Many toxicants commonly found at Superfund sites are capable of inducing oxidative stress in animals and humans. The fact that many agencies induce oxidant stress suggests not only that these agents may act synergistically when mixtures of such chemicals are present, but also, that the ability of organisms to service and adapt to such mixed exposures may depend upon their ability to utilize cellular antioxidants and antioxidant enzymes to combat this stress. A very important enzyme involve din antioxidant defense is glutamate-cysteine ligase (GLCL), the rate limiting enzyme for the synthesis of the cellular antioxidant glutathione (GSH). The primary goal of this project will be to investigate the genetic and biochemical bases of GLCL regulation in mice and humans. We propose to ascertain the factors that control GLCL expression and activity, to develop murine models of GLCL over- expression of GLCL insufficiency, and to assess the frequency of the genetic polymorphisms in GLCL genes in humans affected with diseases or conditions associated with oxidative stress. Such information will be useful in determining the functional significance of this enzyme in defense against toxicants, and its utility as a biomarker of exposure and/or susceptibility to toxicants commonly found at hazardous waste sites that may act individually or synergistically to induce oxidant stress. Ultimately this information will be useful in minimizing uncertainties in risk evaluation for people and animals exposed to low doses of contaminants at Superfund sites.

Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
16
Fiscal Year
2002
Total Cost
$222,045
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Criswell, Susan R; Warden, Mark N; Searles Nielsen, Susan et al. (2018) Selective D2 receptor PET in manganese-exposed workers. Neurology 91:e1022-e1030
Meador, James P; Yeh, Andrew; Gallagher, Evan P (2018) Adverse metabolic effects in fish exposed to contaminants of emerging concern in the field and laboratory. Environ Pollut 236:850-861
Ma, Eva Y; Heffern, Kevin; Cheresh, Julia et al. (2018) Differential copper-induced death and regeneration of olfactory sensory neuron populations and neurobehavioral function in larval zebrafish. Neurotoxicology 69:141-151
Heffern, Kevin; Tierney, Keith; Gallagher, Evan P (2018) Comparative effects of cadmium, zinc, arsenic and chromium on olfactory-mediated neurobehavior and gene expression in larval zebrafish (Danio rerio). Aquat Toxicol 201:83-90
Racette, Brad A; Gross, Anat; Criswell, Susan R et al. (2018) A screening tool to detect clinical manganese neurotoxicity. Neurotoxicology 64:12-18
Barrett, P M; Hull, E A; King, C E et al. (2018) Increased exposure of plankton to arsenic in contaminated weakly-stratified lakes. Sci Total Environ 625:1606-1614
Rooney, James P K; Woods, Nancy F; Martin, Michael D et al. (2018) Genetic polymorphisms of GRIN2A and GRIN2B modify the neurobehavioral effects of low-level lead exposure in children. Environ Res 165:1-10
Chang, Yu-Chi; Cole, Toby B; Costa, Lucio G (2018) Prenatal and early-life diesel exhaust exposure causes autism-like behavioral changes in mice. Part Fibre Toxicol 15:18
Criswell, Susan R; Nielsen, Susan Searles; Warden, Mark et al. (2018) [18F]FDOPA positron emission tomography in manganese-exposed workers. Neurotoxicology 64:43-49
Wang, Hao; Zhang, Liang; Abel, Glen M et al. (2018) Cadmium Exposure Impairs Cognition and Olfactory Memory in Male C57BL/6 Mice. Toxicol Sci 161:87-102

Showing the most recent 10 out of 455 publications