Hepatic transcriptional networks induced by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) serves as a prototype for a range of environmental toxicants and as a pharmacologic probe to study signal transduction by the aryl hydrocarbon receptor (AHR). Despite a detailed understanding of how TCDD exposure leads to the transcriptional up-regulation of cytochrome P450-dependent monooxygenases, we know little about how compounds like TCDD lead to a variety of AHR-dependent toxic end points such as liver pathology, terata, thymic involution, and cancer. Using an acute exposure protocol and the toxic response of the mouse liver as a model system, we have begun a detailed microarray analysis to describe the transcriptional changes that occur after various TCDD doses and treatment times. Through correlation analysis of time- and dose-dependent toxicological end points, we are able to identify coordinately responsive transcriptional events that can be defined as primary transcriptional events and downstream events that may represent mechanistically linked sequelae or that have potential as biomarkers of toxicity.
Hayes
Kevin R
KR
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Avenue, Madison, Wisconsin 53706-1599, USA.
Zastrow
Gina M
GM
Nukaya
Manabu
M
Pande
Kalyan
K
Glover
Ed
E
Maufort
John P
JP
Liss
Adam L
AL
Liu
Yan
Y
Moran
Susan M
SM
Vollrath
Aaron L
AL
Bradfield
Christopher A
CA
D000818:Animals; D015415:Biomarkers; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D020218:Response Elements / Q000502:physiology
D015415:Biomarkers; D000072317:Polychlorinated Dibenzodioxins; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2