We have developed a mammary tumor model in female rats treated with the heterocyclic amine (HA) food carcinogen 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine (PhIP). Tumors are being examined histologically, and genetic alterations determined. Genes under study for amplifications/mutations include erb-B2, p53, c-myc, and c-HA-ras. Cell lines are being derived from tumors for further analyses. The results show that a high fat diet enhances mammary tumorigenicity of PhIP by increasing the incidence and severity of the mammary tumors. DNA adduction of HA adducts in mammary epithelial cells, the target site for mammary cancer induction, was examined. Adduct removal studies show that PhIP-DNA adducts are present in the epithelial cells for several weeks after dosing. We also examined the adduction of HAs in the mammary gland of lactating female rats, the distribution to mammary tissue, and the excretion of HAs and their metabolites into breast milk. DNA adduction occurs in mammary gland with the level of adduction being highest for PhIP, followed by 2-amino-3-methylimidazo[4,5-f]-quinoline (IQ), and then 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). All three compounds are excreted into breast milk. DNA adducts were detected in tissues of the newborn pups. The results suggest that HAs excreted into breast milk may have carcinogenic consequence to the newborn.
