The formation of 3-methylcholanthrene-initiated lung tumors correlates with induction of cytochrome P450IA1 by the carcinogen in fetal but not adult mice

Abstract

The administration of 3-methylcholanthrene (MC) to pregnant mice results in the formation of lung tumors in the offspring. Previous work has shown that fetuses demonstrating inducibility of aryl hydrocarbon metabolism develop two to five times more lung tumors than induction-nonresponsive littermates. In this study, the effects of fetal versus adult MC exposure were compared with regard to both induction of aryl hydrocarbon hydroxylase activity (AHH) in lung and dependence of lung tumorigenesis on the Ah genotype. In inducible (C57BL 6 × DBA 2 )F1 fetal lung supernatants, a single ip injection of 100 mg/kg of MC to the mothers resulted in a maximal 50-fold induction of AHH activity by 8 hr, which persisted for 48 hr. The enzyme data agreed well with RNA blot analysis, as MC caused maximal induction of P450IA1 RNA by 4 hr. For comparison, adult ( F1 × DBA 2 ) mice were given three weekly injections of 100 mg/kg MC and tumor incidences were determined after 16 weeks. No differences were observed between responsive and nonresponsive mice of either sex in the number of mice bearing lung tumors, nor did the tumor multiplicity differ between responsive and nonresponsive males. However, noninducible female mice had a significantly higher tumor multiplicity than their inducible counterparts ( p < 0.025). Single ip injections of MC to adult F1 mice revealed that lung AHH activity was increased only 4- to 7-fold in the adult animal compared to the large fetal induction ratio. The difference in the magnitude of induction was due to the higher constitutive levels of AHH activity seen in adult tissue (4- to 14-fold greater than maximal basal fetal levels), as fetal and adult supernatants showed similar levels of induced activity following MC treatment. These results suggest that the correlation between susceptibility to MC-initiated lung tumors and induction of cytochrome P450IA1 is a unique property of the fetus and may be due, in part, to the low basal levels of fetal activating enzymes and their high induction ratio during the fetal period.