title: Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response.
abstract: BACKGROUND
  Ciguatoxins (CTXs) are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO) and molecular pathway enrichment of the gene expression data.
  
  
  RESULTS
  A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p < 0.0001) with microarray results.
  
  
  CONCLUSIONS
  Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against neuroinflammation. Pathologic activity of the complement/coagulation cascade has been shown in patients suffering from a chronic form of ciguatera poisoning and is of particular interest in this model. Anti-inflammatory processes were at work not only in the brain but were also seen in whole blood and liver of these animals, creating a systemic anti-inflammatory environment to protect against the initial cellular damage caused by the toxin.
authors.affiliation: Marine Biotoxins Program, NOAA Center for Coastal Environmental Health and Biomolecular Research, Charleston, SC, USA. james.ryan@noaa.gov
authors.forename: James C
authors.initials: JC
authors.lastname: Ryan
authors.forename: Jeanine S
authors.initials: JS
authors.lastname: Morey
authors.forename: Marie-Yasmine Dechraoui
authors.initials: MY
authors.lastname: Bottein
authors.forename: John S
authors.initials: JS
authors.lastname: Ramsdell
authors.forename: Frances M
authors.initials: FM
authors.lastname: Van Dolah
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D001769:Blood / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics*; D002922:Ciguatoxins / Q000494:pharmacology*; D020869:Gene Expression Profiling; D017781:Genes, Immediate-Early / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D018696:Neuroprotective Agents; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D015222:Sodium Channels; D002922:Ciguatoxins; D012313:RNA
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