title: Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS.
abstract: Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: (1) identify transcriptional biomarkers of exposure; and (2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences.
authors.affiliation: University of California, Santa Cruz, CA 95064, United States. Electronic address: ehiolski@ucsc.edu.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Hiolski
authors.affiliation: University of Washington, Seattle, WA 98112, United States. Electronic address: psk39@u.washington.edu.
authors.forename: Preston S
authors.initials: PS
authors.lastname: Kendrick
authors.affiliation: NOAA Northwest Fisheries Science Center, Seattle, WA 98112, United States. Electronic address: Elizabeth.Frame@kingcounty.gov.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Frame
authors.affiliation: University of Washington, Seattle, WA 98112, United States. Electronic address: mark.s.myers@noaa.gov.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Myers
authors.affiliation: University of Washington, Seattle, WA 98112, United States. Electronic address: tbammler@u.washington.edu.
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.affiliation: University of Washington, Seattle, WA 98112, United States. Electronic address: dbeyer@u.washington.edu.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.affiliation: University of Washington, Seattle, WA 98112, United States. Electronic address: freddy@u.washington.edu.
authors.forename: Federico M
authors.initials: FM
authors.lastname: Farin
authors.affiliation: University of Washington, Seattle, WA 98112, United States. Electronic address: jasminew@u.washington.edu.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Wilkerson
authors.affiliation: University of California, Santa Cruz, CA 95064, United States. Electronic address: drsmith@ucsc.edu.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Smith
authors.affiliation: University of Washington, Seattle, WA 98112, United States. Electronic address: dmarc@uw.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Marcinek
authors.affiliation: NOAA Northwest Fisheries Science Center, Seattle, WA 98112, United States. Electronic address: kathi.lefebvre@noaa.gov.
authors.forename: Kathi A
authors.initials: KA
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007608:Kainic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D059467:Transcriptome; D015854:Up-Regulation; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000633:toxicity*; D015027:Zebrafish
chemical_list: D015415:Biomarkers; D014874:Water Pollutants, Chemical; C012301:domoic acid; D007608:Kainic Acid
keywords: Chronic toxin exposure; Domoic acid; Microarray; Subclinical effects