4-Aminobiphenyl induces liver DNA adducts in both neonatal and adult mice but induces liver mutations only in neonatal mice.
The mechanisms underlying the susceptibility of neonatal mice to genotoxic carcinogens were investigated by analyzing the DNA adducts and mutations induced in the livers of neonatal and adult Big Blue transgenic mice by 4-aminobiphenyl (4-ABP), a potent human and rodent carcinogen. Neonatal and adult mice were treated with a regimen of 4-ABP known to induce tumors in neonatal mice. Animals were sacrificed 1 day after the last treatment for DNA adduct analysis and 8 weeks after the last treatment for analysis of lacI and cII mutant frequency (MF). N-(Deoxyguanosin-8-yl)-4-ABP was the major DNA adduct identified in the livers of the 4-ABP-treated mice and levels of this adduct were significantly higher in treated animals than in the controls for both the neonates and adults. Adduct levels for adult females (44.0 +/- 4.8 adducts/10(6) nucleotides) were higher than in neonatal females (25.9 +/- 2.2 adducts/10(6) nucleotides), while adduct levels in adult males (13.5 +/- 2.0 adducts/10(6) nucleotides) were lower than in neonatal males (33.8 +/- 4.1 adducts/10(6) nucleotides). 4-ABP treatment significantly increased the liver cII MFs in both sexes of neonatal mice but not in adult mice. Sequence analysis of cII mutant DNA revealed that 4-ABP induced a unique spectrum of mutations in neonatal mice, characterized by a high frequency of G:C-->T:A transversion, while the mutation spectrum in 4-ABP-treated adults was similar to that of control mice. Our results indicate that DNA adduct formation by 4-ABP depends as much on sex as it does on age, whereas the conversion of DNA adducts into mutations differed with animal age. These observations suggest that neonates are more sensitive than adults to genotoxic carcinogens because the relatively high levels of cell division in the developing animal facilitate the conversion of DNA damage into mutation. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html
Chen
Tao
T
Division of Genetic and Reproductive Toxicology, U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, AR 72079, USA. tchen@nctr.fda.gov
Mittelstaedt
Roberta A
RA
Beland
Frederick A
FA
Heflich
Robert H
RH
Moore
Martha M
MM
Parsons
Barbara L
BL
D000375:Aging; D000611:Aminobiphenyl Compounds / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009154:Mutation
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; C006757:4-biphenylamine; D004247:DNA