title: Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats.
abstract: The development of the mammary gland is a hormone-regulated event. Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation. Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer. Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland. Pregnant rats were orally exposed to vehicle, 5 μg DES/kg/day, or 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17β-estradiol for 3 months. Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals. ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells. Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR. Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone. In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Ayelen L
authors.initials: AL
authors.lastname: Gomez
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Melisa B
authors.initials: MB
authors.lastname: Delconte
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Altamirano
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Lucia
authors.initials: L
authors.lastname: Vigezzi
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Bosquiazzo
authors.affiliation: Departamento de Morfologia, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil.
authors.forename: Luís F
authors.initials: LF
authors.lastname: Barbisan
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Jorge G
authors.initials: JG
authors.lastname: Ramos
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Enrique H
authors.initials: EH
authors.lastname: Luque
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina.
authors.forename: Mónica
authors.initials: M
authors.lastname: Muñoz-de-Toro
authors.affiliation: Instituto de Salud y Ambiente del Litoral (ISAL), Universidad Nacional del Litoral (UNL)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Bioquímica y Ciencias Biológicas, UNL, Paraje El Pozo, Casilla de Correo 242, 3000, Santa Fe, Argentina. lkass@fbcb.unl.edu.ar.
authors.forename: Laura
authors.initials: L
authors.lastname: Kass
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D047688:Breast Cyst / Q000139:chemically induced* / Q000662:veterinary; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000139:chemically induced* / Q000662:veterinary; D049109:Cell Proliferation / Q000187:drug effects; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000009:adverse effects*; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects / Q000379:methods; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects*; D010052:Ovariectomy; D010636:Phenols / Q000008:administration & dosage / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012307:Risk Factors; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004054:Diethylstilbestrol; D004958:Estradiol; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Bisphenol A; Diethylstilbestrol; Endocrine disruptor; Estrogen replacement therapy; Mammary gland