- Quantitative carcinogenesis and dosimetry in rainbow trout for aflatoxin B1 and aflatoxicol, two aflatoxins that form the same DNA adduct
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Two exposure protocols were used to establish complete dose-response relationships for the hepatic carcinogenicity and DNA adduction in vivo of aflatoxin B1 (AFB1) and aflatoxicol (AFL) in rainbow trout. By passive egg exposure, AFL was taken up less than AFB1, but was more efficiently sequestered into the embryo itself, to produce an embryotic DNA binding curve that was linear with carcinogen dose and with a DNA binding index three-fold greater than AFNB1. Both aflatoxins produced the same phenotypic respone, predominantly mixed hepatocellular/cholangiocelllular carcinoma. Tumor responses as logit vs. ln were parallel-offset, non-linear response showing a three-fold greater carcinogenic potency of AFL at all doses examined (i.e. 3 times more AFB1 than AFL required to produce an equivalent liver tumor incidence). By molecular dosimetry analysis (logit vs. ln ), the two data sets were coincident, indicating that, per DNA adduct formed in vivo in total embryonic DNA, these two aflatoxins were equally efficient in tumor initiation. By dietary fry exposure, both carcinogens produced linear DNA binding dose response in liver, but with an AFL target organ DNA binding index only 1.14 times of that of AFB1 by this exposure route. The tumor dose-response curves also did not exhibit the three-fold difference shown by embryo exposure, but very closely positioned non-linear curves. Since the DNA binding indices differed by only 14 percent, the resulting molecular dosimetry curves for AFL and AFB1 by dietary exposure were similar to the tumor response curves. These results indicate that differing exposure routes produced differing relative carcinogenicity estimates based on doses applied, as a result of protocol-dependent differences in AFL and AFB1 pharmacokinetic behaviors, but that potency comparisons based on molecular dose receiving were similar for the two protocols. By comparison with standard DNA adducts produced in vitro using the dimethyloxirane-produced 8,9-epoxides of AFB1 and AFL, we conclude that >99 percent of AFL-DNA adducts produced in vivo were identical to those produced by AFB1. Thus similar molecular dosimetry responses should be expected under all exposure protocols in which the two parent carcinogens do not exhibit differing toxicities to the target organ. - Keywords; Aflatoxin B1; Aflatoxicol; Molecular dosimetry; Hepatocarcinogenesis; Rainbow trout; DNA adducts
- Bailey, George S.,Loveland, Patricia M.,Pereira, Cliff,Pierce, Donald,Hendricks, Jerry D.,Groopman, John D.
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- Temporal patterns of DNA adduct formation and glutathione S-transferase activity in the testes of rats fed aflatoxin B1: A comparison with patterns in the liver
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Fisher-344 male rats were fed 1.6 ppm of aflatoxin B1 (AFB1) continuously and intermittently for several weeks. At various time periods, DNA was isolated from the testes and livers and analyzed for AFB1-DNA adducts. The ability of the testis to detoxify AFB1 was also investigated by the glutathione S-transferase (GST) activity assay and compared with that of the liver. The levels of testicular AFB1-DNA adducts were 2.4 to 8.1 times lower than those of the liver after 4 to 16 weeks of continuous treatment and 2.2 to 46.2 times lower after 8 to 20 weeks of intermittent treatment. The testicular DNA adducts markedly decreased over time. By 16 weeks of continuous and 20 weeks of intermittent exposure, they had decreased 37 and 91%, respectively. In contrast, hepatic AFB1-DNA adducts increased four- fold from 4 to 16 weeks of continuous treatment but increased at a much slower rate after intermittent exposure. In both the liver and testis, significant levels of AFB1-DNA adducts persisted for at least 1 month after ending the treatment, suggesting that this type of lesion was poorly repaired. In control rats, the testis showed significantly higher GST activity than the liver. In treated rats, these differences were significant during the first 12 weeks of continuous treatment but not at later times. Tissue-specific differences such as germ-cell depletion and increased testicular detoxification may play an important role in the observed differential pattern of DNA adduct formation between the testis and liver.
- Sotomayor, Rene E.,Sahu, Saura,Washington, Melissa,Hinton, Dennis M.,Chou, Ming
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