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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg076
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received December 20, 2002; accepted February 27, 2003
© 2003 Society of Toxicology

Molecular and Genetic Toxicology

Effects of Intermittent Exposure to Aflatoxin B1 on DNA and RNA Adduct Formation in Rat Liver: Dose-Response and Temporal Patterns

Rene E. Sotomayor 1*, Melissa Washington 1, Linh Nguyen 2, Rahma Nyang'anyi 2, Dennis M. Hinton 1, Ming Chou 3

1 Center for Food Safety and Applied Nutrition, U.S. FDA, College Park, MD, 20740
2 Joint Institute for Food Safety and Applied Nutrition, University of Maryland, College Park, MD 20742
3 National Center for Toxicological Research, U.S. FDA, Jefferson, AR, 72079

* To whom correspondence should be addressed. E-mail: RSotomay{at}cfsan.fda.gov.


  Abstract

The effects of intermittent exposure to aflatoxin B1 (AFB1) on hepatic DNA and RNA adduct formation were studied. Fisher-344 male rats were fed 0.01, 0.04, 0.4 and 1.6 ppm of AFB1 intermittently for 8, 12, 16 and 20 weeks with alternate 4 weeks of dosing and 4 weeks of rest. Other groups of rats were fed 1.6 ppm of AFB1 continuously for 4, 8, 12 and 16 weeks. Control rats received AFB1-free NIH-31 meal diet. AFB1-DNA and -RNA adducts were measured by HPLC with fluorescence detection. The data are presented as total DNA or RNA adducts. The DNA and RNA adduct levels increased or decreased depending on the cycles of dosing and rest. Rats removed from treatment 1 month after 1 or 2 dosing cycles (8 and 16 weeks of intermittent exposure) showed approximately a 2-fold decrease in DNA adduct levels and a 2- to 11-fold decrease in RNA adduct levels compared with rats euthanized immediately after the last dosing cycle (12 and 20 weeks of intermittent exposure). Our data indicate that DNA and RNA adducts increased linearly from 0.01 ppm to 1.6 ppm of AFB1 after 12 and 20 weeks of intermittent treatment. A linear dose-response was also apparent for DNA but not for RNA adducts after 8 and 16 weeks of treatment. As biomarkers of exposure, AFB1-RNA adducts were 3 to 9 times more sensitive than AFB1-DNA adducts but showed greater variability. These results suggest that binding of AFB1 to hepatic DNA is a linear function of the dose regardless of the way this is administered. The dose-response relationship for RNA adducts depends on the length of the no-dosing cycles and on the turnover rate of RNA.

Intermittent exposure, Aflatoxin B1, DNA and RNA adducts, liver, rats .


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