Exposure to the Endocrine Disruptor, Propylparaben, During Pregnancy and Lactation, Alters Typical Parity-Induced Reorganization of the Mouse Mammary Gland

Abstract The mammary gland is a hormone sensitive organ that is susceptible to endocrine disrupting chemicals (EDCs) during several vulnerable periods, including pregnancy and lactation. Mammary gland reorganization during pregnancy and lactation is hormone driven and provides long-term protection against breast cancer risk. It is unknown if EDC exposures during these sensitive windows can alter mammary reorganization to either enhance or offset parity-induced protection against breast cancer. Here, we examined effects of propylparaben (PP), a common preservative used in personal care products and foods with estrogen receptor (ER) agonist properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10,000 µg/kg/day PP throughout pregnancy and lactation. These doses were selected for their relevance to human exposures. We also included an unexposed nulliparous female group to evaluate the typical changes associated with parity. Five weeks post-involution (and five weeks after the last PP exposure), mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. We found that PP reduced many of the typical morphological effects of parity on the mammary gland, resulting in intermediate phenotypes for ductal density and total epithelial structures. Notably, we found increased proliferation in PP-treated mammary glands, despite decreased ductal epithelial volume relative to parous controls. Mammary glands from PP-treated females also had alterations in the expression of ERα-mediated genes, including PgR (the gene that encodes progesterone receptor) and Igf1, with expression levels that were intermediate to both nulliparous and parous control mice. Finally, PP reduced the effect of parity on several immune cell types in the mammary gland including B cells, T-cells, and M2 macrophages. These results suggest that PP, at levels relevant to human exposure, can disrupt the normal response to parity in the mouse mammary gland, including persistent alterations to mammary gland structures. Future studies should address whether PP exposures disturb the protective effects of pregnancy on mammary cancer risk.

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Exposure to propylparaben during pregnancy and lactation induces long-term alterations to the mammary gland in mice

Endocrinology ◽

10.1210/endocr/bqab041 ◽

2021 ◽

Author(s):

Joshua P Mogus ◽

Charlotte D LaPlante ◽

Ruby Bansal ◽

Klara Matouskova ◽

Benjamin R Schneider ◽

...

Keyword(s):

Mammary Gland ◽

Immune Cell ◽

Cell Number ◽

Mouse Mammary Gland ◽

Receptor Expression ◽

Cancer Development ◽

Protective Effects ◽

Sensitive Organ ◽

Pregnancy And Lactation

Abstract The mammary gland is a hormone sensitive organ that is susceptible to endocrine disrupting chemicals (EDCs) during the vulnerable periods of parous reorganization (i.e. pregnancy, lactation, and involution). Pregnancy is believed to have long-term protective effects against breast cancer development, however, it is unknown if EDCs can alter this effect. We examined the long-term effects of propylparaben, a common preservative used in personal care products and foods, with estrogenic properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10,000 µg/kg/day propylparaben throughout pregnancy and lactation. Unexposed nulliparous females were also evaluated. Five weeks post-involution, mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. For several parameters of mammary gland morphology, propylparaben reduced the effects of parity. Propylparaben also increased proliferation, but not stem cell number, and induced modest alterations to expression of ERα-mediated genes. Finally, propylparaben altered the effect of parity on the number of several immune cell types in the mammary gland. These results suggest that propylparaben, at levels relevant to human exposure, can interfere with the effects of parity on the mouse mammary gland and induce long-term alterations to mammary gland structure. Future studies should address if propylparaben exposures negate the protective effects of pregnancy on mammary cancer development.

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Bisphenol A (BPA) Exposure In Utero Leads to Immunoregulatory Cytokine Dysregulation in the Mouse Mammary Gland: A Potential Mechanism Programming Breast Cancer Risk

Hormones and Cancer ◽

10.1007/s12672-016-0254-5 ◽

2016 ◽

Vol 7 (4) ◽

pp. 241-251 ◽

Cited By ~ 26

Author(s):

Catha Fischer ◽

Ramanaiah Mamillapalli ◽

Laura G. Goetz ◽

Elisa Jorgenson ◽

Ysabel Ilagan ◽

...

Keyword(s):

Breast Cancer ◽

Mammary Gland ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Bisphenol A ◽

In Utero ◽

Mouse Mammary Gland ◽

Potential Mechanism ◽

Immunoregulatory Cytokine ◽

Cytokine Dysregulation

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Left–right analysis of mammary gland development in retinoid X receptor-α +/− mice

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0416 ◽

2016 ◽

Vol 371 (1710) ◽

pp. 20150416 ◽

Cited By ~ 2

Author(s):

Jacqulyne P. Robichaux ◽

John W. Fuseler ◽

Shrusti S. Patel ◽

Steven W. Kubalak ◽

Adam Hartstone-Rose ◽

...

Keyword(s):

Breast Cancer ◽

Mammary Gland ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Bilateral Symmetry ◽

Mammary Glands ◽

Network Size ◽

Mammary Development ◽

Retinoid X Receptor ◽

Breast Development

Left–right (L–R) differences in mammographic parenchymal patterns are an early predictor of breast cancer risk; however, the basis for this asymmetry is unknown. Here, we use retinoid X receptor alpha heterozygous null (RXRα +/− ) mice to propose a developmental origin: perturbation of coordinated anterior–posterior (A–P) and L–R axial body patterning. We hypothesized that by analogy to somitogenesis—in which retinoic acid (RA) attenuation causes anterior somite pairs to develop L–R asynchronously—that RA pathway perturbation would likewise result in asymmetric mammary development. To test this, mammary glands of RXRα +/− mice were quantitatively assessed to compare left- versus right-side ductal epithelial networks. Unlike wild-type controls, half of the RXRα +/− thoracic mammary gland (TMG) pairs exhibited significant L–R asymmetry, with left-side reduction in network size. In RXRα +/− TMGs in which symmetry was maintained, networks had bilaterally increased size, with left networks showing greater variability in area and pattern. Reminiscent of posterior somites, whose bilateral symmetry is refractory to RA attenuation, inguinal mammary glands (IMGs) also had bilaterally increased network size, but no loss of symmetry. Together, these results demonstrate that mammary glands exhibit differential A–P sensitivity to RXRα heterozygosity, with ductal network symmetry markedly compromised in anterior but not posterior glands. As TMGs more closely model human breast development than IMGs, these findings raise the possibility that for some women, breast cancer risk may initiate with subtle axial patterning defects that result in L–R asymmetric growth and pattern of the mammary ductal epithelium. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

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Local Insulin-Like Growth Factor-II Mediates Prolactin-Induced Mammary Gland Development

Molecular Endocrinology ◽

10.1210/me.2002-0214 ◽

2003 ◽

Vol 17 (3) ◽

pp. 460-471 ◽

Cited By ~ 57

Author(s):

Russell C. Hovey ◽

Jessica Harris ◽

Darryl L. Hadsell ◽

Adrian V. Lee ◽

Christopher J. Ormandy ◽

...

Keyword(s):

Mammary Gland ◽

Early Pregnancy ◽

Insulin Receptors ◽

Mammary Glands ◽

Mouse Mammary Gland ◽

Mammary Epithelial ◽

Receptor Expression ◽

Mammary Tissue ◽

Alveolar Development

Abstract Prolactin (PRL) is a major determinant of mammary epithelial cell proliferation during alveolar development in sexually mature and pregnant mice. To date, it has not been clear whether PRL effects these responses alone or by also invoking the action of autocrine/paracrine growth factors. In this study, we provide evidence that part of the effect of PRL on mammary gland growth is mediated by IGF-II. During sexual maturity and in early pregnancy, the level of IGF-II mRNA in the mammary gland was increased concurrent with increased PRL receptor expression. The level of IGF-II mRNA was reduced in mammary tissue from PRL receptor−/− mice during early pregnancy, and explants of mouse mammary gland and HC11 mammary epithelial cells both increased their expression of IGF-II after exposure to PRL in vitro. These findings coincided with the demonstration that IGF-II stimulated alveolar development in mammary glands in whole organ culture. PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro. Insight into the mechanism by which PRL induced IGF-II expression was provided by the fact that it was blocked by the Jak2 inhibitor AG490 and the MAPK inhibitor PD98059. Finally, induction of insulin receptor substrate (IRS)-1 in the mammary glands of PRL-treated mice and induction of IRS-1 and IRS-2 after treatment with PRL plus progesterone indicates that these molecules are induced by PRL as potential signaling intermediates downstream from IGF-I/insulin receptors. Together, these data demonstrate a role for IGF-II as a mediator of PRL action in the mouse mammary gland during ductal branching and alveolar development.

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Regulation of lipogenic capacity in lactating rats

Biochemical Journal ◽

10.1042/bj2080611 ◽

1982 ◽

Vol 208 (3) ◽

pp. 611-618 ◽

Cited By ~ 12

Author(s):

M R Grigor ◽

A Geursen ◽

M J Sneyd ◽

S M Warren

Keyword(s):

Mammary Gland ◽

Fatty Acid ◽

Malic Enzyme ◽

Fatty Acid Synthase ◽

Specific Activity ◽

Mammary Glands ◽

Lipogenic Enzymes ◽

Pregnancy And Lactation ◽

Specific Activities

1. The rate of mammary-gland lipogenesis measured in vivo from 3H2O was suppressed after decreasing the milk demand by decreasing the number of pups from ten to two or three, as well as by giving diets containing lipid [Grigor & Warren (1980) Biochem. J. 188, 61-65]. 2. The specific activities of the lipogenic enzymes fatty acid synthase, glucose 6-phosphate dehydrogenase and ‘malic’ enzyme increased between 6- and 10-fold in the mammary gland and between 2- and 3-fold in the livers during the first 10 days of lactation. The increases in specific activity coupled with the doubling of liver mass which occurred during pregnancy and lactation resulted in considerable differences in total liver activities when compared with virgin animals. 3. Although consumption of a diet containing 20% peanut oil suppressed the activities of the three lipogenic enzymes in the livers, only the ‘malic’ enzyme was affected in the mammary glands. 4. In contrast, decreased milk demand did not affect the specific activities of any of the liver enzymes, whereas it resulted in suppression of all three lipogenic enzymes of the mammary glands. There was no effect on either the cytoplasmic malate dehydrogenase or the lactate dehydrogenase of the mammary gland. 5. In all the experiments performed, the activity of the fatty acid synthase correlated with the amount of material precipitated by the rabbit antibody raised against rat fatty acid synthase.

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Lipogranulomas of the mammary glands: diagnosis and treatment

Bulletin of the Academy of Sciences of Moldova. Medical Sciences ◽

10.52692/1857-0011.2021.2-70.25 ◽

2021 ◽

Vol 70 (2) ◽

Author(s):

Natalia Cara ◽

◽

Veronica Svet ◽

Ion Mereuta ◽

◽

...

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Mammary Gland ◽

Inflammatory Process ◽

Pathological Condition ◽

Scar Tissue ◽

Mammary Glands ◽

Diagnosis And Treatment ◽

Breast Lesions ◽

Fat Necrosis

Steatonecrosis of the mammary gland is necrosis of its adipose tissue, followed by replacement with scar tissue. Lipogranuloma is known as a benign inflammatory process, necrosis of breast fat occurs due to iatrogenic breast trauma. Most often, fatty necrosis is seen in women with large breasts – in women with small breasts, it develops much less often. It is important to diagnose lipogranulomas because it can often mimic breast cancer. Fat necrosis of the breast is a common pathological condition, with a wide variety of presentations on mammography, ultrasound and MRI. The incidence of fatty necrosis of the breast is estimated at 0.6%, representing 2.75% of all breast lesions.

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