Modification of transplacental tumorigenesis by 3-methylcholanthrene in mice by genotype at the Ah locus and pretreatment with beta-naphthoflavone.
Transplacental lung and liver tumorigenesis in the mouse by 3-methylcholanthrene (MC) was assessed as a function of inducibility of MC metabolism in fetus and in mother, and of pretreatment of the mothers with a noncarcinogenic inducer, beta-naphthoflavone (beta NF). Pregnant (C57BL/6 X DBA/2)F1 females (genotype Ahb Ahd, inducer responsive) mated to DBA/2 males received 45 or 100 mg/kg MC on gestation day 17, and DBA/2 females (genotype Ahd Ahd, nonresponsive) mated to F1 males were given 5 or 30 mg MC/kg. These crosses generated both responsive and nonresponsive offspring. Phenotype and tumor incidences were determined at 13 months of age. The transplacental action of MC was dose dependent and resulted in more lung and liver tumors in induction-responsive offspring than in nonresponsive littermates in most comparisons. beta NF alone did not result in increased numbers of tumors. Significant, complex effects were seen when the mothers were pretreated with beta NF (150 mg/kg) on gestation day 15, before MC on day 17. The beta NF pretreatment protected the fetuses of the F1 mothers: there was a significant overall 30 to 50% reduction in numbers of lung and liver tumors. The greatest effect was seen in the induction-responsive males, who experienced a 50% reduction in both incidence and multiplicity of lung tumors after 100 mg MC/kg, compared with males exposed to MC only. By contrast, beta NF pretreatment of DBA mothers had no general effect but rather potentiated the action of the 5 mg MC/kg dose on multiplicity of lung tumors in inducible males, causing a significant 4-fold increase. It also caused a 60% increase in inducible male liver tumor multiplicity when given before the 30 mg MC/kg dose. Thus, beta NF pretreatment was protective when the mother was inducible, especially in the inducible fetuses of such a mother, but when the mother was noninducible the beta NF pretreatment had no effect in some situations and potentiated the action of the carcinogen in others, mainly in inducible fetuses. These results underscore the fact that induced maternal and fetal metabolism contribute to risk of transplacental tumorigenesis by MC in qualitatively opposite ways.
Anderson
L M
LM
Division of Cancer Etiology, National Cancer Institute-Frederick Cancer Research Facility, Maryland 21701.
Jones
A B
AB
Riggs
C W
CW
Kovatch
R M
RM
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced*; D005333:Fetus / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D005838:Genotype; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000139:chemically induced*; D008297:Male; D008748:Methylcholanthrene / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000235:genetics*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D005419:Flavonoids; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone