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Your Environment. Your Health.

MATERNAL NANOMATERIAL EXPOSURES: FETAL MICROVASCULAR ENDPOINTS AND PROGRAMMING

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Principal Investigator: Nurkiewicz, Timothy R
Institute Receiving Award West Virginia University
Location Morgantown, WV
Grant Number R01ES015022
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2007 to 31 Aug 2022
DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Despite the ubiquitous inclusion of engineered nanomaterials (ENM) in widespread applications, and their projected proliferation in human endeavors; the consequences of maternal ENM inhalation on the developing fetus and their impacts on future health are at best, vague. The advancement of nanotechnology, and “nano- enabled” devices holds tremendous potential to advance human health exponentially, yet their unknown health effects remain the critical rate limiting step. To date, studies focus on the fetal consequences of artificially injected ENM or the ability of co-incubated ENM to cross the placenta. These fail to address the most relevant health risks: 1) how do inhaled ENM impair the development of a healthy uterine vasculature, and 2) how do inhaled ENM impair placental development, or compromise its function? We will define the fetal consequences of maternal ENM exposure in terms of altered mechanisms of uterine and placental vascular health. ENM aerosol generation and rodent exposures will be performed in state-of-the-art inhalation exposure facilities that have recently undergone significant expansion to directly meet the unique demands of this project. AIM 1: Determine the impact of maternal ENM inhalation on uterine microvascular health during gestation, and characterize the underlying mechanisms of dysfunction. We have defined the impact of ENM inhalation on microvascular health, in the virgin uterus, with novel intravital microscopy studies. We now expand this investigation to discrete stages of pregnancy. We hypothesize that the vasculogenic and angiogenic mechanisms initiated by pregnancy and stimulate rapid microvascular network growth are susceptible targets of the extrapulmonary mediators activated by ENM inhalation. AIM 2: Identify the impact of maternal ENM inhalation on placental health during gestation and characterize the underlying mechanisms of dysfunction. The placenta is a highly vascularized organ critical to fetal health/development, and is a systemic target of extrapulmonary mediators. A second novel technique, the ex vivo perfused placenta will be used to test our working hypothesis – maternal ENM inhalation disrupts placental vascular integrity via prostanoid and nitric oxide mediated mechanisms. AIM 3: Define the cardiovascular health consequences that persist into adulthood that stem from fetal epigenetic alterations that occur during maternal ENM inhalation during gestation. We hypothesize that the hostile gestational environment created by maternal ENM inhalation produces a genotype that not only displays impaired cardiovascular function, but also elevated sensitivity to xenobiotic exposures in adulthood. Project outcomes: the fundamental relationships between uterine, placental, and fetal microvascular health after maternal ENM exposure will be identified. We also expect to have clarified many of the major mechanisms mediating these outcomes. Identifying these relationships will assist and facilitate efforts towards: risk evaluation, development of exposure controls, and safety by design. The integration of such knowledge will be a critical step in advancing sustainable nanotechnologies.
Science Code(s)/Area of Science(s) Primary: 78 - Nanotoxicology
Secondary: 01 - Basic Cellular or Molecular processes
Publications See publications associated with this Grant.
Program Officer Srikanth Nadadur
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