Multi-generational Effects of Maternal Engineered Nano-Material Inhalation Exposure on Microvascular and Reproductive Health Outcomes

母体工程纳米材料吸入暴露对微血管和生殖健康结果的多代影响

• 批准号: 10525726
• 负责人: Elizabeth Compton Bowdridge
• 金额: $ 10.8万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525726
• 关键词: Multi; generational; Effects; Maternal; Engineered

PROJECT SUMMARY Elizabeth Bowdridge, Ph.D., is a reproductive toxicologist whose overarching career goal is to establish a successful laboratory focused on the effects of occupational and environmental factors on microvascular adaptations during gestation that ultimately impact fetal outcomes. Her proposed project combines an occupationally relevant inhalation exposure model during gestation and epigenetic analysis of offspring, which will establish the impact of hormones and vascular adaptations that are critical for healthy reproductive outcomes. Acquiring this knowledge is a critical step for ensuring optimal maternal and fetal health. Career Development Plan: Dr. Bowdridge is a Research Assistant Professor in the Department of Physiology and Pharmacology at West Virginia University (WVU). The proposed career development plan will build upon her previous training with four training goals to enhance her trajectory toward becoming an independent investigator: 1) Acquire advanced training in placental pathologies and identification of nanomaterials using techniques such as FESEM and TEM; 2) Broaden my knowledge of how the dose of specific toxicants are applicable in an occupational setting and ways in which these affect critical windows of embryonic and fetal developmental, oxidant formation, and epigenetics; 3) Increase technical expertise in occupational exposure relevance, dose deposition and epigenetic analysis across generations; 4) Develop professional skills in grant writing, research and laboratory leadership, statistical analysis, and research ethics. Mentors/environment: Dr. Bowdridge and her primary mentor, Dr. Timothy Nurkiewicz, Ph.D., have assembled a strong team of co-mentors and advisors to guide her through the proposed training and research activities. The proposed career development plan utilizes the intellectual, microscopy, free radical biology, and genomics resources available through WVU and at the National Institute for Occupational Safety and Health. The WVU Genomics and Bioinformatics cores provide centralized genomic and biostatistical analysis training to investigators at WVU and other universities across WV. As an institution WVU is committed to supporting junior faculty members through internal grants, administrative support and structured opportunities for faculty networking and education. Research: Adverse reproductive outcomes, such as miscarriages, are common in pregnant women working in occupational settings. These women are exposed to ENM such as, nano-titanium dioxide (nano-TIO2) via inhalation. One likely, but uninvestigated, way that ENM may mediate these poor outcomes in an occupational setting is by decreasing hormones critical pregnancy hormones such as estradiol (E2). This proposal is the first step in linking E2 and the peptide Kiss with vascular dysfunction and adverse reproductive outcomes due to occupationally relevant maternal nano-TiO2 inhalation exposure. Aim 1 identifies the roles of E2 and Kiss and oxidant load across timepoints in gestation on uterine microvascular function and fetal health following maternal nano-TiO2 inhalation exposure. Aim 2 determines the impact of maternal nano-TiO2 inhalation exposure on reproductive health of F1 female progeny. The completion of these aims will identify the roles of E2 and Kiss in establishing a healthy fetal environment by regulating vascular and endocrine function during occupational exposures.

项目摘要 伊丽莎白·鲍德里奇博士是一个生殖毒理学家，其首要的职业目标是建立一个 一个成功的实验室专注于职业和环境因素对微血管的影响， 妊娠期间的适应，最终影响胎儿的结果。她提出的项目结合了 妊娠期职业相关吸入暴露模型和后代的表观遗传分析， 将建立激素和血管适应的影响，这对健康的生殖至关重要， 结果。获得这些知识是确保最佳孕产妇和胎儿健康的关键步骤。 Bowdridge博士是该部门的研究助理教授。 生理学和药理学在西弗吉尼亚大学（WVU）。职业发展计划将 在她之前的培训基础上，制定四个培训目标，以增强她成为一名 独立研究者：1）获得胎盘病理学和识别 使用FESEM和TEM等技术研究纳米材料; 2）关于纳米材料的剂量如何影响纳米材料的 特定的有毒物质适用于职业环境，以及这些物质影响 胚胎和胎儿发育，氧化剂形成和表观遗传学; 3）增加技术专长， 跨代职业接触相关性、剂量沉积和表观遗传分析; 4） 专业技能，在赠款写作，研究和实验室的领导，统计分析和研究道德。 导师/环境：Bowdridge博士和她的主要导师Timothy Nurkiewicz博士，有 组建了一个强大的共同导师和顾问团队，指导她完成拟议的培训和研究 活动拟议的职业发展计划利用智力，显微镜，自由基生物学， 通过西弗吉尼亚大学和国家职业安全与健康研究所提供的基因组学资源。 西弗吉尼亚大学基因组学和生物信息学核心提供集中的基因组和生物统计分析培训 西弗吉尼亚大学和西弗吉尼亚州其他大学的调查人员。作为一个机构，西弗吉尼亚大学致力于支持 初级教员通过内部赠款，行政支持和教师结构化的机会 网络和教育。 研究：不良生殖结果，如流产，在怀孕的妇女中很常见， 职业环境。这些妇女通过以下途径暴露于ENM，例如纳米二氧化钛（纳米TiO 2） 吸入。一种可能的，但未经调查的方式，ENM可能介导这些不良后果的职业 设置是通过减少激素关键怀孕激素，如雌二醇（E2）。这一建议是第一个 将E2和Kiss肽与血管功能障碍和不良生殖结果联系起来的步骤， 与职业相关的母体纳米TiO 2吸入暴露。目标1确定了E2和Kiss的作用， 妊娠期不同时间点的氧化负荷对子宫微血管功能和胎儿健康的影响 母体纳米TiO 2吸入暴露。目的2确定母体吸入纳米TiO 2的影响 暴露对F1雌性后代生殖健康的影响。这些目标的完成将确定以下方面的作用： E2和Kiss通过调节血管和内分泌功能建立健康的胎儿环境 职业暴露。