Mitochondrial Mechanisms, Microvascular Function, and Gestational Nanotoxicology

 描述(申请人提供)：孕妇体内平衡和胎儿环境在妊娠期极易受到各种外部或环境暴露(例如营养不良、毒物暴露)。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敌对的妊娠环境(HGE)，导致毁灭性的胎儿后果。有人假设，HGE内的胎儿发育可能是成人疾病和/或敏感性的未得到充分认识的病因。线粒体效率低下一直被认为是HGE内发育和成人疾病发展之间的一种机械联系。工程纳米材料(ENM)(一维100纳米)的持续发展，加上它们在生物医学和商业产品中的日益使用，引起了人们对潜在暴露和由此产生的人类健康影响的担忧。来自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(Ti02)可导致HGE的发生，损害母体和胎儿的微血管功能。本实验室的现有证据表明，吸入ENM(多壁碳纳米管、二氧化钛和CeO2)可损害健康雄性大鼠的冠状动脉微血管功能，并伴随着一氧化氮(NO)生物利用度的下降。此外，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，这些障碍会系统性地持续到成年。本研究建议通过吸入方式使怀孕大鼠暴露于MWCNT，以：(1)确定线粒体健康作为高通量预测筛查试验，(2)确定与孕期ENM暴露的不利影响相关的毒代动力学“关键窗口”，(3)确定是否由MWCNT暴露引起的HGE引起的母体、胎儿和成年后代系统性微血管功能障碍，以及(4)为独立和富有成效的研究生涯提供必要的线粒体功能评估和职业指导方面的技能。工作假说是，MWCNT暴露创造了一个不利的妊娠环境，导致胎儿线粒体不足的发展，以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，使用怀孕的大鼠来确定ENM暴露于当前和未来世代的机械性微血管变化。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的暴露。这项研究具有重要意义，因为它将产生重要的毒物动力学和机械学数据，从而为在消费品中安全生产和谨慎使用ENM制定循证战略和监管政策，特别是与育龄妇女相关的产品；总体而言，使纳米技术的真正潜力得以充分实现。

 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.