Important components in estimating risks associated with exposure to nanomaterials include understanding the uptake, distribution, and elimination;the mode of action;and the pharmacodynamics of the effects of nanoparticles. Pregnancy and lactation are physiological states in which the distribution and effects of nanomaterials have not been extensively investigated. This project will investigate the absorption, distribution, metabolism, and excretion of several nanoparticles with different size and charge properties. Investigations will be conducted with fullerene 060 and forms of multi-walled carbon nanotubes in female rats and mice, pregnant rats and mice, and in lactating rats and mice. The nanoparticles will be carbon-14 uniformly labeled by the RTI Synthesis and Characterization Core for conduct of these studies. Using three different routes of administration in female rats and mice (oropharyngeal aspiration, oral gavage, and intravenous [i.v.] injection) will provide information regarding the uptake and distribution processes for nanoparticles. Administration of the labeled nanoparticles to pregnant rats and mice by i.v, injection at different times in pregnancy will provide information about the ability of the nanoparticles to cross the placenta and result in fetal exposure. Analogously, i.v. administration to lactating rats and mice will enable evaluation ofthe secretion of nanoparticles into milk, resulting in exposure to offspring. The determination of the mass balance of radiolabel in urine, feces, blood tissues, and carcass at 5 time points over a period of 30 days following dosing will provide an enhanced understanding of the long-term fate of nanoparticles in the body. Quantitative whole body autoradiography will enable detailed characterization of the distribution of the nanoparticles. Examination of tissue samples with transmission electron microscopy will provide information on the subcellular localization of the nanomaterials. The effects of exposure to the carbon nanomaterials by oropharyngeal aspiration and i.v. administration will be investigated in the non-pregnant and pregnant (i.v. only) rodent by measuring arterial vascular reactivity, blood pressure, and cardiac ultrasound. The determination of markers of inflammation (cytokines), reproduction and development (hormones), and oxidative stress (8-hydroxydeoxyguanosine;8- OHdG) will be conducted. The data obtained from Project 2 will be used in the development ofthe physiologically based pharmacokinetic and pharmacodynamic models constructed in Project 3.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19ES019525-04
Application #
8464710
Study Section
Special Emphasis Panel (ZES1-SET-V)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$845,628
Indirect Cost
$287,819
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Vidanapathirana, A K; Thompson, L C; Herco, M et al. (2018) Acute intravenous exposure to silver nanoparticles during pregnancy induces particle size and vehicle dependent changes in vascular tissue contractility in Sprague Dawley rats. Reprod Toxicol 75:10-22
Thompson, Leslie C; Sheehan, Nicole L; Walters, Dianne M et al. (2018) Airway Exposure to Modified Multi-walled Carbon Nanotubes Perturbs Cardiovascular Adenosinergic Signaling in Mice. Cardiovasc Toxicol :
Holland, Nathan A; Fraiser, Chad R; Sloan 3rd, Ruben C et al. (2017) Ultrafine Particulate Matter Increases Cardiac Ischemia/Reperfusion Injury via Mitochondrial Permeability Transition Pore. Cardiovasc Toxicol 17:441-450
Fennell, Timothy R; Mortensen, Ninell P; Black, Sherry R et al. (2017) Disposition of intravenously or orally administered silver nanoparticles in pregnant rats and the effect on the biochemical profile in urine. J Appl Toxicol 37:530-544
Holland, Nathan A; Thompson, Leslie C; Vidanapathirana, Achini K et al. (2016) Impact of pulmonary exposure to gold core silver nanoparticles of different size and capping agents on cardiovascular injury. Part Fibre Toxicol 13:48
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
Shannahan, Jonathan H; Bai, Wei; Brown, Jared M (2015) Implications of scavenger receptors in the safe development of nanotherapeutics. Receptors Clin Investig 2:e811
Sumner, Susan C J; Snyder, Rodney W; Wingard, Christopher et al. (2015) Distribution and biomarkers of carbon-14-labeled fullerene C60 ([(14) C(U)]C60 ) in female rats and mice for up to 30 days after intravenous exposure. J Appl Toxicol 35:1452-64
Anderson, Donald S; Patchin, Esther S; Silva, Rona M et al. (2015) Influence of particle size on persistence and clearance of aerosolized silver nanoparticles in the rat lung. Toxicol Sci 144:366-81
Shannahan, Jonathan H; Podila, Ramakrishna; Brown, Jared M (2015) A hyperspectral and toxicological analysis of protein corona impact on silver nanoparticle properties, intracellular modifications, and macrophage activation. Int J Nanomedicine 10:6509-21

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