Enhanced hormonal responsiveness in mammary glands from parous mice: molecular mechanisms

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Mammary glands from parous mice required lower concentrations of hormones in vitro than those from virgins to effect differentiation, as measured by lactose synthetase activity. This phenomenon could not be explained by changes in receptor levels, since both mammary gland insulin and prolactin binding, although elevated at midpregnancy, returned to baseline in tissue from parous mice. Ethidium bromide, an intercalating dye, was a potent inhibitor of lactose synthetase induction in expiants from virgins but much less potent in tissue from pregnant mice; expiants from parous animals displayed intermediate sensitivity, suggesting that DNA structure was permanently altered. However, casein synthesis in glands from parous mice required hormone concentrations as high as in virgins and are just as susceptible to ethidium bromide as in virgins. Similarly, the vulnerability of the casein gene to DNAase I digestion is low in mammary epithelial cells from virgins, high in cells from pregnant mice, and low again in cells from parous animals. These data suggest that during the first pregnancy of mice, there are changes in the chromatin configuration that may facilitate the transcription of milk-related mRNA. Furthermore, after mammary gland involution these changes in the casein gene undergo reversion, while those involved with lactose synthetase activity persist; this may explain the disparate hormonal responsiveness seen in these animals with respect to casein and lactose synthesis.