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2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagen and rodent mammary gland carcinogen found in the human diet. 2-Hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP) is the proximate reactive metabolite of PhIP associated with PhIP-DNA adduct formation and mutagenesis. In the current study, whole mammary glands obtained from transgenic C57Bl/6 mice carrying the plasmid-lacZ mutational reporter gene were cultured in defined medium and exposed to various concentrations of N-hydroxy-PhIP for 24 h. At various times after N-hydroxy-PhIP exposure, PhIP-DNA adduct levels were determined by the (32)P-post-labeling assay and the lacZ(-) mutant frequency determined by the positive selection system. Glands were cultured in either medium containing insulin (I medium), necessary for maintenance of the gland, or I medium containing prolactin, aldosterone and hydrocortisone (IPAH medium) to induce lobuloalveolar development. At 3 and 7 days after exposure to 10 micro M N-hydroxy-PhIP, mutant frequency was upwards of 9-fold higher in glands incubated in IPAH medium than in I medium (15.2 +/- 1.9 and 1.6 +/- 0.7 x 10(-3), respectively, 3 day time point). PhIP-DNA adduct levels were 1.7-fold higher in glands cultivated in IPAH medium than in I medium immediately after exposure to 10 micro M N-hydroxy-PhIP. A statistically significant reduction in PhIP-DNA adduct levels occurred with time in glands cultivated in IPAH medium but not I medium (one-way analysis of variance, P &lt; 0.05). By 7 days after exposure, PhIP-DNA adduct levels were similar in glands cultured in I and IPAH medium (3.2 +/- 0.2 and 2.8 +/- 0.29 adducts/10(7) nucleotides, respectively). DNA synthesis as measured by [(3)H]thymidine labeling was approximately 2-fold higher in glands cultured in IPAH medium than in I medium. The higher mutant frequency in glands cultivated in IPAH medium versus I medium appeared to be due to a combination of higher initial PhIP-DNA adduct levels and a greater fixation of mutations that occurred at higher proliferation rates. The findings indicate that mammotrophic hormones influence the mutagenicity of PhIP in the mammary gland in vitro and emphasize the importance of hormonal milieu on carcinogen-DNA adduct-induced mutations in this organ.

mutagenesis

Mutagenesis and DNA adduct formation in the mouse mammary gland exposed to 2-hydroxyamino-1-methyl-6-phenylimidazo-[4,5-b]pyridine in whole organ culture