Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

• Published in: Aquatic toxicology Vol. 155; pp. 151 - 159
• Main Authors: Hiolski, Emma M., Kendrick, Preston S., Frame, Elizabeth R., Myers, Mark S., Bammler, Theo K., Beyer, Richard P., Farin, Federico M., Wilkerson, Hui-wen, Smith, Donald R., Marcinek, David J., Lefebvre, Kathi A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.10.2014; Elsevier
• Subjects: Animals; Biological and medical sciences; Biomarkers; Brain - drug effects; Brain - metabolism; Chronic toxin exposure; Danio rerio; Domoic acid; Down-Regulation; Humans; Kainic Acid - administration & dosage; Kainic Acid - analogs & derivatives; Kainic Acid - toxicity; Male; Medical sciences; Mice; Microarray; Miscellaneous; Mitochondria - drug effects; Mitochondria - metabolism; Subclinical effects; Toxicology; Transcription, Genetic - drug effects; Transcriptome; Up-Regulation; Water Pollutants, Chemical - administration & dosage; Water Pollutants, Chemical - toxicity; Zebrafish; Subclinical effects; Microarray; Domoic acid; Chronic toxin exposure; Animal model; Transcription; Toxicity; Asymptomatic; Toxin; Vertebrata; Brachydanio rerio; Chronic; Gene; Pisces; Neurotoxin; Central nervous system disease; Excitatory aminoacid; Cell respiration
• ISSN: 0166-445X; 1879-1514
• DOI: 10.1016/j.aquatox.2014.06.006

•Low-level seafood toxin exposure alters gene transcription in the CNS.•Transcriptional responses to low-level exposure are highly dynamic over time.•Transcriptome alterations occur in genes related to nervous system function.•Low-level seafood toxin exposure impairs mitochondrial function.•Low-level seafood toxin exposure induces compensatory mitochondrial biogenesis. 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.