Advertisement

Hormones and Cancer

, Volume 7, Issue 4, pp 241–251 | Cite as

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

  • Catha Fischer
  • Ramanaiah MamillapalliEmail author
  • Laura G. Goetz
  • Elisa Jorgenson
  • Ysabel Ilagan
  • Hugh S. Taylor
Original Paper

Abstract

Bisphenol-A (BPA) is a ubiquitous estrogen-like endocrine disrupting compound (EDC). BPA exposure in utero has been linked to breast cancer and abnormal mammary gland development in mice. The recent rise in incidence of human breast cancer and decreased age of first detection suggests a possible environmental etiology. We hypothesized that developmental programming of carcinogenesis may involve an aberrant immune response. Both innate and adaptive immunity play a role in tumor suppression through cytolytic CD8, NK, and Th1 T-cells. We hypothesized that BPA exposure in utero would lead to dysregulation of both innate and adaptive immunity in the mammary gland. CD1 mice were exposed to BPA in utero during gestation (days 9–21) via osmotic minipump. At 6 weeks, the female offspring were ovariectomized and estradiol was given at 8 weeks. RNA and protein were extracted from the posterior mammary glands, and the mRNA and protein levels were measured by PCR array, qRT-PCR, and western blot. In mouse mammary tissue, BPA exposure in utero significantly decreased the expression of members of the chemokine CXC family (Cxcl2, Cxcl4, Cxcl14, and Ccl20), interleukin 1 (Il1) gene family (Il1β and Il1rn), interleukin 2 gene family (Il7 receptor), and interferon gene family (interferon regulatory factor 9 (Irf9), as well as immune response gene 1 (Irg1). Additionally, BPA exposure in utero decreased Esr1 receptor gene expression and increased Esr2 receptor gene expression. In utero exposure of BPA resulted in significant changes to inflammatory modulators within mammary tissue. We suggest that dysregulation of inflammatory cytokines, both pro-inflammatory and anti-inflammatory, leads to a microenvironment that may promote disordered cell growth through inhibition of the immune response that targets cancer cells.

Keywords

Mammary Gland Breast Cancer Risk Mammary Tissue Interferon Regulatory Factor Estradiol Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Human and Animal Rights and Informed Consent

All animal experiments were conducted in accordance with the Yale University Animal Care Committee Guidelines.

Funding

This work was supported by NIH Grant RO1 HD076422.

Conflict of Interest

The authors declare that they have no conflicts of interests.

Supplementary material

12672_2016_254_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 20 kb)
12672_2016_254_Fig5_ESM.jpg (325 kb)
Fig. S5

(JPG 324 kb)

References

  1. 1.
    Ehrlich S, Calafat AM, Humblet O, Smith T, Hauser R (2014) Handling of thermal receipts as a source of exposure to bisphenol A. JAMA 311:859–860CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Rubin BS (2011) Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol 127:27–34CrossRefPubMedGoogle Scholar
  3. 3.
    Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJ, Schoenfelder G (2010) Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspect 118:1055–1070CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Richter CA, Taylor JA, Ruhlen RL, Welshons WV, Vom Saal FS (2007) Estradiol and Bisphenol A stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate mesenchyme cells. Environ Health Perspect 115:902–908CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Liao C, Kannan K (2011) Widespread occurrence of bisphenol A in paper and paper products: implications for human exposure. Environ Sci Technol 45:9372–9379CrossRefPubMedGoogle Scholar
  6. 6.
    Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL (2008) Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ Health Perspect 116:39–44CrossRefPubMedGoogle Scholar
  7. 7.
    Rochester JR (2013) Bisphenol A and human health: a review of the literature. Reprod Toxicol 42:132–155CrossRefPubMedGoogle Scholar
  8. 8.
    De Coster S, van Larebeke N (2012) Endocrine-disrupting chemicals: associated disorders and mechanisms of action. J Environ Public Health 2012:713696CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gerona RR, Woodruff TJ, Dickenson CA, Pan J, Schwartz JM, Sen S, Friesen MW, Fujimoto VY, Hunt PA (2013) Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in mid gestation umbilical cord serum in a northern and central California population. Environ Sci Technol 47:12477–12485CrossRefPubMedGoogle Scholar
  10. 10.
    Corbel T, Gayrard V, Viguie C, Puel S, Lacroix MZ, Toutain PL, Picard-Hagen N (2013) Bisphenol A disposition in the sheep maternal-placental-fetal unit: mechanisms determining fetal internal exposure. Biol Reprod 89:11CrossRefPubMedGoogle Scholar
  11. 11.
    Nishikawa M, Iwano H, Yanagisawa R, Koike N, Inoue H, Yokota H (2010) Placental transfer of conjugated bisphenol A and subsequent reactivation in the rat fetus. Environ Health Perspect 118:1196–1203CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Calhoun KC, Padilla-Banks E, Jefferson WN, Liu L, Gerrish KE, Young SL, Wood CE, Hunt PA, Vandevoort CA, Williams CJ (2014) Bisphenol A exposure alters developmental gene expression in the fetal rhesus macaque uterus. PLoS One 9, e85894CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Horstman KA, Naciff JM, Overmann GJ, Foertsch LM, Richardson BD, Daston GP (2012) Effects of transplacental 17-alpha-ethynyl estradiol or bisphenol A on the developmental profile of steroidogenic acute regulatory protein in the rat testis. Birth Defects Res B Dev Reprod Toxicol 95:318–325CrossRefPubMedGoogle Scholar
  14. 14.
    Elsworth JD, Jentsch JD, Vandevoort CA, Roth RH, Jr DE, Leranth C (2013) Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates. Neurotoxicology 35:113–120CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wolstenholme JT, Edwards M, Shetty SR, Gatewood JD, Taylor JA, Rissman EF, Connelly JJ (2012) Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. Endocrinology 153:3828–3838CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chapalamadugu KC, Vandevoort CA, Settles ML, Robison BD, Murdoch GK (2014) Maternal bisphenol a exposure impacts the fetal heart transcriptome. PLoS One 9:e89096CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Susiarjo M, Hassold TJ, Freeman E, Hunt PA (2007) Bisphenol A exposure in utero disrupts early oogenesis in the mouse. PLoS Genet 3:e5CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hijazi A, Guan H, Cernea M, Yang K (2015) Prenatal exposure to bisphenol A disrupts mouse fetal lung development. FASEB J 12:4968–4977CrossRefGoogle Scholar
  19. 19.
    Tharp AP, Maffini MV, Hunt PA, VandeVoort CA, Sonnenschein C, Soto AM (2012) Bisphenol A alters the development of the rhesus monkey mammary gland. Proc Natl Acad Sci U S A 109:8190–8195CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM (2007) Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland. Endocrinology 148:116–127CrossRefPubMedGoogle Scholar
  21. 21.
    Munoz de Toro MM, Markey CM, Wadia PR, Luque EH, Rubin BS et al (2005) Perinatal exposure to bisphenol A alters peripubertal mammary gland development in mice. Endocrinology 146:4138–4147CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Markey CM, Luque EH, Munoz 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 65:1215–1223PubMedGoogle Scholar
  23. 23.
    Fenton SE (2006) Endocrine-disrupting compounds and mammary gland development: early exposure and later life consequences. Endocrinology 147:S18–S24CrossRefPubMedGoogle Scholar
  24. 24.
    Ayyanan A, Laribi O, Schuepbach-Mallepell S, Schrick C, Gutierrez M et al (2011) Perinatal exposure to bisphenol a increases adult mammary gland progesterone response and cell number. Mol Endocrinol 25:1915–1923CrossRefPubMedGoogle Scholar
  25. 25.
    Li X, Xie W, Xie C, Huang C, Zhu J, Liang Z, Deng F, Zhu M, Zhu W, Wu R, Wu J, Geng S, Zhong C (2014) Curcumin modulates miR-19/PTEN/AKT/p53 axis to suppress bisphenol A-induced MCF-7 breast cancer cell proliferation. Phytother Res 28:1553–1560CrossRefPubMedGoogle Scholar
  26. 26.
    Pupo M, Pisano A, Lappano R, Santolla MF, De Francesco EM, Abonante S, Rosano C, Maggiolini M (2012) Bisphenol A induces gene expression changes and proliferative effects through GPER in breast cancer cells and cancer-associated fibroblasts. Environ Health Perspect 120:1177–1182CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wadia PR, Cabaton NJ, Borrero MD, Rubin BS, Sonnenschein C et al (2013) Low-dose BPA exposure alters the mesenchymal and epithelial transcriptomes of the mouse fetal mammary gland. PLoS One 8, e63902CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Paulose T, Speroni L, Sonnenschein C, Soto AM (2015) Estrogens in the wrong place at the wrong time: fetal BPA exposure and mammary cancer. Reprod Toxicol 54:58–65CrossRefPubMedGoogle Scholar
  29. 29.
    Vandenberg LN, Maffini MV, Schaeberle CM, Ucci AA, Sonnenschein C et al (2008) Perinatal exposure to the xenoestrogen bisphenol-A induces mammary intraductal hyperplasias in adult CD-1 mice. Reprod Toxicol 26:210–219CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    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 23:383–390CrossRefPubMedGoogle Scholar
  31. 31.
    Durando M, Kass L, Piva J, Sonnenschein C, Soto AM et al (2007) Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats. Environ Health Perspect 115:80–86CrossRefPubMedGoogle Scholar
  32. 32.
    Lamartiniere CA, Jenkins S, Betancourt AM, Wang J, Russo J (2011) Exposure to the endocrine disruptor Bisphenol A alters susceptibility for mammary cancer. Horm Mol Biol Clin Invest 5:45–52Google Scholar
  33. 33.
    Crain DA, Janssen SJ, Edwards TM et al (2008) Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril 90:911–940CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Soto AM, Brisken C, Schaeberle C, Sonnenschein C (2013) Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors. J Mammary Gland Biol Neoplasia 18:199–208CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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 24:2273–2280CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    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 150:3376–3382CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lacobuzio-Donahue CA (2009) Epigenetic changes in cancer. Annu Rev Pathol 4:229–249CrossRefGoogle Scholar
  38. 38.
    Cipelli R, Harries L, Okuda K et al (2014) Bisphenol A modulates the metabolic regulator oestrogen-related receptor-α in T-cells. Reproduction 147:419–426CrossRefPubMedGoogle Scholar
  39. 39.
    Barr A, Manning D (1999) G Proteins Techniques of Analysis, Manning DR, ed. Boca Raton, FL: CRC Press, Inc. 227–245. 48. Mi H, Dong Q, Muruganujan A, Gaudet P, Lewis S, Thomas PDGoogle Scholar
  40. 40.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  41. 41.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  42. 42.
    Markey CM, Wadia PR, Rubin BS et al (2005) Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract. Biol Reprod 72:1344–1351CrossRefPubMedGoogle Scholar
  43. 43.
    Moral R, Wang R, Russo IH, Lamartiniere CA, Pereira J, Russo J (2008) Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature. J Endocrinol 196:101–112CrossRefPubMedGoogle Scholar
  44. 44.
    Owen JL, Criscitiello MF, Libreros S et al (2011) Expression of the inflammatory chemokines CCL2, CCL5 and CXCL2 and the receptors CCR1-3 and CXCR2 in T lymphocytes from mammary tumor-bearing mice. Cell Immunol 270:172–182CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Biondo C, Mancuso G, Midiri A (2014) The IL-1beta/CXCL1/2/neutrophil axis mediates host protection against group B streptococcal infection. Infect Immun 82:4508–4517CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kurth I, Willimann K, Schaerli P, Hunziker T, Clark-Lewis I, Moser B (2001) Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development. J Exp Med 194:855–861CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Shurin GV, Ferris R, Tourkova IL, Perez L, Lokshin A, Balkir L, Collins B, Chatta GS, Shurin MR (2005) Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. J Immun 174:5490–5498CrossRefPubMedGoogle Scholar
  48. 48.
    Kozai TD, Li X, Bodily LM et al (2014) Effects of caspase-1 knockout on chronic neural recording quality and longevity: insight into cellular and molecular mechanisms of the reactive tissue response. Biomaterials 35:9620–9634CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ubertini V, Norelli G, D’Arcangelo D et al (2014) Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist. Oncogene 34:2493–2504CrossRefPubMedGoogle Scholar
  50. 50.
    Normanton M, Alvarenga H, Hamerschlak N et al (2014) Interleukin 7 plays a role in T Lymphocyte apoptosis inhibition driven by mesenchymal stem cell without favoring proliferation and cytokines secretion. PLoS One 9:e106673CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ribeiro D, Melao A, Barata JT (2013) IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia. Adv Biol Regul 53:211–222CrossRefPubMedGoogle Scholar
  52. 52.
    Chen HZ, Guo S, Li ZZ et al (2014) A critical role for interferon regulatory factor 9 in cerebral ischemic stroke. J Neurosci 34:11897–11912CrossRefPubMedGoogle Scholar
  53. 53.
    Michelucci A, Cordes T, Ghelfi J et al (2013) Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A 110:7820–7825CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wang PX, Zhang R, Huang L (2014) Interferon regulatory factor 9 is a key mediator of hepatic ischemia/reperfusion injury. J Hepat 62:111–120CrossRefGoogle Scholar
  55. 55.
    Hall CJ, Boyle RH, Astin JW et al (2013) Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. Cell Metab 18:265–278CrossRefPubMedGoogle Scholar
  56. 56.
    Asztalos S, Gann PH, Hayes MK et al (2010) Gene expression patterns in the human breast after pregnancy. Cancer Prev Res (Phila) 3:301–311CrossRefGoogle Scholar
  57. 57.
    Balfe P, McCann A, McGoldrick A et al (2004) Estrogen receptor alpha and beta profiling in human breast cancer. Eur J Surg Oncol 30:469–474CrossRefPubMedGoogle Scholar
  58. 58.
    Baek JM, Chae BJ, Song BJ (2015) The potential role of estrogen receptor β2 in breast cancer. Int J Surg 14:17–22CrossRefPubMedGoogle Scholar
  59. 59.
    Hu YF, Lau KM, Ho SM et al (1998) Increased expression of estrogen receptor beta in chemically transformed human breast epithelial cells. Int J Oncol 12:1225–1228PubMedGoogle Scholar
  60. 60.
    Chen Y, Chen L, Li JY et al (2011) ERbeta and PEA3 co-activate IL-8 expression and promote the invasion of breast cancer cells. Cancer Biol Ther 11:497–511CrossRefPubMedGoogle Scholar
  61. 61.
    Williams C, Edvardsson K, Lewandowski SA et al (2008) A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells. Oncogene 27:1019–1032CrossRefPubMedGoogle Scholar
  62. 62.
    Polanczyk M, Yellayi S, Zamora A et al (2004) Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice. Am J Pathol 164:1915–1924CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yakimchuk K, Jondal M, Okret S (2013) Estrogen receptor α and β in the normal immune system and in lymphoid malignancies. Mol Cell Endocrinol 375:121–129CrossRefPubMedGoogle Scholar
  64. 64.
    Melzer D, Harries L, Cipelli R et al (2011) Bisphenol A exposure is associated with in vivo estrogenic gene expression in adults. Environ Health Perspect 119:1788–1793CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Armstrong CM, Billimek AR, Allred KF et al (2013) Allred CDA novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation. Endocr Relat Cancer 20:515–525CrossRefPubMedGoogle Scholar
  66. 66.
    Ashworth JJ, Smyth JV, Pendleton N et al (2008) Polymorphisms spanning the 0N exon and promoter of the estrogen receptor-beta (ERbeta) gene ESR2 are associated with venous ulceration. Clin Genet 73:55–61CrossRefPubMedGoogle Scholar
  67. 67.
    Moore JT, McKee DD, Slentz-Kesler K et al (1998) Cloning and characterization of human estrogen receptor beta isoforms. Biochem Biophys Res Commun 247:75–78CrossRefPubMedGoogle Scholar
  68. 68.
    Poola I, Fuqua SA, Witty RL et al (2005) Estrogen receptor alpha-negative breast cancer tissues express significant levels of estrogen-independent transcription factors, ERbeta1 and ERbeta5: potential molecular targets for chemoprevention. Clin Cancer Res 11:7579–7585CrossRefPubMedGoogle Scholar
  69. 69.
    Welshons WV, Nagel SC, vom Saal FS (2006) Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology 147 S:56–69CrossRefGoogle Scholar
  70. 70.
    Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS (2010) In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer 1:146–155CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Peretz J, Vrooman L, Ricke WA et al (2014) Bisphenol a and reproductive health: update of experimental and human evidence 2007-2013. Environ Health Perspect 122:775–786PubMedPubMedCentralGoogle Scholar
  72. 72.
    Aldad TS, Rahmani N, Leranth C, Taylor HS (2011) Bisphenol-A exposure alters endometrial progesterone receptor expression in the nonhuman primate. Fertil Steril 96:175–179CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Smith CC, Taylor HS (2007) Xenoestrogen exposure imprints expression of genes (Hoxa10) required for normal uterine development. FASEB J 21:239–246CrossRefPubMedGoogle Scholar
  74. 74.
    Akbas GE, Song J, Taylor HS (2004) A HOXA10 estrogen response element (ERE) is differentially regulated by 17 beta-estradiol and diethylstilbestrol (DES). J Mol Biol 340:1013–1023CrossRefPubMedGoogle Scholar
  75. 75.
    Block K, Kardana A, Igarashi P, Taylor HS (2000) In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing müllerian system. FASEB J 200014:1101–1108Google Scholar
  76. 76.
    Kim JH, Sartor MA, Rozek LS et al (2014) Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome. BMC Genomics 15:30CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Nahar MS, Kim JH, Sartor MA, Dolinoy DC (2014) Bisphenol A-associated alterations in the expression and epigenetic regulation of genes encoding xenobiotic metabolizing enzymes in human fetal liver. Environ Mol Mutagen 55:184–195CrossRefPubMedGoogle Scholar
  78. 78.
    Ko KP, Kim SW, Ma SH et al (2013) Dietary intake and breast cancer among carriers and noncarriers of BRCA mutations in the Korean Hereditary Breast Cancer Study. Am J Clin Nutr 98:1493–1501CrossRefPubMedGoogle Scholar
  79. 79.
    Bhan A, Hussain I, Ansari KI, Bobzean SA, Perrotti LI, Mandal SS (2014) Histone methyltransferase EZH2 is transcriptionally induced by estradiol as well as estrogenic endocrine disruptors bisphenol-A and diethylstilbestrol. J Mol Biol 426:3426–3441CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Obstetrics, Gynecology, and Reproductive SciencesYale School of MedicineNew HavenUSA
  2. 2.Department of Molecular, Cellular, and Developmental BiologyYale UniversityNew HavenUSA

Personalised recommendations