Mitochondrial Mechanisms, Microvascular Function, and Gestational Nanotoxicology

 描述（由申请方提供）：妊娠期间，母体内稳态和胎儿环境对各种外部或环境暴露（例如营养不良、毒物暴露）高度敏感。妊娠期间营养和废物协调交换的任何功能障碍都可能造成恶劣的妊娠环境（HGE），导致毁灭性的胎儿后果。据推测，HGE内的胎儿发育可能是成人疾病和/或敏感性的未被充分认识的病因。线粒体效率低下已被理论化为HGE内的发展与成人疾病的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使用越来越多，引起了人们对潜在接触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颗粒（TiO 2）可导致HGE的发展，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），TiO 2和CeO 2）可损害健康雄性大鼠的冠状动脉微血管功能，并降低一氧化氮（NO）的生物利用度。此外，候选人最近的初步研究结果提供了线粒体效率低下和胎儿微血管功能障碍的证据，这些证据持续全身性地持续到成年。本研究建议通过吸入将妊娠大鼠暴露于多壁碳纳米管，以便：（1）将线粒体健康鉴定为高通量预测性筛选试验，（2）确定与妊娠期ENM暴露的副作用相关的暴露的毒代动力学“临界窗口”，（3）确定是否显著的母体，胎儿，并且成年后代的全身性微血管功能障碍是由多壁碳纳米管暴露产生的HGE引起的，和（4）提供线粒体功能评估和职业指导方面的必要技能，以实现独立和富有成效的研究生涯。工作假设是多壁碳纳米管暴露创造了一个不利的妊娠环境，导致胎儿线粒体不稳定的发展，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，使用妊娠大鼠来确定ENM暴露于当前和未来几代人的机制微血管改变。这项研究是前瞻性的，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。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，允许制定循证策略和监管政策，以安全生产和谨慎使用消费品中的ENM，特别是与育龄妇女有关的产品;总体而言，使纳米技术的真正潜力得到充分实现。

 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.