title: New insights into fetal mammary gland morphogenesis: differential effects of natural and environmental estrogens.
abstract: An increased breast cancer risk during adulthood has been linked to estrogen exposure during fetal life. However, the impossibility of removing estrogens from the feto-maternal unit has hindered the testing of estrogen's direct effect on mammary gland organogenesis. To overcome this limitation, we developed an ex vivo culture method of the mammary gland where the direct action of estrogens can be tested during embryonic days (E)14 to 19. Mouse mammary buds dissected at E14 and cultured for 5 days showed that estrogens directly altered fetal mammary gland development. Exposure to 0.1 pM, 10 pM, and 1 nM 17 β-estradiol (E2) resulted in monotonic inhibition of mammary buds ductal growth. In contrast, Bisphenol-A (BPA) elicited a non-monotonic response. At environmentally relevant doses (1 nM), BPA significantly increased ductal growth, as previously observed in vivo, while 1 μM BPA significantly inhibited ductal growth. Ductal branching followed the same pattern. This effect of BPA was blocked by Fulvestrant, a full estrogen antagonist, while the effect of estradiol was not. This method may be used to study the hormonal regulation of mammary gland development, and to test newly synthesized chemicals that are released into the environment without proper assessment of their hormonal action on critical targets like the mammary gland.
authors.affiliation: Dept. of Integrated Physiology and Pathobiology, 136 Harrison Avenue, Tufts University School of Medicine, Boston MA 02111 USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Speroni
authors.affiliation: Developmental Biology Program, Institute of Biotechnology, University of Helsinki, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Voutilainen
authors.affiliation: Developmental Biology Program, Institute of Biotechnology, University of Helsinki, Finland.
authors.forename: Marja L
authors.initials: ML
authors.lastname: Mikkola
authors.affiliation: Dept. of Integrated Physiology and Pathobiology, 136 Harrison Avenue, Tufts University School of Medicine, Boston MA 02111 USA.
authors.forename: Skylar A
authors.initials: SA
authors.lastname: Klager
authors.affiliation: Dept. of Integrated Physiology and Pathobiology, 136 Harrison Avenue, Tufts University School of Medicine, Boston MA 02111 USA.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Schaeberle
authors.affiliation: Dept. of Integrated Physiology and Pathobiology, 136 Harrison Avenue, Tufts University School of Medicine, Boston MA 02111 USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sonnenschein
authors.affiliation: Dept. of Integrated Physiology and Pathobiology, 136 Harrison Avenue, Tufts University School of Medicine, Boston MA 02111 USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Soto
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000166:cytology; D000077267:Fulvestrant; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004958:Estradiol; D000077267:Fulvestrant; D010636:Phenols; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C532507:GPER1 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds