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ToxSci Advance Access published online on March 18, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn055
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Published by Oxford University Press 2008.

Liver Genomic Responses to Ciguatoxin: Evidence for Activation of Phase I and Phase II Detoxification Pathways Following an Acute Hypothermic Response in Mice

Jeanine S. Morey*, James C. Ryan*, Marie-Yasmine Bottein Dechraoui*, Amir H. Rezvani{dagger}, Edward D. Levin{dagger}, Christopher J. Gordon{ddagger}, John S. Ramsdell* and Frances M. Van Dolah*

* Marine Biotoxins Program, NOAA Center for Coastal Environmental Health and Biomolecular Research, Charleston, SC, 29414, USA {dagger} Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, 27710, USA {ddagger} Neurotoxicology Division, U.S. EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, 27711, USA

Address for correspondence: Frances M. Van Dolah, NOAA/NOS/CCEHBR, 219 Fort Johnson Rd., Charleston, SC 29412, Tele: (843)762-8529, Fax: (843)762-8700, Email: Fran.VanDolah{at}noaa.gov

Received January 8, 2008; revision received March 11, 2008; accepted March 11, 2008


  Abstract

Ciguatoxins (CTX) are polyether neurotoxins that target voltage gated sodium channels and are responsible for ciguatera, the most common fish-borne food poisoning in humans. This study characterizes the global transcriptional response of mouse liver to a symptomatic dose (0.26 ng/g) of the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h post exposure 2.4% of features on a 44K whole genome array were differentially expressed (p ≤ 0.0001), increasing to 5.2% at 4 h and decreasing to 1.4% by 24 h post-CTX exposure. Data were filtered (|fold change| ≥ 1.5 and p ≤ 0.0001 in at least one time point) and a trend set of 1550 genes were used for further analysis. Early gene expression was likely influenced prominently by an acute 4 °C decline in core body temperature by 1 h, which resolved by 8 h following exposure. An initial down-regulation of 32 different solute carriers, many involved in sodium transport, was observed. Differential gene expression in pathways involving eicosanoid biosynthesis and cholesterol homeostasis was also noted. Cytochrome P450s were of particular interest due to their role in xenobiotic metabolism. Twenty-seven genes, mostly members of Cyp2 and Cyp4 families, showed significant changes in expression. Many Cyps underwent an initial down-regulation at 1 h but were quickly and strongly up-regulated at 4 and 24 h post exposure. In addition to Cyps, increases in several glutathione S-transferases were observed, an indication that both phase I and phase II metabolic reactions are involved in the hepatic response to CTX in mice.

Key Words: Cytochrome P450; Ciguatoxin; biotoxin; microarray; liver; gene expression; hypothermia.

Email addresses: JSM: Jeanine.Morey{at}noaa.gov JCR: James.Ryan{at}noaa.gov, MYBD: Marie-Yasmine.Bottein{at}noaa.gov, AHR: azadi{at}duke.edu, EDL: edlevin{at}duke.edu, CJG: Gordon.Christopher{at}epamail.epa.gov, JSR: John.Ramsdell{at}noaa.gov, FMVD: Fran.Vandolah{at}noaa.gov


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