TitleTemporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-Mediated hepatotoxicity.
Publication TypeJournal Article
Year of Publication2005
AuthorsBoverhof, DR, Burgoon, LD, Tashiro, C, Chittim, B, Harkema, JR, Jump, DB, Zacharewski, TR
JournalToxicol Sci
Volume85
Issue2
Pagination1048-63
Date Published2005 Jun
ISSN1096-6080
KeywordsAlanine Transaminase, Animals, Cell Differentiation, Chemical and Drug Induced Liver Injury, Cholesterol, Dose-Response Relationship, Drug, Environmental Pollutants, Fatty Acids, Fatty Acids, Nonesterified, Female, Gene Expression, Immunity, Cellular, Liver, Liver Neoplasms, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Polychlorinated Dibenzodioxins, Receptors, Aryl Hydrocarbon, RNA, Time Factors, Triglycerides
Abstract
 

In an effort to further characterize the mechanisms of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated toxicity, comprehensive temporal and dose-response microarray analyses were performed on hepatic tissue from immature ovariectomized C57BL/6 mice treated with TCDD. For temporal analysis, mice were gavaged with 30 microg/kg of TCDD or vehicle and sacrificed after 2, 4, 8, 12, 18, 24, 72, or 168 h. Dose-response mice were gavaged with 0, 0.001, 0.01, 0.1, 1, 10, 100, or 300 microg/kg of TCDD and sacrificed after 24 h. Hepatic gene expression profiles were monitored using custom cDNA microarrays containing 13,362 cDNA clones. Gene expression analysis identified 443 and 315 features which exhibited a significant change at one or more doses or time points, respectively, as determined using an empirical Bayes approach. Functional gene annotation extracted from public databases associated gene expression changes with physiological processes such as oxidative stress and metabolism, differentiation, apoptosis, gluconeogenesis, and fatty acid uptake and metabolism. Complementary histopathology (H&E and Oil Red O stains), clinical chemistry (i.e., alanine aminotransferase [ALT], triglyceride [TG], free fatty acids [FFA], cholesterol) and high-resolution gas chromatography/mass spectrometry assessment of hepatic TCDD levels were also performed in order to phenotypically anchor changes in gene expression to physiological end points. Collectively, the data support a proposed mechanism for TCDD-mediated hepatotoxicity, including fatty liver, which involves mobilization of peripheral fat and inappropriate increases in hepatic uptake of fatty acids.

DOI10.1093/toxsci/kfi162
Alternate JournalToxicol. Sci.
PubMed ID15800033
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
P42-ES04911 / ES / NIEHS NIH HHS / United States
R01-ES12245 / ES / NIEHS NIH HHS / United States