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 #
5U19ES019525-05
Application #
8675238
Study Section
Special Emphasis Panel (ZES1-SET-V)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$784,085
Indirect Cost
$229,192
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Aldossari, Abdullah A; Shannahan, Jonathan H; Podila, Ramakrishna et al. (2015) Influence of physicochemical properties of silver nanoparticles on mast cell activation and degranulation. Toxicol In Vitro 29:195-203
Poitras, Eric P; Levine, Michael A; Harrington, James M et al. (2015) Development of an analytical method for assessment of silver nanoparticle content in biological matrices by inductively coupled plasma mass spectrometry. Biol Trace Elem Res 163:184-92
Thompson, Leslie C; Urankar, Rakhee N; Holland, Nathan A et al. (2014) C?? exposure augments cardiac ischemia/reperfusion injury and coronary artery contraction in Sprague Dawley rats. Toxicol Sci 138:365-78
Vidanapathirana, Achini K; Thompson, Leslie C; Mann, Erin E et al. (2014) PVP formulated fullerene (C60) increases Rho-kinase dependent vascular tissue contractility in pregnant Sprague Dawley rats. Reprod Toxicol 49:86-100
Smith, Matthew J; Brown, Jared M; Zamboni, William C et al. (2014) From immunotoxicity to nanotherapy: the effects of nanomaterials on the immune system. Toxicol Sci 138:249-55
Thompson, Leslie C; Frasier, Chad R; Sloan, Ruben C et al. (2014) Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts. Nanotoxicology 8:38-49
Shannahan, Jonathan H; Lai, Xianyin; Ke, Pu Chun et al. (2013) Silver nanoparticle protein corona composition in cell culture media. PLoS One 8:e74001