Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats.
The nephrotoxic/carcinogenic mycotoxin ochratoxin A (OTA) occurs as a contaminant in food and feed and may be linked to human endemic Balkan nephropathy. The mechanism of OTA-derived carcinogenicity is still under debate, since reactive metabolites of OTA and DNA adducts have not been unambiguously identified. Oxidative DNA damage, however, has been observed in vitro after incubation of mammalian cells with OTA. In this study, we investigated whether OTA induces oxidative DNA damage in vivo as well. Male F344 rats were dosed with 0, 0.03, 0.1, 0.3 mg/kg bw per day OTA for 4 wk (gavage, 7 days/wk, five animals per dose group). Subsequently, oxidative DNA damage was determined in liver and kidney by the comet assay (single cell gel electrophoresis) with/without use of the repair enzyme formamido-pyrimidine-DNA-glycosylase (FPG). The administration of OTA had no effect on basic DNA damage (determined without FPG); however, OTA-mediated oxidative damage was detected with FPG treatment in kidney and liver DNA of all dose groups. Since the doses were in a range that had caused kidney tumors in a 2-year carcinogenicity study with rats, the oxidative DNA damage induced by OTA may help to explain its mechanism of carcinogenicity. For the selective induction of tumors in the kidney, increased oxidative stress in connection with severe cytotoxicity and increased cell proliferation might represent driving factors.
Kamp
Hennicke G
HG
Department of Chemistry, Division of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Erwin-Schroedinger-Strasse 52, D-67663 Kaiserslautern, Germany. hennicke.kamp@basf-ag.de
Eisenbrand
Gerhard
G
Janzowski
Christine
C
Kiossev
Jetchko
J
Latendresse
John R
JR
Schlatter
Josef
J
Turesky
Robert J
RJ
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004032:Diet; D005506:Food Contamination; D007668:Kidney / Q000737:chemistry / Q000187:drug effects*; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D009793:Ochratoxins / Q000008:administration & dosage* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011506:Proteins / Q000032:analysis / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009793:Ochratoxins; D011506:Proteins; C025589:ochratoxin A