Perinatal Exposure to Bisphenol-A Alters Peripubertal Mammary Gland Development in Mice

Abstract Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of perinatal exposure to low, environmentally relevant doses of BPA [25 and 250 ng BPA/kg body weight (bw)·d] on the peripubertal development of the mammary gland. BPA exposure enhanced the mammary glands’ sensitivity to estradiol in ovariectomized CD-1 mice. In their intact 30-d-old littermates, the area and numbers of terminal end buds relative to the gland ductal area increased whereas their apoptotic activity decreased. There was a positive correlation between ductal length and the age at first proestrus; that was reduced as the BPA dose increased, suggesting that BPA exposure slows down ductal invasion of the stroma. There was also a significant increase of progesterone receptor-positive ductal epithelial cells that were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in mice exposed to 25 ng BPA /kg bw·d. In conclusion, perinatal exposure to environmentally relevant BPA doses results in persistent alterations in mammary gland morphogenesis. Of special concern is the increased terminal end bud density at puberty as well as the increased number of terminal ends reported previously in adult animals, as these two structures are the sites at which cancer arises in humans and rodents.

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Perinatal Exposure to Bisphenol A Increases Adult Mammary Gland Progesterone Response and Cell Number

Molecular Endocrinology ◽

10.1210/me.2011-1129 ◽

2011 ◽

Vol 25 (11) ◽

pp. 1915-1923 ◽

Cited By ~ 79

Author(s):

Ayyakkannu Ayyanan ◽

Ouahiba Laribi ◽

Sonia Schuepbach-Mallepell ◽

Christina Schrick ◽

Maria Gutierrez ◽

...

Keyword(s):

Mammary Gland ◽

Bisphenol A ◽

Cell Number ◽

Perinatal Exposure

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Perinatal Exposure to Bisphenol-A and the Development of Metabolic Syndrome in CD-1 Mice

Endocrinology ◽

10.1210/en.2009-1218 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2603-2612 ◽

Cited By ~ 117

Author(s):

Karen K. Ryan ◽

April M. Haller ◽

Joyce E. Sorrell ◽

Stephen C. Woods ◽

Ronald J. Jandacek ◽

...

Keyword(s):

Bisphenol A ◽

High Fat Diet ◽

Perinatal Exposure ◽

High Fat ◽

Endocrine Society ◽

Endocrine Disrupting Chemical ◽

Obesity And Diabetes ◽

Food And Beverage ◽

Relevant Dose ◽

Increased Susceptibility

Bisphenol-A (BPA) is an endocrine-disrupting chemical used in the production of plastic food and beverage containers, leading to ubiquitous low-dose human exposure. It has been suggested that exposure to even low doses of BPA during development may be associated with increased susceptibility to obesity and diabetes later in life. Despite growing public concern, the existing empirical data are equivocal, prompting The Endocrine Society, the National Institute of Environmental Health Sciences, and others to call for further research. In this study, we tested the hypothesis that perinatal exposure to an ecologically relevant dose of BPA (1 part per billion via the diet) results in increased susceptibility to high-fat diet-induced obesity and glucose intolerance in adult CD-1 mice. The data did not support this hypothesis. In agreement with previous reports, we find that weanling mice exposed to BPA during gestation and lactation are heavier compared with control mice. We also find that BPA mice are longer than controls at 4 wk of age, but these differences are no longer apparent when the mice reach adulthood, even when tested on a high-fat diet. We conclude that this larger size-for-age represents a faster rate of growth early in development rather than an obese, diabetic phenotype in adulthood.

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Perinatal exposure to bisphenol A impacts in the mammary gland morphology of adult Mongolian gerbils

Experimental and Molecular Pathology ◽

10.1016/j.yexmp.2020.104374 ◽

2020 ◽

Vol 113 ◽

pp. 104374

Author(s):

Ellen Cristina Rivas Leonel ◽

Silvana Gisele Pegorin Campos ◽

Carolina Marques Baraldi Bedolo ◽

Luiz Henrique Alves Guerra ◽

Patrícia Simone Leite Vilamaior ◽

...

Keyword(s):

Mammary Gland ◽

Bisphenol A ◽

Perinatal Exposure ◽

Mongolian Gerbils ◽

Mammary Gland Morphology

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Perinatal exposure to bisphenol A modifies the transcriptional regulation of the β-Casein gene during secretory activation of the rat mammary gland

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2016.09.032 ◽

2017 ◽

Vol 439 ◽

pp. 407-418 ◽

Cited By ~ 12

Author(s):

Gabriela A. Altamirano ◽

Jorge G. Ramos ◽

Ayelen L. Gomez ◽

Enrique H. Luque ◽

Monica Muñoz-de-Toro ◽

...

Keyword(s):

Transcriptional Regulation ◽

Mammary Gland ◽

Bisphenol A ◽

Perinatal Exposure ◽

Casein Gene ◽

Secretory Activation ◽

Rat Mammary Gland

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Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats

Hormones and Cancer ◽

10.1007/s12672-016-0282-1 ◽

2017 ◽

Vol 8 (2) ◽

pp. 78-89 ◽

Cited By ~ 8

Author(s):

Ayelen L. Gomez ◽

Melisa B. Delconte ◽

Gabriela A. Altamirano ◽

Lucia Vigezzi ◽

Veronica L. Bosquiazzo ◽

...

Keyword(s):

Mammary Gland ◽

Bisphenol A ◽

Replacement Therapy ◽

Estrogen Replacement Therapy ◽

Perinatal Exposure ◽

Aged Rats ◽

Estrogen Replacement ◽

Middle Aged

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207. Effect of TGFB1 on mammary gland development is dependent on cellular source of gene expression

Reproduction Fertility and Development ◽

10.1071/srb08abs207 ◽

2008 ◽

Vol 20 (9) ◽

pp. 7

Author(s):

W. V. Ingman ◽

SA Robertson

Keyword(s):

Gene Expression ◽

Mammary Gland ◽

Mammary Glands ◽

Comparable Amount ◽

Mammary Gland Tissue ◽

Terminal End Buds ◽

Cellular Source ◽

Mammary Gland Morphogenesis ◽

Gland Morphogenesis ◽

The Impact

The cytokine TGFB1 is implicated in development of the mammary gland through regulation of epithelial cell proliferation and differentiation during puberty and pregnancy. We have compared mammary gland morphogenesis in virgin Tgfb1+/+, Tgfb1+/− and Tgfb1−/− mice, and transplanted Tgfb1+/+ and Tgfb1−/− epithelium to determine the impact of TGFB1 deficiency on development. When mammary gland tissue was evaluated respective to timing of puberty, invasion through the mammary fat pad of the ductal epithelium progressed similarly irrespective of genotype, albeit fewer terminal end buds were observed in mammary glands from Tgfb1−/− mice. The terminal end buds appeared morphologically normal, and a comparable amount of epithelial proliferation was evident. However, when transplanted into wildtype recipients, Tgfb1−/− epithelium showed accelerated invasion compared with Tgfb1+/+ epithelium. This suggests that the normal rate of ductal extension in Tgfb1−/− null mutant mice is the net result of impaired endocrine or paracrine support acting to limit the consequences of unrestrained epithelial growth. By adulthood, mammary glands in cycling virgin Tgfb1−/− mice were morphologically similar to those in Tgfb1+/+ and Tgfb1+/− animals, a normal branching pattern was observed, and the tissue differentiated into early alveolar structures in the diestrus phase of the ovarian cycle. Transplanted mammary gland epithelium showed a similar extent of ductal branching and evidence of secretory differentiation of luminal cells in pregnancy. These results reveal two opposing actions of TGFB1 during pubertal mammary gland morphogenesis, dependent on the cellular source of gene expression. When expressed in the epithelium, TGFB1 inhibits epithelial ductal growth, when expressed systemically, TGFB1 promotes epithelial ductal growth.

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In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

Journal of Endocrinology ◽

10.1530/joe-12-0395 ◽

2012 ◽

Vol 216 (2) ◽

pp. 245-263 ◽

Cited By ~ 18

Author(s):

H El Sheikh Saad ◽

A Toullec ◽

S Vacher ◽

M Pocard ◽

I Bieche ◽

...

Keyword(s):

Mammary Gland ◽

Muscle Development ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Female Offspring ◽

Perinatal Exposure ◽

Hormone Response ◽

Functional Categories ◽

Mammary Gland Morphogenesis ◽

Gland Morphogenesis

Exposure to low doses of environmental estrogens such as bisphenol A and genistein (G) alters mammary gland development. The effects of environmental anti-androgens, such as the fungicide vinclozolin (V), on mammary gland morphogenesis are unknown. We previously reported that perinatal exposure to G, V, and the GV combination causes histological changes in the mammary gland during the peripubertal period, suggesting alterations to the peripubertal hormone response. We now investigate whether perinatal exposure to these compounds alters the gene expression profiles of the developing glands to identify the dysregulated signaling pathways and the underlying mechanisms. G, V, or GV (1 mg/kg body weight per day) was added to diet of Wistar rats, from conception to weaning; female offspring mammary glands were collected at postnatal days (PNDs) 35 and 50. Genes displaying differential expression and belonging to different functional categories were validated by quantitative PCR and immunocytochemistry. At PND35, G had little effect; the slight changes noted were in genes related to morphogenesis. The changes following exposure to V concerned the functional categories associated with development (Cldn1,Krt17, andSprr1a), carbohydrate metabolism, and steroidogenesis. The GV mixture upregulated genes (Krt17,Pvalb, andTnni2) involved in muscle development, indicating effects on myoepithelial cells during mammary gland morphogenesis. Importantly, at PND50, cycling females exposed to GV showed an increase in the expression of genes (Csn2,Wap, andElf5) related to differentiation, consistent with the previously reported abnormal lobuloalveolar development previously described. Thus, perinatal exposure to GV alters the mammary gland hormone response differently at PND35 (puberty) and in animals with established cycles.

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