The proposed U19 Center will foster collaboration between RTI researchers who have developed capabilities to synthesize and characterize unlabeled and uniformly carbon-14 labeled carbon-based nanoparticles and that have investigated the fate of these materials in pregnant and lactating rodent models, with East Carolina University (ECU) researchers who have experimental programs funded by the National Institute of Environmental Health Sciences to investigate the cardiovascular and pulmonary responses of carbon nanotubes. Data developed by RTI and ECU researchers will be used by scientists at The Hamner Institutes for Health Sciences to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models for assessment of health risks. Experimental data collection with concurrent modeling will greatly enhance the power of the scientific method in that the model will sen/e as a conceptual framework to capture the knowledge and intuitions ofthe investigators in a quantitatively predictive structure. ECU's research demonstrates that pulmonary exposure to MWCNTs can exacerbate an episode of ischemic/reperfusion injury in the heart of normal healthy animals, and that the mechanism underlying this process may be driven by systemic inflammation and changes in vascular reactivity. Pregnancy and lactation may be susceptible conditions with respect to the effects of nanoparticles on the mothers and their offspring, and it is likely that changes in the vasculature can led to alterations in the blood flow to organs and contribute to how nanomaterials distribute to the organs of the mother, fetus, and neonates. Preliminary data developed by RTI demonstrate that carbon-based nanoparticles can transfer from an exposed rodent dam to the fetus and nursing pup. These data raise concerns for potential developmental effects;however, evaluation of the human relevance of these findings requires consideration ofthe physiological differences between rodents and humans. In Project 1, we propose to determine how characteristics of C60 fullerene (C60) and MWCNTs affect cellular uptake, clearance, and responses in endothelial and epithelial cells isolated from the heart, lung, and placenta. In project 2, we propose to determine the PK and absorption, distribution, metabolism, and excretion of these nanoparticles in the female rodent, pregnant rodent (and fetus), and lactating rodent (and neonate), and to determine how exposure affects the vascular reactivity ofthe heart, lung, and uterus. Further, we propose to measure markers of inflammation (cytokines), oxidative stress (8- hydroxydeoxyguanosine), and reproductive and developmental effects (hormones and phenotypic anchors).

Public Health Relevance

The ultimate goal of the U19 Center is to develop PBPK/PD models for the disposition and effects of C60 nd MWCNTs to provide a firm basis for predicting exposure conditions that could elicit adverse effects in he mother, fetus, or neonate. These models will test hypotheses related to the direct or indirect mechanism of particle-induced vascular effects and provide a description of the relationship between particle load and nflammatory cytokine production;the circulation ofthe cytokines to remote tissues, including the fetus and up;and the relationship between cytokine concentrations and vascular effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19ES019525-03
Application #
8274458
Study Section
Special Emphasis Panel (ZES1-SET-V (03))
Program Officer
Nadadur, Srikanth
Project Start
2010-09-27
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,245,213
Indirect Cost
$578,923
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
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Thompson, Leslie C; Holland, Nathan A; Snyder, Ryan J et al. (2016) Pulmonary instillation of MWCNT increases lung permeability, decreases gp130 expression in the lungs, and initiates cardiovascular IL-6 transsignaling. Am J Physiol Lung Cell Mol Physiol 310:L142-54
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