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...