Abstract
The mammary gland is exceptionally a complex tissue. It is a sexually dimorphic organ in function, size, response to hormone signaling, and cellular structure. Unlike most organs, the mammary gland has several critical periods of growth and development after birth, and is only fully developed after a full-term pregnancy. Mammary gland development is dependent on complex endocrine signaling as well as paracrine and autocrine signaling between the stroma and parenchyma cells. Even outside of the critical windows of growth and development, the mammary gland is constantly changing with normal hormone fluctuations, most notably during the estrous/menstrual cycle. It is particularly sensitive to endocrine disrupting chemicals (EDCs). An EDC can affect both females and males, resulting in abnormal mammary gland development in adolescents. Later in life, EDCs can influence cancer outcomes. In adult females, alterations in mammary gland development can result in lactational impairment. This chapter describes the stages of development, the key hormone actions, and common EDCs and their effects on the mammary gland.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA (1998) A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A 95(9):5076–5081
Hens JR, Wysolmerski JJ (2005) Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland. Breast Cancer Res 7(5):220–224
Maller O, Martinson H, Schedin P (2010) Extracellular matrix composition reveals complex and dynamic stromal-epithelial interactions in the mammary gland. J Mammary Gland Biol Neoplasia 15(3):301–318
Brisken C, O’Malley B (2010) Hormone action in the mammary gland. Cold Spring Harb Perspect Biol 2(12):a003178
Hennighausen L, Robinson GW (2001) Signaling pathways in mammary gland development. Dev Cell 1(4):467–475
Hovey RC, Trott JF, Vonderhaar BK (2002) Establishing a framework for the functional mammary gland: from endocrinology to morphology. J Mammary Gland Biol Neoplasia 7(1):17–38
Howard BA, Gusterson BA (2000) Human breast development. J Mammary Gland Biol Neoplasia 5(2):119–137
Rudel RA, Fenton SE, Ackerman JM, Euling SY, Makris SL (2011) Environmental exposures and mammary gland development: state of the science, public health implications, and research recommendations. Environ Health Perspect 119(8):1053–1061
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) (2016) SEER cancer statistics review, 1975–2013. National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/csr/1975_2013/ (based on November 2015 SEER data submission)
American Cancer Society (ACS) (2016) Cancer facts and figures 2016. American Cancer Society, Atlanta
American Cancer Society (ACS) (2015) Breast cancer facts and figures 2015–2016. American Cancer Society, Inc., Atlanta
IBCERCC (2013) www.niehs.nih.gov/about/boards/ibcercc
Macon MB, Fenton SE (2013) Endocrine disruptors and the breast: early life effects and later life disease. J Mammary Gland Biol Neoplasia 18(1):43–61
Forman MR, Winn DM, Collman GW, Rizzo J, Birnbaum LS (2015) Environmental exposures, breast development and cancer risk: through the looking glass of breast cancer prevention. Reprod Toxicol 54:6–10
Drife JO (1986) Breast development in puberty. Ann N Y Acad Sci 464(1 Endocrinology):58–65
Russo J, Russo IH (2004) Development of the human breast. Maturitas 49(1):2–15
Jolicoeur F (2005) Intrauterine breast development and the mammary myoepithelial lineage. J Mammary Gland Biol Neoplasia 10(3):199–210
Robinson GW, Karpf ABC, Kratochwil K (1999) Regulation of mammary gland development by tissue interaction. J Mammary Gland Biol Neoplasia 4(1):9–19
Macias H, Hinck L (2012) Mammary gland development. Wiley Interdiscip Rev Dev Biol 1(4):533
Gusterson BA, Stein T (2012) Human breast development. Semin Cell Dev Biol 23(5):567
Hassiotou F, Geddes D (2013) Anatomy of the human mammary gland: current status of knowledge. Clin Anat 26(1):29–48
Javed A, Lteif A (2013) Development of the human breast. Semin Plast Surg 27(1):005–012
Alexander JM, Campbell MJ (1997) Prevalence of inverted and non-protractile nipples in antenatal women who intend to breast-feed. Breast 6(2):72–78
Montagna W, Yun JS (1972) The glands of montgomery. Br J Dermatol 86(2):126–133
Anbazhagan R, Bartek J, Monaghan P, Gusterson BA (1991) Growth and development of the human infant breast. Am J Anat 192(4):407–417
Marshall WA, Tanner JM (1969) Variations in pattern of pubertal changes in girls. Arch Dis Child 44(235):291–303
Neville MC, McFadden TB, Forsyth I (2002) Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia 7(1):49–66
Anderson E, Clarke RB (2004) Steroid receptors and cell cycle in normal mammary epithelium. J Mammary Gland Biol Neoplasia 9(1):3–13
Visvader JE (2009) Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 23(22):2563–2577
Russo J, Lynch H, Russo IH (2001) Mammary gland architecture as a determining factor in the susceptibility of the human breast to cancer. Breast J 7(5):278–291
Beesley R, Johnson J (2008) Glob. libr. women’s med
Davis B, Fenton S (2013) Mammary gland. In: Haschek WM, Rousseaux CG, Wallig MA (eds) Haschek and Rousseaux’s handbook of toxicologic pathology, vol 3. Elsevier Academic Press, New York, NY, pp 2665–2694
Lamote I, Meyer E, Massart-Leën AM, Burvenich C (2004) Sex steroids and growth factors in the regulation of mammary gland proliferation, differentiation, and involution, vol 69. Elsevier Inc., United States
Taylor D, Pearce CL, Hovanessian-Larsen L, Downey S, Spicer DV, Bartow S et al (2009) Progesterone and estrogen receptors in pregnant and premenopausal non-pregnant normal human breast. Breast Cancer Res Treat 118(1):161–168
Russo J, Russo IH (2014) Techniques and methodological approaches in breast cancer research, vol 1. Springer, New York, NY
Cowin P, Wysolmerski J (2010) Molecular mechanisms guiding embryonic mammary gland development. Cold Spring Harb Perspect Biol 2(6):a003251–a003251
Robinson GW, Hennighausen L (1997) Inhibins and activins regulate mammary epithelial cell differentiation through mesenchymal-epithelial interactions. Development 124(14):2701
Hatsell S, Rowlands T, Hiremath M, Cowin P (2003) β-catenin and tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia 8(2):145–158
Lindvall C, Bu W, Williams BO, Li Y (2007) Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev 3(2):157–168
Osin PP, Anbazhagan R, Bartkova J, Nathan B, Gusterson BA (1998) Breast development gives insights into breast disease. Histopathology 33(3):275–283
Gallego MI, Binart N, Robinson GW, Okagaki R, Coschigano KT, Perry J, Kopchick JJ, Oka T, Kelly PA, Hennighausen L (2001) Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. Dev Biol 229(1):163–175
Feldman M, Ruan W, Tappin I, Wieczorek R, Kleinberg D (1999) The effect of GH on estrogen receptor expression in the rat mammary gland. J Endocrinol 163(3):515–522
Ciarloni L, Mallepell S, Brisken C (2007) Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development. Proc Natl Acad Sci U S A 104(13):5455–5460
McBryan J, Howlin J, Napoletano S, Martin F (2008) Amphiregulin: role in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 13(2):159–169
Obr AE, Edwards DP (2012) The biology of progesterone receptor in the normal mammary gland and in breast cancer. Mol Cell Endocrinol 357(1–2):4–17
Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ (2013) Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Res 15(3):R44
Beleut M, Rajaram RD, Caikovski M, Ayyanan A, Germano D, Choi Y et al (2010) Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci U S A 107(7):2989–2994
Forsyth IA, Wallis M (2002) Growth hormone and prolactin – molecular and functional evolution. J Mammary Gland Biol Neoplasia 7(3):291–312
Monks J (2007) TGFβ as a potential mediator of progesterone action in the mammary gland of pregnancy. J Mammary Gland Biol Neoplasia 12(4):249–257
Navarrete MAH, Maier CM, Falzoni R, de Azevedo Quadros LG, Lima GR, Baracat EC, Nazário ACP (2005) Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle. Breast Cancer Res 7(3):R306–R313
Oakes SR, Rogers RL, Naylor MJ, Ormandy CJ (2008) Prolactin regulation of mammary gland development. J Mammary Gland Biol Neoplasia 13(1):13–28
Harris J, Stanford PM, Sutherland K, Oakes SR, Naylor MJ, Robertson FG, Blazek KD, Kazlauskas M, Hilton HN, Wittlin S, Alexander WS, Lindeman GJ, Visvader JE, Ormandy CJ (2006) Socs2 and Elf5 mediate prolactin-induced mammary gland development. Mol Endocrinol 20(5):1177–1187
Knight CH, Peaker M, Wilde CJ (1998) Local control of mammary development and function. Rev Reprod 3(2):104–112. doi:10.1530/revreprod/3.2.104
Allan GJ, Beattie J, Flint DJ (2004) The role of IGFBP-5 in mammary gland development and involution. Domest Anim Endocrinol 27(3):257–266
Baxter FO, Neoh K, Tevendale MC (2007) The beginning of the end: death signaling in early involution. J Mammary Gland Biol Neoplasia 12(1):3–13
Sutherland KD, Lindeman GJ, Visvader JE (2007) The molecular culprits underlying precocious mammary gland involution. J Mammary Gland Biol Neoplasia 12(1):15–23
Barash I (2006) Stat5 in the mammary gland: controlling normal development and cancer. J Cell Physiol 209(2):305–313
Watson C (2006) Key stages in mammary gland development – involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res 8(2):203
Furth PA (1999) Mammary gland involution and apoptosis of mammary epithelial cells. J Mammary Gland Biol Neoplasia 4(2):123–127
Zinser GM, Welsh J (2004) Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice. Mol Endocrinol 18(9):2208–2223
Tonner E, Allan G, Flint D (2000) Hormonal control of plasmin and tissue-type plasminogen activator activity in rat milk during involution of the mammary gland. J Endocrinol 167(2):265–273
Hughes K, Wickenden JA, Allen JE, Watson CJ (2012) Conditional deletion of Stat3 in mammary epithelium impairs the acute phase response and modulates immune cell numbers during post-lactational regression. J Pathol 227(1):106–117
Mandrup KR, Hass U, Christiansen S, Boberg J (2012) Perinatal ethinyl oestradiol alters mammary gland development in male and female Wistar rats. Int J Androl 35(3):385–396
de Assis S, Warri AM, Cruz I, Laja O, Tian Y, Zhang B, Wang Y, Huang TH, Hilakivi-Clarke L (2012) High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring. Nat Commun 3:1053
Wingo PA, Lee NC, Ory HW, Beral V, Peterson HB, Rhodes P (1993) Age-specific differences in the relationship between oral contraceptive use and breast cancer. Cancer 71(S4):1506–1517
Hilakivi-Clarke L, Wärri A, Bouker KB, Zhang X, Cook KL, Jin L, Zwart A, Nguyen N, Hu R, Cruz MI, de Assis S, Wang X, Xuan J, Wang Y, Wehrenberg B, Clarke R (2017) Effects of in utero exposure to ethinyl estradiol on tamoxifen resistance and breast cancer recurrence in a preclinical model. J Natl Cancer Inst 109(1.) p.djw188
American Cancer Society (ACS) (2015) Menopausal hormone therapy and cancer risk. American Cancer Society, Inc., Atlanta
NTP National Toxicology Program (2011) Diethylstilbestrol. 12th Report on Carcinogens 12:159–161
IARC (2012) Diethylstilbestrol. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum 100A:175–218
Reed CE, Fenton SE (2013) Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects. Birth Defects Res C Embryo Today 99(2):134
Palmer JR, Wise LA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter W, Kaufman R, Herbst AL, Noller KL, Hyer M, Hoover RN (2006) Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 15(8):1509–1514
Hovey RC, Asai-Sato M, Warri A, Terry-Koroma B, Colyn N, Ginsburg E, Vonderhaar BK (2005) Effects of neonatal exposure to diethylstilbestrol, tamoxifen, and toremifene on the BALB/c mouse mammary gland. Biol Reprod 72(2):423–435
NTP National Toxicology Program (2008) Toxicology and carcinogenesis studies of genistein (cas no. 446-72-0) in Sprague-Dawley rats (feed study). National Toxicology Program Technical Report Series, vol (545), p 1
Strom BL, Schinnar R, Ziegler EE, Barnhart KT, Sammel MD, Macones GA, Stallings VA, Drulis JM, Nelson SE, Hanson SA (2001) Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA 286(7):807–814
Spagnuolo C, Russo GL, Orhan IE, Habtemariam S, Daglia M, Sureda A, Nabavi SF, Devi KP, Loizzo MR, Tundis R, Nabavi SM (2015) Genistein and cancer: current status, challenges, and future directions. Adv Nutr 6(4):408
Lamartiniere CA, Zhang JX, Cotroneo MS (1998) Genistein studies in rats: potential for breast cancer prevention and reproductive and developmental toxicity. American Society for Clinical Nutrition, Inc., United States
Hilakivi-Clarke L, Onojafe I, Raygada M, Cho E, Skaar T, Russo I, Clarke R (1999) Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis. Br J Cancer 80(11):1682–1688
Delclos KB, Bucci TJ, Lomax LG, Latendresse JR, Warbritton A, Weis CC, Newbold RR (2001) Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reprod Toxicol 15(6):647–663
Cabanes A, Wang M, Olivo S, DeAssis S, Gustafsson J, Khan G, Hilakivi-Clarke L (2004) Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis 25(5):741–748
Caëtano B, Le Corre L, Chalabi N, Delort L, Bignon Y, Bernard-Gallon DJ (2006) Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines. Br J Nutr 95(2):406
Hilakivi-Clarke L, Cho E, Clarke R (1998) Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring. Oncol Rep 5(3):609–616
Hilakivi-Clarke L, Cho E, Cabanes A, DeAssis S, Olivo S, Helferich W, Lippman MC, Clarke R (2002) Dietary modulation of pregnancy estrogen levels and breast cancer risk among female rat offspring. Clin Cancer Res 8(11):3601–3610
Foster WG, Younglai EV, Boutross-Tadross O, Hughes CL, Wade MG (2004) Mammary gland morphology in Sprague-Dawley rats following treatment with an organochlorine mixture in utero and neonatal genistein. Toxicol Sci 77(1):91–100
Latendresse JR, Bucci TJ, Olson G, Mellick P, Weis CC, Thorn B, Newbold RR, Delclos KB (2009) Genistein and ethinyl estradiol dietary exposure in multigenerational and chronic studies induce similar proliferative lesions in mammary gland of male Sprague–Dawley rats. Reprod Toxicol 28(3):342–353
vom Saal FS, Nagel SC, Coe BL, Angle BM, Taylor JA (2012) The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity. Mol Cell Endocrinol 354(1–2):74–84
Voelkel W, Colnot T, Csanady G, Filser J, Dekant W (2002) Metabolism and kinetics of bisphenol A in humans at low doses following oral administration. Chem Res Toxicol 15(10):1281–1287
Durando M, Kass L, Piva J, Sonnenschein C, Soto AM, Luque EH, Muñoz-de-Toro M (2007) Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats. Environ Health Perspect 115(1):80–86
Markey CM, Luque EH, de Toro MM, Sonnenschein C, Soto AM (2001) In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod 65(4):1215–1223
Muñoz-de-Toro M, Markey CM, Wadia PR, Luque EH, Rubin BS, Sonnenschein C, Soto AM (2005) Perinatal exposure to bisphenol-A alters peripubertal mammary gland development in mice. Endocrinology 146(9):4138–4147
Murray TJ, Maffini MV, Ucci AA, Sonnenschein C, Soto AM (2007) Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reprod Toxicol 23(3):383–390
Vandenberg LN, Maffini MV, Schaeberle CM, Ucci AA, Sonnenschein C, Rubin BS, Soto AM (2008) Perinatal exposure to the xenoestrogen bisphenol-A induces mammary intraductal hyperplasias in adult CD-1 mice. Reprod Toxicol 26(3):210–219
Shelby MD (2008) NTP-CERHR monograph on the potential human reproductive and developmental effects of bisphenol A. NTP CERHR MON (22):v-v
Acevedo N, Davis B, Schaeberle CM, Sonnenschein C, Soto AM (2013) Perinatally administered bisphenol a as a potential mammary gland carcinogen in rats. Environ Health Perspect 121(9):1040–1046
Mandrup K, Boberg J, Isling LK, Christiansen S, Hass U (2016) Low-dose effects of bisphenol A on mammary gland development in rats. Andrology 4(4):673–683
NTP National Toxicology Program (2008) NTP-CERHR monograph on the potential human reproductive and developmental effects of bisphenol A. RTP, NC 27709
FDA (2016) Bisphenol A (BPA): use in food contact application. http://www.fda.gov/newsevents/publichealthfocus/ucm064437.htm
EFSA. European Food Safety Authority (2015) Scientific opinion on bisphenol A (2015). https://www.efsa.europa.eu/sites/default/files/corporate_publications/files/factsheetbpa150121.pdf
Vandenberg LN, Prins GS (2016) Clarity in the face of confusion: new studies tip the scales on bisphenol A(BPA). Andrology 4:561–564
Bhargava HN, Leonard PA (1996) Triclosan: applications and safety. Am J Infect Control 24:209–218
Halden RU, Paull DH (2005) Co-occurrence of triclocarban and triclosan in U.S. water resources. Environ Sci Technol 39(6):1420–1426
Sandborgh-Englund G, Adolfsson-Erici M, Odham G, Ekstrand J (2006) Pharmacokinetics of triclosan following oral ingestion in humans. J Toxicol Environ Health A 69:1861–1873
Adolfsson-Erici M, Pettersson M, Parkkonen J, Sturve J (2002) Triclosan, a commonly used bactericide found in human milk and in the aquatic environment in Sweden. Chemosphere 46:1485–1489
Calafat XY, Wong L, Reidy JA, Needham LL (2008) Urinary concentrations of triclosan in the U.S. population: 2003–2004 Antonia M. Environ Health Perspect 116(3):303–307
Allmyr M, Adolfsson-Erici M, McLachlan MS, Sandborgh Englund G (2006) Triclosan in plasma and milk from Swedish nursing mothers and their exposure via personal care products. Sci Total Environ 372:87–93
Crofton KM, Paul KB, Devito MJ, Hedge JM (2007) Short-term in vivo exposure to the water contaminant triclosan: evidence for disruption of thyroxine. Environ Toxicol Pharmacol 24(2):194–197
Gee RH, Charles A, Taylor N, Darbre PD (2008) Oestrogenic and androgenic activity of triclosan in breast cancer cells. J Appl Toxicol 28:78–91
Stoker TE, Gibson EK, Zorrilla LM (2010) Triclosan exposure modulates estrogen-dependent responses in the female Wistar rat. Toxicol Sci 117(1):45–53
Darbre PD, Charles AK (2010) Environmental oestrogens and breast cancer: evidence for combined involvement of dietary, household and cosmetic xenoestrogens. Anticancer Res 30(3):815
Dinwiddie MT, Terry PD, Chen J (2014) Recent evidence regarding triclosan and cancer risk. Int J Environ Res Public Health 11(2):2209–2209
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm378542.htm
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm517478.htm
US EPA (2000) Reregistration eligibility decision (RED) vinclozolin. Office of Prevention, Pesticides and Toxic Substances. US Environmental Protection Agency
Kelce WR, Monosson E, Gamcsik MP, Laws SC, Gray LEJ (1994) Environmental hormone disruptors: evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites. Toxicol Appl Pharmacol 126:276–285
Monosson E, Kelce WR, Lambright C, Ostby J, Gray LE Jr (1999) Peripubertal exposure to the antiandrogenic fungicide, vinclozolin, delays puberty, inhibits the development of androgen-dependent tissues, and alters androgen receptor function in the male rat. Toxicol Ind Health 15:65–79
Gray LE Jr, Ostby J, Furr J, Wolf CJ, Lambright C, Parks L, Veeramachaneni DN, Wilson V, Price M, Hotchkiss A, Orlando E, Guillette L (2001) Effects of environmental antiandrogens on reproductive development in experimental animals. Hum Reprod 7:248–264
Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, Hass U (2009) Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environ Health Perspect 117:1839–1846
Yeh S, Hu YC, Wang P, Xie C, Xu Q, Tsai M, Dong Z, Wang R, Lee T, Chang C (2003) Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor. J Exp Med 198:1899–1908
Irigaray P, Newby JA, Clapp R, Hardell L, Howard V, Montagnier L, Epstein S, Belpomme D (2007) Lifestyle-related factors and environmental agents causing cancer: an overview. Biomed Pharmacother 61:640–658
Guerrero-Bosagna C, Settles M, Lucker BJ, Skinner MK (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS One 5:e13100
Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308:1466–1469
Anway MD, Leathers C, Skinner MK (2006) Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147(12):5515–5523
El Sheikh Saad H, Meduri G, Phrakonkham P, Bergès R, Vacher S, Djallali M, Auger J, Canivenc-Lavier MC, Perrot-Applanat M (2011) Abnormal peripubertal development of the rat mammary gland following exposure in utero and during lactation to a mixture of genistein and the food contaminant vinclozolin. Reprod Toxicol 32(1):15–25
El Sheikh Saad H, Toullec A, Vacher S, Pocard M, Bieche I, Perrot-Applanat M (2013) In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland. J Endocrinol 216(2):245–263
Knower KC, To, S. Q, Leung YK, Ho SM, Clyne CD (2014) Endocrine disruption of the epigenome: a breast cancer link. Endocr Relat Cancer 21:T33–T55
Rudel RA, Ackerman JM, Attfield KR, Brody JG (2014) New exposure biomarkers as tools for breast cancer epidemiology, biomonitoring, and prevention: a systematic approach based on animal evidence. National Institute of Environmental Health Sciences, United States
Emond C, DeVito M, Warner M, Eskenazi B, Mocarelli P, Birnbaum LS (2016) An assessment of dioxin exposure across gestation and lactation using a PBPK model and new data from seveso. Environ Int 92–93:23–32
Bruner-Tran KL, Gnecco J, Ding T, Glore DR, Pensabene V, Osteen KG (2016) Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: translating lessons from murine models. Reprod Toxicol 68:59–71
Safe SH (1995) Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. Pharmacol Ther 67(2):247–281
Rogers JM, Denison MS (2002) Analysis of the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human ovarian carcinoma BG-1 cells. Mol Pharmacol 61(6):1393–1403
Brown N, Manzolillo P, Zhang J, Wang J, Lamartiniere C (1998) Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis 19(9):1623–1629
Fenton S, Hamm J, Birnbaum L, Youngblood G (2002) Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Sci 67(1):63–74
Vorderstrasse BA, Fenton SE, Bohn AA, Cundiff JA, Lawrence B (2004) A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation. Toxicol Sci 78(2):248–257
Lew BJ, Collins LL, O’Reilly MA, Lawrence BP (2009) Activation of the aryl hydrocarbon receptor during different critical windows in pregnancy alters mammary epithelial cell proliferation and differentiation. Toxicol Sci 111(1):151–162
Warner M, Mocarelli P, Samuels S, Needham L, Brambilla P, Eskenazi B (2011) Dioxin exposure and cancer risk in the seveso women’s health study. Environ Health Perspect 119(12):1700–1705
Warner M, Eskenazi B, Mocarelli P, Gerthoux PM, Samuels S, Needham L, Patterson D, Brambilla P (2002) Serum dioxin concentrations and breast cancer risk in the seveso women’s health study. Environ Health Perspect 110(7):625–628
Leijs MM, Koppe JG, Olie K, Aalderen WMC v, Voogt P d, Vulsma T, Westra M, ten Tusscher GW (2008) Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study. Chemosphere 73(6):999–1004
Pup LD, Mantovani A, Cavaliere C, Facchini G, Luce A, Sperlongano P, Caraglia M, Berretta M (2016) Carcinogenetic mechanisms of endocrine disruptors in female cancers (review). Oncol Rep 36(2):603–612
IARC (1993) Monographs on the Evaluation of the carcinogenic risk of chemicals to humans. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. International Agency for Research on Cancer, Lyon, France
Garcia-Morales P, Saceda M, Kenney N, Kim N, Salomon DS, Gottardis MM, Solomon HB, Sholler PF, Jordan VC, Martin MB (1994) Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. J Biol Chem 269(24):16896
Martin MB, Reiter R, Trock B, Paik S, Lirio AA, Kenney N, Stoica A, Foss C, Chepko G, Singh B, Hilakivi-Clarke L, Clarke R, Sholler PF, Johnson MD (2003) Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med 9(8):1081–1084
Davis J, Khan G, Martin MB, Hilakivi-Clarke L (2013) Effects of maternal dietary exposure to cadmium during pregnancy on mammary cancer risk among female offspring. J Carcinog 12(1):11–11
Öhrvik H, Yoshioka M, Oskarsson A, Tallkvist J, Sveriges lantbruksuniversitet (2006) Cadmium-induced disturbances in lactating mammary glands of mice. Toxicol Lett 164(3):207–213
Fenga C (2016) Occupational exposure and risk of breast cancer. Biomed Rep 4(3):282–292
Lin J, Zhang F, Lei Y (2016) Dietary intake and urinary level of cadmium and breast cancer risk: a meta-analysis. Cancer Epidemiol 42:101–107
Filgo AJ, Quist EM, Hoenerhoff MJ, Brix AE, Kissling GE, Fenton SE (2015) Perfluorooctanoic acid (PFOA)–induced liver lesions in two strains of mice following developmental exposures: PPARα is not required. Toxicol Pathol 43(4):558–568
Olsen GW, Burris JM, Ehresman DJ, Froehlich JW, Seacat AM, Butenhoff JL, Zobel LR (2007) Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect 115(9):1298–1305
Lau C (2012) Perfluorinated compounds. Springer Basel, Basel, pp 47–86
Yang C, Tan YS, Harkema JR, Haslam SZ (2009) Differential effects of peripubertal exposure to perfluorooctanoic acid on mammary gland development in C57Bl/6 and Balb/c mouse strains. Reprod Toxicol 27(3):299–306
Macon MB, Villanueva LR, Tatum-Gibbs K, Zehr RD, Strynar MJ, Stanko JP, White SS, Helfant L, Fenton SE (2011) Prenatal perfluorooctanoic acid exposure in CD-1 mice: low-dose developmental effects and internal dosimetry. Toxicol Sci 122(1):134–145
White SS, Stanko JP, Kato K, Calafat AM, Hines EP, Fenton SE (2011) Gestational and chronic low-dose PFOA exposures and mammary gland growth and differentiation in three generations of CD-1 mice. Environ Health Perspect 119(8):1070–1076
Tucker DK, Macon MB, Strynar MJ, Dagnino S, Andersen E, Fenton SE (2015) The mammary gland is a sensitive pubertal target in CD-1 and C57Bl/6 mice following perinatal perfluorooctanoic acid (PFOA) exposure. Reprodu Toxicol 54:26–36
Zhao Y, Tan YS, Haslam SZ, Yang C (2010) Perfluorooctanoic acid effects on steroid hormone and growth factor levels mediate stimulation of peripubertal mammary gland development in C57BL/6 mice. Toxicol Sci 115(1):214–224
Bonefeld-Jorgensen EC, Long M, Bossi R, Ayotte P, Asmund G, Krüger T, Ghisari M, Mulvad G, Kern P, Nzulumiki P, Dewailly E (2011) Perfluorinated compounds are related to breast cancer risk in greenlandic inuit: a case control study. Environ Health 10(1):88
US EPA (2016) Drinking water health advisory for perfluorooctanoic acid (PFOA). Office of Water. US Environmental Protection Agency
IARC (2016) Monograph on the evaluation of carcinogenic risk to humans: some chemicals used as solvents and in polymer manufacture. International Agency for Research on Cancer, Lyon, France
IARC (1999) Monograph on the evaluation of carcinogenic risk to humans: occupational exposure in insecticide application and some Pesticides. International Agency for Research on Cancer, Lyon, France
Cooper RL, Laws SC, Das PC, Narotsky MG, Goldman JM, Tyrey EL, Stoker TE (2007) Atrazine and reproductive function: mode and mechanism of action studies. Birth Defects Res B Dev Reprod Toxicol 80(2):98–112
Rayner JL, Wood C, Fenton SE (2004) Exposure parameters necessary for delayed puberty and mammary gland development in Long–Evans rats exposed in utero to atrazine. Toxicol Appl Pharmacol 195(1):23–34
Rayner JL, Enoch RR, Fenton SE (2005) Adverse effects of prenatal exposure to atrazine during a critical period of mammary gland growth. Toxicol Sci 87(1):255–266
Wetzel L, Luempert LI, Breckenridge C, Tisdel M, Stevens J, Thakur A, Extrom P, Eldridge J (1994) Chronic effects of atrazine on estrus and mammary tumor formation in female Sprague-Dawley and Fischer 344 rats. J Toxicol Environ Health 43(2):169–182
Wirbisky SE, Freeman JL (2015) Atrazine exposure and reproductive dysfunction through the hypothalamus-pituitary-gonadal (HPG) axis. Toxics 3(4):414–450
US EPA (2003) Memorandum. Review of atrazine cancer epidemiology, DP Barcode D2950200, chemical #080803. Office of Prevention, Pesticides and Toxic Substances. US Environmental Protection Agency
Rayner JL, Fenton SE (2011) Atrazine: an environmental endocrine disruptor that alters mammary gland development and tumor susceptibility. Springer New York, New York, NY, pp 167–183
Knudson AG (1996) Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol 122(3):135–140
NTP (National Toxicology Program) (2016) Report on carcinogens, 14th edn. U.S. Department of Health and Human Services, Public Health Service, Research Triangle Park, NC. http://ntp.niehs.nih.gov/go/roc14/
Nguyen D, Oketch-Rabah H, Illa-Bochaca I, Geyer F, Reis-Filho J, Mao J, Ravani S, Zavadil J, Borowsky A, Jerry D, Dunphy K, Seo J, Haslam S, Medina D, Barcellos-Hoff M (2011) Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 19(5):640–651
Osborne G, Rudel R, Schwarzman M (2015) Evaluating chemical effects on mammary gland development: a critical need in disease prevention. Reprod Toxicol 54:148–155
Vandenberg LN, Schaeberleb CM, Rubinb BS, Sonnenscheinb C, Soto AM (2013) The male mammary gland: a target for the xenoestrogen bisphenol A. Reprod Toxicol 37:15–23
Diamanti-Kandarakis E, Jean-Pierre Bourguignon J-E, Gore AC (2009) Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocr Rev 30(4):293–342
Pinter A, Torok G, Borzsonyi M, Surjan A, Calk M, Kelecsenvi Z, Kocsis Z (1990) Long-term carcinogenicity bioassay of the herbicide atrazine in F344 rats. Neoplasma 37(5):533–544
Brown NM, Lamartiniere CA (1995) Xenoestrogens alter mammary gland differentiation and cell proliferation in the rat. Environ Health Perspect 103:708–713
Jenkins S, Rowell C, Wang J, Lamartiniere CA (2007) Prenatal TCDD exposure predisposes for mammary cancer in rats. Reprod Toxicol 23:391–396
Radisky DC, Hartmann LC (2009) Mammary involution and breast cancer risk: transgenic models and clinical studies. J Mammary Gland Biol Neoplasia 14:181–191
Simpkins JW, Swenberg JA, Weiss N, Brusick D, Eldridge JC, Stevens JT, Handa RJ, Hovey RC, Plant TM, Pastoor TP, Breckenridge CB (2011) Atrazine and breast cancer: a framework assessment of the toxicological and epidemiological evidence. Toxicol Sci 123(2):441–459
IARC (International Agency for Research on Cancer) (1997) Polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans. IARC Monogr Eval Carcinog Risks Hum 69
Steenland K, Bertazzi P, Baccarelli A, Kogevinas M (2004) Dioxin revisited: developments since the 1997 IARC classification of dioxin as a human carcinogen. Environ Health Perspect 112(13):1265–1268
Boffetta P, Mundt KA, Adami HO, Cole P, Mandel JS (2011) TCDD and cancer: a critical review of epidemiologic studies. Crit Rev Toxicol 41(7):622–636. (review)
Herbst AL, Ulfelder H, Poskanzer DC (1971) Adenocarcinoma of the vagina: Association of Maternal Stilbestrol Therapy with tumor appearance in young women. N Engl J Med 284(16):878–881
Bromer JG, Zhou Y, Taylor MB, Doherty L, Taylor HS (2010) Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J 24(7):2273–2280
Bromer JG, Wu J, Zhou Y, Taylor HS (2009) Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: an epigenetic mechanism for altered developmental programming. Endocrinology 150(7):3376–3382
Haynes BA, Mookadam F (2009) Male gynecomastia. Mayo Clin Proc 84(8):672–672
Felner EL, White PC (2000) Prepubertal gynecomastia: indirect exposure to estrogen cream. Pediatrics 105(4):e55–E55
Henley DV, Lipson N, Korach KS, Bloch CA (2007) Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med 356(5):479–485
Thayer KA, Foster PM (2007) Workgroup Report: National Toxicology Program Workshop on hormonally induced reproductive tumors: relevance of rodent bioassays. Environ Health Perspect 115(9):1351–1356
Rudel RA, Attfield KR, Schifano JN, Brody JG (2007) Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention. Cancer 109:2635–2666
Cohn BA, Wolff MS, Cirillo PM, Sholtz RI (2007) DDT and breast cancer in young women: new data on the significance of age at exposure. Environ Health Perspect 115(10):1406–1414
Ly D, Forman D, Ferlay J, Brinton LA, Cook MB (2013) An international comparison of male and female breast cancer incidence rates. Int J Cancer 132(8):1918–1926
Skinner MK (2007) Endocrine disruptors and epigenetic transgenerational disease etiology. Pediatr Res 61:48R–50R
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media New York
About this protocol
Cite this protocol
Filgo, A.J., Faqi, A.S. (2017). Effects of Chemicals on Mammary Gland Development. In: Faqi, A. (eds) Developmental and Reproductive Toxicology. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/7653_2017_69
Download citation
DOI: https://doi.org/10.1007/7653_2017_69
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-7206-7
Online ISBN: 978-1-4939-7208-1
eBook Packages: Springer Protocols