure associated with adverse effects of gestational ENM exposure, (3) determine if significant maternal, fetal, and adult progeny systemic microvascular dysfunction arises from the creation of HGE stemming from MWCNT exposure, and (4) provide the necessary skills in mitochondrial functional assessment and career-mentoring for an independent and productive research career. The working hypothesis is that MWCNT exposure creates a hostile gestational environment leading to the development of fetal mitochondrial insufficiencies in an attempt to adapt to the unfavorable intrauterine milieu. This study is innovative because it challenges the long-standing status quo of nanotechnology with the use of pregnant rats to determine the mechanistic microvascular alterations of ENM exposure to current and future generations. This study is forward thinking as it establishes the conceptual framework that predisposition to adult disease (or fetal programming) could be due to in utero nanomaterial exposure. This study is significant because it will yield important toxicokinetic and mechanistic data, permitting the development of evidence-based strategies and regulatory policy for the safe production and prudent use of ENM in consumer products, especially relevant to women of childbearing years; overall, allowing the true potential of nanotechnology to be fully realized.

 描述（由申请人提供）：母亲体内平衡和胎儿环境对妊娠期间的各种外部或环境暴露高度敏感（例如营养不良、有毒物质暴露）。妊娠期间营养物质和废物的协调交换中的任何功能障碍都可能造成恶劣的妊娠环境（HGE），从而导致灾难性的胎儿后果。据推测，HGE 内的胎儿发育可能是成人疾病和/或敏感性的一个未被充分认识的病因。线粒体效率低下已被理论化为 HGE 内发育与成人疾病发展之间的一种机制联系。工程纳米材料 (ENM)（一维<100 nm）的持续发展，加上其在生物医学和商业产品中的日益广泛使用，引起了人们对潜在暴露及其对人类健康影响的担忧。该实验室的最新证据表明，怀孕大鼠吸入二氧化钛纳米粒子 (TiO2) 会导致 HGE 的发生，损害母体和胎儿的微血管功能。该实验室的现有证据表明，吸入 ENM（多壁碳纳米管 (MWCNT)、TiO2 和 CeO2）会损害健康雄性大鼠的冠状动脉微血管功能，并导致一氧化氮 (NO) 生物利用度降低。此外，该候选人最近的初步发现提供了线粒体效率低下和胎儿微血管功能障碍的证据，这些功能障碍会全身持续到成年期。本研究建议通过吸入将怀孕大鼠暴露于 MWCNT，以便：（1）将线粒体健康确定为高通量预测筛选测试，（2）确定与妊娠 ENM 暴露的不利影响相关的毒代动力学“关键窗口”，（3）确定是否因 HGE 的产生而导致显着的母体、胎儿和成年后代全身微血管功能障碍 多壁碳纳米管暴露，(4) 提供线粒体功能评估和职业指导方面的必要技能，以实现独立且富有成效的研究生涯。目前的假设是，多壁碳纳米管暴露会产生不利的妊娠环境，导致胎儿线粒体功能不全，试图适应不利的宫内环境。这项研究具有创新性，因为它挑战了纳米技术的长期现状，利用怀孕的大鼠来确定当代和后代接触 ENM 的机械微血管变化。这项研究具有前瞻性，因为它建立了一个概念框架，即成人疾病（或胎儿编程）的易感性可能是由于子宫内纳米材料暴露所致。这项研究意义重大，因为它将产生重要的毒代动力学和机制数据，从而可以制定基于证据的战略和监管政策，以安全生产和谨慎使用 ENM 在消费品中，特别是与育龄妇女相关的；总体而言，使纳米技术的真正潜力得以充分发挥。