Excretion of food-derived heterocyclic amine carcinogens into breast milk of lactating rats and formation of DNA adducts in the newborn.
The distribution, DNA adduction and excretion into breast milk of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were examined in lactating female F344 rats with 5 day old pups. Six hours after a single dose (10 mg/kg, p.o.) of radiolabeled IQ, MeIQx or PhIP to lactating dams, radioactivity in the dams was highest in the liver and kidney followed, in descending order, by the mammary gland, omental fat and brain. By 24 h after carcinogen administration, all tissues of the dams showed significantly reduced levels of radioactivity except for omental fat which changed only marginally from 6 to 24 h. 32P-Postlabeling analysis showed that the level of DNA adducts in mammary gland 6 h after dosing was 2.2, 0.7 and 0.2 adducts/10(7) nucleotides for PhIP, IQ and MeIQx respectively. In contrast, in hepatic DNA, the levels of IQ-DNA adducts (5.5 adducts/10(7) nucleotides) were 11-fold higher than those of PhIP or MeIQx. The stomach contents, liver, kidney and urine of pups nursed by dams given radiolabeled IQ, MeIQx or PhIP were radioactive, indicating that these carcinogens (and/or metabolites) were excreted into breast milk and absorbed by the pups. After a 6 h suckling period, the amount of PhIP-derived radioactivity in the stomach contents of the pups was approximately 10-fold higher than that seen with IQ or MeIQx. Urine from pups from the three groups was mutagenic in the Ames assay with Salmonella TA98 in the presence of an S9 activating system. IQ-, MeIQx- and PhIP-DNA adducts, at levels in the range of 0.25-0.46 adducts per 10(8) nucleotides, were detected in the livers of pups using the 32P-postlabeling method under intensification conditions. The results from this study indicate that breast milk is a route of exposure of the newborn to heterocyclic amines. The presence of DNA adducts in the tissues of pups further suggests that this route of exposure may have a carcinogenic consequence to the newborn.
Ghoshal
A
A
Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-0037.
Snyderwine
E G
EG
D000821:Animal Feed; D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D005260:Female; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D007668:Kidney / Q000378:metabolism; D007774:Lactation; D008099:Liver / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism; D008892:Milk / Q000737:chemistry / Q000378:metabolism*; D009152:Mutagenicity Tests; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects
D002273:Carcinogens; D007093:Imidazoles; D011804:Quinolines; D011810:Quinoxalines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine