Exposure to ethinyl estradiol during lactation reduces maternal mammary gland complexity and restricts pup growth in...

The mammary gland undergoes dramatic changes during pregnancy and lactation, remodeling a relatively simple ductal structure into an extensive network of milk secreting alveoli. Estradiol, through activation of estrogen receptor (ER), plays an essential role in the early expansion of the mammary epithelium during pregnancy, but has little role during lactation when circulating levels are low. Yet, ER is present in the epithelium during lactation and exposure to estrogenic endocrine disrupting chemicals (EDCs) could disrupt the lactational capability of the mammary gland. To understand the effects of ER agonists during lactation, we exposed CD-1 mice to ethinyl estradiol [20 μg/kg] from lactation day 1 (LD1) until weaning at LD21. To assess changes in lactational output, pup weight gain was assessed throughout the lactation period. Both maternal weight gain and maternal behavior were observed as well. Maternal mammary glands were collected and assessed for changes in histomorphology and molecular indicators of differentiation and cell death. We observed that EE2 exposure restricted weight growth in dams, increased time nursing on the nest and reduced other maternal activities. EE2 exposed pups had restricted growth and development. At weaning, EE2 exposed dams had less epithelial complexity than VEH controls despite no changes in alveolar structure. Molecular analysis of the mammary gland at weaning indicated that EE2 reduced epithelial pSTAT3 expression, an early indicator of cell degradation, without altering differentiation markers or apoptosis. These findings indicate that EE2 exposure reduces epithelial expansion in lactation prior to weaning, resulting in restricted growth and development in pups.