Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis.
Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogen-induced changes in gene expression. Male Eker and wild-type rats were gavaged daily with AA (10 mg/kg body weight) or OTA (210 microg/kg body weight). After 1, 3, 7, and 14 days of exposure, renal histopathology, tubular cell proliferation, and Affymetrix gene expression profiles from renal cortex/outer medulla were analyzed. AA-treated Eker and wild-type rats were qualitatively comparable in all variables assessed, suggesting a Tsc2-independent mechanism of action. OTA treatment resulted in slightly increased cortical pathology and significantly elevated cell proliferation in both strains, although Eker rats were more sensitive. Deregulated genes involved in the phosphatidylinositol 3-kinase-AKT-Tsc2-mammalian target of rapamycin signaling, among other important genes prominent in tumorigenesis, in conjunction with the enhanced cell proliferation and presence of preneoplastic lesions suggested involvement of Tsc2 in OTA-mediated toxicity and carcinogenicity, especially as deregulation of genes involved in this pathway was more prominent in the Tsc2 mutant Eker rat.
Stemmer
Kerstin
K
Human and Environmental Toxicology, University of Konstanz, Konstanz, Germany.
Ellinger-Ziegelbauer
Heidrun
H
Ahr
Hans-Juergen
HJ
Dietrich
Daniel R
DR
D000818:Animals; D034341:Aristolochic Acids / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009793:Ochratoxins / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D034341:Aristolochic Acids; D002273:Carcinogens; D009793:Ochratoxins; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C025589:ochratoxin A; C000228:aristolochic acid I; D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases