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: 8994283
• 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/8994283
• 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; Vascular Smooth Muscle; 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; 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（由适用提供）：孕产妇体内平衡和胎儿环境在妊娠期间非常容易受到各种外部或环境暴露的影响（例如营养不良，毒物暴露）。妊娠期间营养和废物的协调交换中的任何功能障碍都可能会产生敌对的妊娠环境（HGE），从而导致遭受毁灭性的​​胎儿后果。据推测，HGE内的胎儿发育可能是成人疾病和/或敏感性的病因不足。线粒体效率低效率已被理论化为HGE内发育与成人疾病发展之间的一种机械联系。工程纳米材料（ENM）的持续开发（一个维度<100 nm）以及它们在生物医学和商业产品中的使用日益增加引起了人们对潜在暴露和导致人类健康影响的关注。该实验室的最新证据表明，怀孕大鼠吸入二氧化钛纳米颗粒（TIO2）可能会导致HGE，损害母子和胎儿微血管功能的发展。该实验室的现有证据表明，与一氧化氮（NO）生物可用性相关的健康雄性大鼠中，合并ENM（多壁碳纳米管（MWCNT），TIO2和CEO2）可能会损害健康雄性大鼠的冠状动脉微血管功能。此外，候选人的最新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，这些效率持续到成年。本研究建议通过吸入暴露于MWCNT，以：（1）确定线粒体健康是高吞吐量预测性筛选测试，（2）确定与疫苗ENM暴露的不良影响相关的有毒动力学的“关键窗口”，（3）确定是否会产生较大的胎儿和成人的dys dys，并确定是否存在较大的胎儿和成人的dys。 MWCNT暴露，（4）为独立和生产性研究职业提供线粒体功能评估和职业学业的必要技能。有效的假设是，MWCNT暴露创造了一种敌对的妊娠环境，导致胎儿线粒体不足的发展，试图适应这项研究是具有创新性的，因为它挑战了纳米技术的长期现状，因为它使用怀孕的大鼠使用孕妇的机械微血管曝光来确定ENM eNM eNM eNM eNM eNM eNM eNM的现状。这项研究是前瞻性思维，因为它建立了概念框架，即对成人疾病（或胎儿编程）的易感性可能是由于子宫纳米材料暴露。这项研究之所以重要，是因为它将产生重要的毒素和机械数据，从而制定基于证据的策略和监管政策，以在消费产品中安全生产和谨慎使用ENM，尤其是与生育时代的妇女有关；总体而言，允许纳米技术的真正潜力得到充分实现。