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  • Title: Metabolism of transplacental carcinogens.
    Author: Anderson LM, Jones AB, Miller MS, Chauhan DP.
    Journal: IARC Sci Publ; 1989; (96):155-88. PubMed ID: 2680945.
    Abstract:
    Literature on fetal metabolism of carcinogens since 1980 has been systematically listed and selectively discussed. The published data continues to support the conclusion that animal and human fetal tissues have the capacity to metabolize carcinogens, but at a low rate compared to the adult. Metabolism of low-molecular-weight chemicals, including nitrosamines, appears only near term in the rodent and is poorly inducible transplacentally; these agents are correspondingly relatively ineffective as fetal carcinogens. Metabolism of aromatic carcinogens, by contrast, appears early in gestation and is highly inducible transplacentally in rodents by chemicals such as polycyclic aromatic hydrocarbons (PAH) and tetrachlorodibenzo-p-dioxin, resulting in dramatic percent increases in enzyme activity. Transplacental induction has not been unequivocally demonstrated for the human fetus. Phase II enzymes, metabolizing aromatic compounds to water-soluble forms, generally have higher constitutive activity but lower degree of inducibility in the fetus, compared with phase I (activating) enzymes, and appear to show quantitatively different patterns in the human compared with the rodent. Specific and sensitive new technologies, including 32P-postlabelling, immunodetection of specific proteins, and use of cDNA probes, are beginning to be applied to fetal systems and are providing a more definitive and detailed understanding of the ontogeny and modulation of fetal carcinogen metabolizing enzymes. Fetal and maternal metabolism of PAH, especially methylcholanthrene (MC), have been found to be important determinants in susceptibility of the fetus to tumorigenesis. In particular, we have utilized a mouse model system wherein a single dominant gene, Ah, confers responsiveness to induction of PAH metabolism by cytochrome Pl450 (IA1); the recessive allele, Ah, is associated with nonresponsiveness. In appropriate backcrosses between C57BL/6 (AhAh) and DBA/2 (AhAh) mice, responsive and nonresponsive fetuses were carried together in mothers who were, themselves, either responsive or nonresponsive. In both cases, responsive fetuses later developed more lung and liver tumours after transplacental MC, compared with nonresponsive littermates. Fetuses of responsive mothers, however, experienced a lower cancer risk than did those of nonresponsive mothers at a comparable MC dose. Pretreatment of the pregnant mice with the noncarcinogenic inducer, beta-naphthoflavone (BNF) had a uniform protective effect for all of the fetuses, especially the responsive ones, if the mother was responsive. For nonresponsive mothers, by contrast, BNF pretreatment led to an enhancement of tumorigenesis, in the responsive fetuses only, under certain conditions of dose and fetal sex.(ABSTRACT TRUNCATED AT 400 WORDS)
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