Pacific salmon populations have declined markedly in the Western United States. Of particular concern has been sublethal neurological injury occurring in salmon exposed to certain pesticides and trace metals. These behavioral impacts include loss of predator detection and prey selection, altered reproductive timing and loss of homing. These aforementioned neurobehavioral effects observed in individuals are now linked to population impacts. The salmon olfactory system is a sensitive target for the neurotoxicity of environmental chemicals, including metals and pesticides commonly found in Superfund sites. However, little is known about the mechanisms of chemical olfactory neurotoxicity in fish. Studies from our first funding cycle have produced important findings that will be explored in detail in our competitive renewal. Specifically, we know that: 1) the olfactory tissues of salmon are important site of chemical biotransformation, and in particular, cytochrome P4503A and flavin monooxygenases (FMO) appear to mediate tissue- and compound-specific differences in organophosphate biotransformation with potential impacts on neurotoxicity, 2) the olfactory injury by a model superfund organophosphate chemical (chlorpyrifos) and metal (copper) involves disruption of olfactory signal transduction pathways. However, copper primarily impacts G-protein coupled olfactory receptor signaling, likely through oxidative stress, whereas chlorpyrifos activates genes involved in the inhibition of olfactory signal transduction, and 3) transcriptional signatures can help us identify unique gene targets relevant to mixtures, as well differentiating metal- and organophosphate-driven affects. Based upon our findings, the objectives of the competing renewal are to: 1) use cDNA cloning, recombinant protein expression, microarray analysis and enzymatic approaches to determine the role of olfactory CYP3A and flavin monooxygenases in organophosphate neurotoxicity in salmon during movement from freshwater to saltwater, 2) use in situ hybridization and immunohistochemistry analyses coupled with behavioral studies to understand the role of oxidative stress in copper and cadmium-mediated olfactory injury, 3) use proteomics approaches to identify and discriminate important olfactory protein targets of copper and chlorpyrifos, 4) use a suite of olfactory biomarkers generated from the aforementioned studies to assess sublethal olfactory neurotoxicity in salmon migrating through Superfund sites.

Public Health Relevance

The results this project will greatly increase our understanding of the mechanisms and consequences of sublethal neurotoxicity in salmon populations, and will use mechanistically-based biomarkers to identify salmon undergoing behavioral injuries as a consequence of chemical exposures at Superfund sites. Furthermore, this study has global implications for the consequences of aquatic pollution to freshwater and marine fish, which rely heavily upon proper olfactory functioning for the maintenance of normal behaviors critical to survival and reproduction.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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University of Washington
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Meador, James P; Yeh, Andrew; Gallagher, Evan P (2017) Determining potential adverse effects in marine fish exposed to pharmaceuticals and personal care products with the fish plasma model and whole-body tissue concentrations. Environ Pollut 230:1018-1029
Chang, Yu-Chi; Cole, Toby B; Costa, Lucio G (2017) Behavioral Phenotyping for Autism Spectrum Disorders in Mice. Curr Protoc Toxicol 72:11.22.1-11.22.21
Roqué, Pamela J; Costa, Lucio G (2017) Co-Culture of Neurons and Microglia. Curr Protoc Toxicol 74:11.24.1-11.24.17
Wang, Hao; Engstrom, Anna K; Xia, Zhengui (2017) Cadmium impairs the survival and proliferation of cultured adult subventricular neural stem cells through activation of the JNK and p38 MAP kinases. Toxicology 380:30-37
Yeh, Andrew; Marcinek, David J; Meador, James P et al. (2017) Effect of contaminants of emerging concern on liver mitochondrial function in Chinook salmon. Aquat Toxicol 190:21-31
Mills, Margaret G; Gallagher, Evan P (2017) A targeted gene expression platform allows for rapid analysis of chemical-induced antioxidant mRNA expression in zebrafish larvae. PLoS One 12:e0171025
Costa, Lucio G; Cole, Toby B; Coburn, Jacki et al. (2017) Neurotoxicity of traffic-related air pollution. Neurotoxicology 59:133-139
Costa, Lucio G; Cole, Toby B; Garrick, Jacqueline M et al. (2017) Metals and Paraoxonases. Adv Neurobiol 18:85-111
Al-Lozi, Amal; Nielsen, Susan Searles; Hershey, Tamara et al. (2017) Cognitive control dysfunction in workers exposed to manganese-containing welding fume. Am J Ind Med 60:181-188
Criswell, Susan R; Nielsen, Susan Searles; Warden, Mark et al. (2017) [18F]FDOPA positron emission tomography in manganese-exposed workers. Neurotoxicology :

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