Fetal mouse susceptibility to transplacental lung and liver carcinogenesis by 3-methylcholanthrene: positive correlation with responsiveness to inducers of aromatic hydrocarbon metabolism.
The role of metabolic activation of carcinogens in fetal tissue as a determinant of sensitivity in transplacental carcinogenesis was investigated in a pharmacogenetic experiment utilizing backcrosses of C57BL/6 (AhbAhb, responsive to induction of aromatic hydrocarbon metabolism) and DBA/2 (AhdAhd, non-responsive) mice. Responsive (C57BL/6 X DBA/2)F1 and non-responsive DBA mothers, all carrying both responsive (AhbAhd) and non-responsive (AhdAhd) fetuses, were given i.p. doses of the carcinogen 3-methylcholanthrene (MC) ranging from 5 to 175 mg/kg on gestation day 17. At 10 months of age the metabolic phenotype of each offspring was determined, and correlated with number of lung and liver tumors. Both male and female AhbAhd (responsive) offspring in most dose groups presented a consistent two- to three-fold higher incidence of lung tumors than did non-responsive AhdAhd littermates. The difference held for offspring of both (C57BL/6 X DBA)F1 and DBA mothers and it was of statistical significance for one or both sexes at most dosage levels. Hepatocellular tumors were also significantly more frequent in responsive male AhbAhd progeny of (C57BL/6 X DBA/2)F1 mothers than in non-responsive AhdAhd littermates. Progeny of the DBA mothers exhibited significantly more liver and lung tumors than did those of the (C57BL/6 X DBA/2)F1 mothers receiving the same dose. These results suggest that in this model system both maternal and fetal genotype for responsiveness to induction of aromatic hydrocarbon metabolism are important factors modulating fetal carcinogenic risk.
D000818:Animals; D001711:Biotransformation; D005260:Female; D005333:Fetus / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000139:chemically induced*; D008297:Male; D008431:Maternal-Fetal Exchange; D008748:Methylcholanthrene / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011083:Polycyclic Compounds / Q000378:metabolism*; D011247:Pregnancy
D011083:Polycyclic Compounds; D008748:Methylcholanthrene