Among the most sensitive neuropatholgic effects of gestational methylmercury exposure in both animals and humans is impaired cell proliferation. Previous investigations in this laboratory have revealed a concentration-dependent effect of MeHg on the in vitro proliferation of rat midbrain neuroepithelial cells, and these effects were associated with an increase in the mRNA and the protein content of the cell cycle regulatory molecules p21, GADD 45 and GADD153. Because MeHg is known to inhibit both mRNA and protein synthesis, it is suspected that the observed increase in mRNA and protein content arise from impaired degradation rather than induced synthesis, and propose experiments to examine this hypothesis. The principal investigator proposes to examine whether methylmercury can inhibit calpain- and ubiquitin/proteasome-mediated proteolysis, whether this inhibition increases the mRNA and protein content of cell cycle regulatory molecules, and whether these increases are associated with altered neuroepithelial cell proliferation. The PI proposes to use positive control agents known to inhibit calpain- and ubiquitin-mediated proteolysis, and to examine the relative effect of proteolytic inhibition on the intracellular content of specific cell cycle regulatory mRNA and proteins. Finally, the PI proposes to examine the observed elevation in cell cycle phase dependencies in mRNA and protein content following exposure to MeHg or thiol protease inhibitory agents by using flow cytometrically sorted neuroepithelial cell populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010613-03
Application #
6525315
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Thompson, Claudia L
Project Start
2000-08-15
Project End
2004-12-31
Budget Start
2002-08-01
Budget End
2004-12-31
Support Year
3
Fiscal Year
2002
Total Cost
$272,258
Indirect Cost
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yu, Xiaozhong; Sidhu, Jaspreet S; Hong, Sungwoo et al. (2011) Cadmium induced p53-dependent activation of stress signaling, accumulation of ubiquitinated proteins, and apoptosis in mouse embryonic fibroblast cells. Toxicol Sci 120:403-12
Robinson, Joshua F; Yu, Xiaozhong; Moreira, Estefania G et al. (2011) Arsenic- and cadmium-induced toxicogenomic response in mouse embryos undergoing neurulation. Toxicol Appl Pharmacol 250:117-29
Robinson, Joshua F; Yu, Xiaozhong; Hong, Sungwoo et al. (2010) Embryonic toxicokinetic and dynamic differences underlying strain sensitivity to cadmium during neurulation. Reprod Toxicol 29:279-85
Moreira, Estefania G; Yu, Xiaozhong; Robinson, Joshua F et al. (2010) Toxicogenomic profiling in maternal and fetal rodent brains following gestational exposure to chlorpyrifos. Toxicol Appl Pharmacol 245:310-25
Yu, Xiaozhong; Robinson, Joshua F; Sidhu, Jaspreet S et al. (2010) A system-based comparison of gene expression reveals alterations in oxidative stress, disruption of ubiquitin-proteasome system and altered cell cycle regulation after exposure to cadmium and methylmercury in mouse embryonic fibroblast. Toxicol Sci 114:356-77
Robinson, Joshua F; Griffith, William C; Yu, Xiaozhong et al. (2010) Methylmercury induced toxicogenomic response in C57 and SWV mouse embryos undergoing neural tube closure. Reprod Toxicol 30:284-91
Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong et al. (2010) Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders. Birth Defects Res A Clin Mol Teratol 88:920-30
Robinson, Joshua F; Guerrette, Zachariah; Yu, Xiaozhong et al. (2010) A systems-based approach to investigate dose- and time-dependent methylmercury-induced gene expression response in C57BL/6 mouse embryos undergoing neurulation. Birth Defects Res B Dev Reprod Toxicol 89:188-200
Robinson, Joshua F; Yu, Xiaozhong; Hong, Sungwoo et al. (2009) Cadmium-induced differential toxicogenomic response in resistant and sensitive mouse strains undergoing neurulation. Toxicol Sci 107:206-19
Yu, Xiaozhong; Robinson, Joshua F; Gribble, Elizabeth et al. (2008) Gene expression profiling analysis reveals arsenic-induced cell cycle arrest and apoptosis in p53-proficient and p53-deficient cells through differential gene pathways. Toxicol Appl Pharmacol 233:389-403

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