Virgin Sprague-Dawley rats exhibiting regular estrous cycles were used as a model system to determine whether the level of circulating
estrogen modifies the alkylation pattern of mammary gland
DNA by a direct-acting
carcinogen,
N-methyl-N-nitrosourea (NMU). The concentration of
7-methylguanine and
O6-methylguanine were similar in mammary epithelial
DNA 0.25, 0.50, and 1.0 h after i.v. injection of 50 mg/kg
body weight NMU on different days of the rat estrous cycle. However,
O6-methylguanine was significantly higher in mammary gland
DNA 8 and 24 h after a single i.v. dose of
carcinogen on proestrus or estrus, compared to rats receiving
carcinogen on diestrus. There was no difference in the
7-methylguanine levels at 8 h in any group, but this adduct was higher in estrous-treated rats at 24 h. The ratio of
O6-methylguanine to
7-methylguanine was significantly lower at 8 h in mammary gland
DNA from diestrous-injected rats, and this difference reflected the lower level of
O6-methylguanine adducts in this group. In contrast,
O6-methylguanine concentrations in
DNA extracted from the liver of the same animals were virtually identical at all time periods examined.
7-Methylguanine levels were higher in the liver at 0.5, 1, 8, and 24 h post-NMU in proestrus as compared with diestrous-injected rats. The observed adduct clearance suggests that rat mammary epithelium may contain repair systems capable of removing
O6-methylguanine. These results also suggest that the initial removal of the
O6-methylguanine lesions in mammary epithelial
DNA (rather than the initial rate of alkylation) is affected by the hormonal environment during
carcinogen exposure. This effect may be tissue specific since removal of
O6-methylguanine from liver
DNA is apparently not altered by the stage of the estrous cycle at which NMU is administered.