This proposal is for a 5-year competing renewal of the University of Washington (UW) Superfund Research Program (SRP). The overarching theme of the program is to investigate the mechanisms and ramifications of metal neurotoxicity in humans and aquatic species. Based upon our work, we are developing biomarkers predictive of; 1) exposure to neurotoxic agents, 2) early indicators of neurotoxic injury at the cellular and organismal levels, and/or 3) genetic determinants that underlie unusual susceptibility to environmental neurotoxicants. The physiological processes under investigation adversely affect cognition, olfaction and neurobehavioral processes, and are associated with the risk of developing Alzheimer's and non-Alzheimer's related dementia, Parkinson's disease, and other neurodevelopmental diseases. Our research focuses upon metals that commonly occur at Superfund hazardous waste sites for which there are important data gaps impeding the full understanding of their neurotoxic effects on human health and aquatic species. These data gaps include an understanding of mechanisms of toxicity, inter-individual or gender susceptibility, and biogeochemical factors that govern their fate in their environment. A key theme of our projects is addressing the role of cellular oxidative stress during metal-induced neurotoxicity. The UW program will include four research projects (two environmental science and two biomedical projects). The research projects include investigations of (1) mechanisms and biomarkers of metal olfactory injury to Pacific salmon, with a primary focus on cadmium; (2) cellular and molecular mechanisms of cadmium-mediated neurotoxicity in rodents, including effects on olfaction and cognition; (3) the role of paraoxonases as modifiers of cadmium and manganese neurotoxicity; and (4) biogeochemistry and bioavailability of arsenic in an urbanized lake system in Washington State. Our projects include collaborations among projects and cores, and each project is interdisciplinary in nature. The UW SRP includes a Training Core that is multi- and interdisciplinary, and will support predoctoral trainees from participating departments. The Research Translation Core will continue to ensure timely and appropriate communication of our research findings to NIEHS and other appropriate stakeholders, partner effectively with agencies, identify potential patents, and develop and support translation opportunities with other end-users of our scientific findings. The Community Engagement Core (a new Core beginning with 2015 funding) will build upon existing partnerships and expand partnerships with other communities, such as those directly affected by the toxicants we are studying, and with other community groups that have concerns about environmental toxicants. The Administrative Core will stimulate interactions among projects and cores ensuring full program integration, assure appropriate communication with NIEHS and other governmental agencies, oversee personnel and budgetary matters, and organize meetings and interactions with the Internal Executive Committee and the External Advisory Board.

Public Health Relevance

The overarching goal of the UW SRP is to understand the mechanisms of metal neurotoxicity in the context of disease susceptibility in humans and aquatic organisms. At a mechanistic level, the processes we study underlie risk to diseases that affect cognitive processes and neurological function, including; mental retardation, Parkinson's disease, Alzheimer's disease and non-Alzheimer's dementia, and also threaten the survivorship of aquatic species. Our transdisciplinary research program and its technologies inform hazard remediation and disease prevention strategies, and we work with a number of stakeholders, including US EPA Region 10, ATSDR, Washington Departments of Health and Ecology, as well as local communities impacted by hazardous wastes, including the Northwest Toxics Cleanup Coalition, Duwamish River Cleanup Coalition, and tribal entities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
2P42ES004696-29
Application #
9255136
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Carlin, Danielle J
Project Start
1997-04-01
Project End
2022-03-31
Budget Start
2017-07-01
Budget End
2018-03-31
Support Year
29
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
605799469
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

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