Dissecting modes of action of non-genotoxic carcinogens in primary mouse hepatocytes.
Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity and chronic bioassays are no longer regularly performed, this class of carcinogens will go undetected. Therefore, test systems detecting non-genotoxic carcinogens, or even better their modes of action, are required. Here, we investigated whether gene expression profiling in primary hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens. For this, primary mouse hepatocytes were exposed to 16 non-genotoxic carcinogens with diverse modes of action. Upon profiling, pathway analysis was performed to obtain insight into the biological relevance of the observed changes in gene expression. Subsequently, both a supervised and an unsupervised comparison approach were applied to recognize the modes of action at the transcriptomic level. These analyses resulted in the detection of three of eight compound classes, that is, peroxisome proliferators, metalloids and skin tumor promotors. In conclusion, gene expression profiles in primary hepatocytes, at least in rodent hepatocytes, appear to be useful to detect some, certainly not all, modes of action of non-genotoxic carcinogens.
Laboratory for Health Protection Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Mirjam M
MM
Schaap
Edwin P
EP
Zwart
Paul F K
PF
Wackers
Ilse
I
Huijskens
Bob
B
van de Water
Timo M
TM
Breit
Harry
H
van Steeg
Martijs J
MJ
Jonker
Mirjam
M
Luijten
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*
D002273:Carcinogens; D009153:Mutagens