Skip to main content
×
Home
    • Aa
    • Aa

Cancer as development gone awry: the case for bisphenol-A as a carcinogen

  • C. Sonnenschein (a1), P. R. Wadia (a1), B. S. Rubin (a1) and A. M. Soto (a1)
  • DOI: http://dx.doi.org/10.1017/S2040174411000043
  • Published online: 23 February 2011
Abstract

The discovery of a rare clear cell carcinoma of the vagina in young women gestationally exposed to the estrogen diethylstilbestrol (DES) lent empirical support to the hypothesis that prenatal exposure to xenoestrogens might cause cancer. This fact contradicted two well-accepted notions: (i) mammalian development was merely the unfolding of a genetic program and (ii) only mutagenic agents could cause cancer. The ecological developmental biology (eco–devo) movement revitalized the concept of developmental plasticity through the occurrence of polyphenisms whereby a single genotype produces diverse phenotypes which are determined by environmental cues. Based on the principles of eco–devo and the tissue organization field theory of carcinogenesis, we hypothesized that developmental exposure to xenoestrogens increased the propensity to develop mammary cancer during adulthood. Bisphenol-A (BPA), a ubiquitous xenoestrogen, was chosen as a model for environmental estrogen exposure. In mice, perinatal exposure to environmentally relevant BPA levels induced alterations of the mammary gland architecture which manifested during fetal morphogenesis and throughout life, including the development of pre-neoplastic lesions. In rats, gestational exposure to BPA induced pre-neoplastic lesions and carcinoma in situ that manifested in adulthood in the absence of any additional treatment. Emerging epidemiological data reveal an increased incidence of breast cancer in women exposed to DES during gestation. Hence, both animal experiments and epidemiological data strengthen the hypothesis that fetal exposure to xenoestrogens may be an underlying cause of the increased incidence of breast cancer observed over the past 50 years.

Copyright
Corresponding author
*Address for correspondence: Dr A. M. Soto, Program in Cellular Molecular and Developmental Biology, Tufts University School of Medicine, Boston, MA 02111, USA. (Emails ana.soto@tufts.edu, cheryl.michaelson@tufts.edu)
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1.CM Markey , MA Coombs , C Sonnenschein , AM Soto . Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evol Dev. 2003; 5, 19.

3.TJ Murray , MV Maffini , AA Ucci , C Sonnenschein , AM Soto . Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reprod Toxicol. 2007; 23, 383390.

4.RR Newbold , E Padilla-Banks , RJ Snyder , WN Jefferson . Developmental exposure to estrogenic compounds and obesity. Birth Defects Res A Clin Mol Teratol. 2005; 73, 478480.

5.BS Rubin , MK Murray , DA Damassa , JC King , AM Soto . Perinatal exposure to low doses of bisphenol-A affects body weight, patterns of estrous cyclicity and plasma LH levels. Environ Health Perspect. 2001; 109, 675680.

10.SF Gilbert . Mechanisms for the environmental regulation of gene expression: ecological aspects of animal development. J Biosci. 2005; 30, 6574.

12.AM Soto , C Sonnenschein . Emergentism as a default: cancer as a problem of tissue organization. J Biosci. 2005; 30, 103118.

14.DJP Barker , MA Hanson . Altered regional blood flow in the fetus: the origins of cardiovascular disease? Acta Paediatricia. 2004; 93, 15591560.

16.DE Ingber . Mechanical control of tissue morphogenesis during embryological development. Int J Dev Biol. 2006; 50, 255266.

17.P Patwari , RT Lee . Mechanical control of tissue morphogenesis. Circ Res. 2008; 103, 234243.

18.AM Soto , C Sonnenschein , P-A Miquel . On physicalism and downward causation in developmental and cancer biology. Acta Biotheor. 2008; 56, 257274.

22.WC Hahn , RA Weinberg . Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002; 2, 331342.

23.AM Soto , C Sonnenschein . The somatic mutation theory of cancer: growing problems with the paradigm? BioEssays. 2004; 26, 10971107.

24.SG Baker , A Cappuccio , JD Potter . Research on early-stage carcinogenesis: are we approaching paradigm instability? J Clin Oncol. 2010; 28, 32153218.

26.NE Skakkebaek , ER Meyts , N Jorgensen , Germ cell cancer and disorders of spermatogenesis: an environmental connection? APMIS. 1998; 106, 312.

28.R Mittendorf . Teratogen update: carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero. Teratology. 1995; 51, 435445.

29.AL Herbst , D Anderson . Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine exposure to diethylstilbestrol. Semin Surg Oncol. 1990; 6, 343346.

30.EE Hatch , R Troisi , LA Wise , Age at natural menopause in women exposed to diethylstilbestrol in utero. Am J Epidemiol. 2006; 164, 682688.

31.JR Palmer , LA Wise , EE Hatch , Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidem Biomar. 2006; 15, 15091514.

32.JG Lemmen , JLM Broekhof , GGJM Kuiper , Expression of estrogen receptor alpha and beta during mouse embryogenesis. Mech Dev. 1999; 81, 163167.

33.JM Veltmaat , AA Mailleux , JP Thiery , S Bellusci . Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation. Differentiation. 2003; 71, 117.

34.LN Vandenberg , MV Maffini , PR Wadia , Exposure to the xenoestrogen bisphenol-A alters development of the fetal mammary gland. Endocrinology. 2007; 148, 116127.

36.CW Daniel , GH Smith . The mammary gland: a model for development. J Mammary Gland Biol Neoplasia. 1999; 4, 38.

37.AM Soto , C Sonnenschein . Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010; 6, 363370.

39.MM Munoz de Toro , CM Markey , PR Wadia , Perinatal exposure to bisphenol A alters peripubertal mammary gland development in mice. Endocrinology. 2005; 146, 41384147.

40.PR Wadia , LN Vandenberg , CM Schaeberle , Perinatal bisphenol-A exposure increases estrogen sensitivity of the mammary gland in diverse mouse strains. Environ Health Perspect. 2007; 115, 592598.

43.M Durando , L Kass , J Piva , Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats. Environ Health Perspect. 2007; 115, 8086.

44.S Jenkins , N Raghuraman , I Eltoum , Oral exposure to bisphenol A increases dimethylbenzanthracene-induced mammary cancer in rats. Environ Health Perspect. 2009; 117, 910915.

45.IH Russo , J Russo . Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect. 1996; 104, 938967.

47.CE Land , M Tokunaga , K Koyama , Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950–1990. Radiat Res. 2003; 160, 707717.

48.S-M Ho , WY Tang , J Belmonte de Frausto , GS Prins . Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res. 2006; 66, 56245632.

50.C Sonnenschein , AM Soto . Theories of carcinogenesis: an emerging perspective. Semin Cancer Biol. 2008; 18, 372377.

51.MV Maffini , AM Soto , JM Calabro , AA Ucci , C Sonnenschein . The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci. 2004; 117, 14951502.

54.T Kurita , A Mills , GR Cunha . Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis. Development. 2004; 131, 16391649.

55.GR Cunha . Stromal induction and specification of morphogenesis and cytodifferentiation of the epithelia of the Mullerian ducts and urogenital sinus during development of the uterus and vagina in mice. J Exp Zool. 1976; 196, 361370.

56.Y Yin , C Lin , L Ma . MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol. Mol Endocrinol. 2006; 20, 15351546.

57.SJ Weber-Hall , DJ Phippard , CC Niemeyer , TC Dale . Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland. Differentiation. 1994; 57, 205214.

59.JM Fleming , EL Long , E Ginsburg , Interlobular and intralobular mammary stroma: genotype may not reflect phenotype. BMC Cell Biol. 2008; 9, 46.

60.LJ Martin , NF Boyd . Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res. 2008; 10, 201214.

61.PP Provenzano , DR Inman , KW Eliceiri , Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008; 6, 11.

62.MJ Paszek , VM Weaver . The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia. 2004; 9, 325342.

63.MJ Paszek , N Zahir , KR Johnson , Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005; 8, 241254.

64.E Diamanti-Kandarakis , JP Bourguignon , LC Giudice , Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocr Rev. 2009; 30, 293342.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of Developmental Origins of Health and Disease
  • ISSN: 2040-1744
  • EISSN: 2040-1752
  • URL: /core/journals/journal-of-developmental-origins-of-health-and-disease
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords: