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Modification of Transplacental Tumorigenesis by 3-Methylcholanthrene in Mice by Genotype at the Ah Locus and Pretreatment with ß-Naphthoflavone

Laboratory of Comparative Carcinogenesis, Division of Cancer Etiology, National Cancer Institute-Frederick Cancer Research Facility [L. M. A., A. B. J.]; Data Management Services, Frederick, Maryland 21701 [C. W. R.]; and Pathology Associates, Ijamsville, Maryland 21754 [R. M. K.]

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, ß-naphthoflavone (ßNF). Pregnant (C57BL/6 x DBA/2)F₁ females (genotype Ah^bAh^d, inducer responsive) mated to DBA/2 males received 45 or 100 mg/kg MC on gestation day 17, and DBA/2 females (genotype Ah^dAh^d, 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. ßNF alone did not result in increased numbers of tumors. Significant, complex effects were seen when the mothers were pretreated with ßNF (150 mg/kg) on gestation day 15, before MC on day 17. The ßNF 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, ßNF 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, ßNF pretreatment was protective when the mother was inducible, especially in the inducible fetuses of such a mother, but when the mother was noninducible the ßNF 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.

¹ To whom requests for reprints should be addressed, at the Laboratory of Comparative Carcinogenesis, National Cancer Institute-Frederick Cancer Research Facility, Building 538, Room 205E, Frederick, MD 21701.

Received 7/26/88. Revised 12/28/88. Accepted 1/ 5/89.

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