Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-25T06:24:37.991Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  23 February 2011

C. Sonnenschein ,
P. R. Wadia ,
B. S. Rubin  and
A. M. Soto
C. Sonnenschein
Affiliation:
Program in Cellular Molecular and Developmental Biology, Tufts University School of Medicine, Boston, MA, USA
P. R. Wadia
Affiliation:
Program in Cellular Molecular and Developmental Biology, Tufts University School of Medicine, Boston, MA, USA
B. S. Rubin
Affiliation:
Program in Cellular Molecular and Developmental Biology, Tufts University School of Medicine, Boston, MA, USA
A. M. Soto*
Affiliation:
Program in Cellular Molecular and Developmental Biology, Tufts University School of Medicine, Boston, MA, USA
*
*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)
Get access Rights & Permissions [Opens in a new window]

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.

Keywords

endocrine disruptorsfetal mammary gland developmentfetal origins of adult diseasestroma–epithelium interactionstissue organization field theory
Type
Themed Content: Role of Environmental Stressors in the Developmental Origins of Disease
Information
Journal of Developmental Origins of Health and Disease , Volume 2 , Issue 1: Including Themed Content: Role of Environmental Stressors in the Developmental Origins of Disease , 23 February 2011 , pp. 9 - 16
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Markey, CM, Coombs, MA, Sonnenschein, C, Soto, AM. Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evol Dev. 2003; 5, 1–9.CrossRefGoogle Scholar
2.Vandenberg, LN, Maffini, MV, Schaeberle, CM, et al. Perinatal exposure to the xenoestrogen bisphenol-A induces mammary intraductal hyperplasias in adult CD-1 mice. Reprod Toxicol. 2008; 3–4, 210–219.CrossRefGoogle Scholar
3.Murray, TJ, Maffini, MV, Ucci, AA, Sonnenschein, C, Soto, AM. Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reprod Toxicol. 2007; 23, 383–390.CrossRefGoogle ScholarPubMed
4.Newbold, RR, Padilla-Banks, E, Snyder, RJ, Jefferson, WN. Developmental exposure to estrogenic compounds and obesity. Birth Defects Res A Clin Mol Teratol. 2005; 73, 478–480.CrossRefGoogle ScholarPubMed
5.Rubin, BS, Murray, MK, Damassa, DA, King, JC, Soto, AM. Perinatal exposure to low doses of bisphenol-A affects body weight, patterns of estrous cyclicity and plasma LH levels. Environ Health Perspect. 2001; 109, 675–680.CrossRefGoogle ScholarPubMed
6.Herbst, AL, Bern, HA. Developmental Effects of Diethylstilbestrol (DES) in Pregnancy, 1988. Thieme-Stratton, New York.Google Scholar
7.McLachlan, JA, Newbold, RR, Bullock, BC. Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res. 1980; 40, 3988–3999.Google ScholarPubMed
8.Boylan, ES, Calhoon, RE. Transplacental action of diethylstilbestrol on mammary carcinogenesis in female rats given one or two doses of 7,12-dimethylbenz(a)anthracene. Cancer Res. 1983; 43, 4879–4884.Google ScholarPubMed
9.Soto, AM, Sonnenschein, C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010; 6, 363–370.CrossRefGoogle ScholarPubMed
10.Gilbert, SF. Mechanisms for the environmental regulation of gene expression: ecological aspects of animal development. J Biosci. 2005; 30, 65–74.CrossRefGoogle ScholarPubMed
11.Moss, L. What Genes Can't Do, 2003. MIT Press, Cambridge, MA.Google Scholar
12.Soto, AM, Sonnenschein, C. Emergentism as a default: cancer as a problem of tissue organization. J Biosci. 2005; 30, 103–118.CrossRefGoogle ScholarPubMed
13.Schrödinger, E. What is Life? The Physical Aspect of the Living Cell, 1945. The University Press, Cambridge, England.Google Scholar
14.Barker, DJP, Hanson, MA. Altered regional blood flow in the fetus: the origins of cardiovascular disease? Acta Paediatricia. 2004; 93, 1559–1560.CrossRefGoogle ScholarPubMed
15.Thompson, DW. On Growth and Form, 1942. Cambridge University Press, Cambridge.Google Scholar
16.Ingber, DE. Mechanical control of tissue morphogenesis during embryological development. Int J Dev Biol. 2006; 50, 255–266.CrossRefGoogle ScholarPubMed
17.Patwari, P, Lee, RT. Mechanical control of tissue morphogenesis. Circ Res. 2008; 103, 234–243.CrossRefGoogle ScholarPubMed
18.Soto, AM, Sonnenschein, C, Miquel, P-A. On physicalism and downward causation in developmental and cancer biology. Acta Biotheor. 2008; 56, 257–274.CrossRefGoogle ScholarPubMed
19.Sonnenschein, C, Soto, AM. The Society of Cells: Cancer and Control of Cell Proliferation, 1999. Springer Verlag, New York.Google Scholar
20.Noble, D. The Music of Life: Biology beyond the Genome, 2006. Oxford University Press, Oxford.CrossRefGoogle Scholar
21.Triolo, VA. Nineteenth century foundations of cancer research advances in tumor pathology, nomenclature, and theories of oncogenesis. Cancer Res. 1965; 25, 76–98.Google ScholarPubMed
22.Hahn, WC, Weinberg, RA. Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002; 2, 331–342.CrossRefGoogle ScholarPubMed
23.Soto, AM, Sonnenschein, C. The somatic mutation theory of cancer: growing problems with the paradigm? BioEssays. 2004; 26, 1097–1107.CrossRefGoogle ScholarPubMed
24.Baker, SG, Cappuccio, A, Potter, JD. Research on early-stage carcinogenesis: are we approaching paradigm instability? J Clin Oncol. 2010; 28, 3215–3218.CrossRefGoogle ScholarPubMed
25.Maffini, MV, Calabro, JM, Soto, AM, Sonnenschein, C. Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma. Am J Pathol. 2005; 67, 1405–1410.CrossRefGoogle Scholar
26.Skakkebaek, NE, Meyts, ER, Jorgensen, N, et al. Germ cell cancer and disorders of spermatogenesis: an environmental connection? APMIS. 1998; 106, 3–12.CrossRefGoogle ScholarPubMed
27.Soto, AM, Sonnenschein, C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010; 6, 363–370.CrossRefGoogle ScholarPubMed
28.Mittendorf, R. Teratogen update: carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero. Teratology. 1995; 51, 435–445.CrossRefGoogle ScholarPubMed
29.Herbst, AL, Anderson, D. Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine exposure to diethylstilbestrol. Semin Surg Oncol. 1990; 6, 343–346.CrossRefGoogle ScholarPubMed
30.Hatch, EE, Troisi, R, Wise, LA, et al. Age at natural menopause in women exposed to diethylstilbestrol in utero. Am J Epidemiol. 2006; 164, 682–688.CrossRefGoogle ScholarPubMed
31.Palmer, JR, Wise, LA, Hatch, EE, et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidem Biomar. 2006; 15, 1509–1514.CrossRefGoogle ScholarPubMed
32.Lemmen, JG, Broekhof, JLM, Kuiper, GGJM, et al. Expression of estrogen receptor alpha and beta during mouse embryogenesis. Mech Dev. 1999; 81, 163–167.CrossRefGoogle ScholarPubMed
33.Veltmaat, JM, Mailleux, AA, Thiery, JP, Bellusci, S. Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation. Differentiation. 2003; 71, 1–17.CrossRefGoogle Scholar
34.Vandenberg, LN, Maffini, MV, Wadia, PR, et al. Exposure to the xenoestrogen bisphenol-A alters development of the fetal mammary gland. Endocrinology. 2007; 148, 116–127.CrossRefGoogle Scholar
35.Humphreys, RC, Krajewska, M, Krnacik, S, et al. Apoptosis in the terminal end bud of the murine mammary gland: a mechanism of ductal morphogenesis. Development. 1996; 122, 4013–4022.CrossRefGoogle Scholar
36.Daniel, CW, Smith, GH. The mammary gland: a model for development. J Mammary Gland Biol Neoplasia. 1999; 4, 3–8.CrossRefGoogle Scholar
37.Soto, AM, Sonnenschein, C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010; 6, 363–370.CrossRefGoogle ScholarPubMed
38.Markey, CM, Luque, EH, Munoz de Toro, MM, Sonnenschein, C, Soto, AM. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod. 2001; 65, 1215–1223.CrossRefGoogle ScholarPubMed
39.Munoz de Toro, MM, Markey, CM, Wadia, PR, et al. Perinatal exposure to bisphenol A alters peripubertal mammary gland development in mice. Endocrinology. 2005; 146, 4138–4147.CrossRefGoogle ScholarPubMed
40.Wadia, PR, Vandenberg, LN, Schaeberle, CM, et al. Perinatal bisphenol-A exposure increases estrogen sensitivity of the mammary gland in diverse mouse strains. Environ Health Perspect. 2007; 115, 592–598.CrossRefGoogle ScholarPubMed
41.Rothschild, TC, Boylan, ES, Calhoon, RE, Vonderhaar, BK. Transplacental effects of diethylstilbestrol on mammary development and tumorigenesis in female ACI rats. Cancer Res. 1987; 47, 4508–4516.Google ScholarPubMed
42.Schor, SL, Schor, AM, Howell, A, Haggie, J. The possible role of abnormal fibroblasts in the pathogenesis of breast cancer. In Breast Cancer: Scientific and Chemical Progress (eds. Rich MA, Hagar JC, Lopez DM), 1988; pp. 142–157. Kluwer Academic Publishers, Boston.CrossRefGoogle Scholar
43.Durando, M, Kass, L, Piva, J, et al. Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats. Environ Health Perspect. 2007; 115, 80–86.CrossRefGoogle ScholarPubMed
44.Jenkins, S, Raghuraman, N, Eltoum, I, et al. Oral exposure to bisphenol A increases dimethylbenzanthracene-induced mammary cancer in rats. Environ Health Perspect. 2009; 117, 910–915.CrossRefGoogle ScholarPubMed
45.Russo, IH, Russo, J. Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect. 1996; 104, 938–967.CrossRefGoogle ScholarPubMed
46.Grubbs, CJ, Peckham, JC, Cato, KD. Mammary carcinogenesis in rats in relation to age at time of N-nitroso-N-methylurea administration. J Nat Cancer Inst. 1983; 70, 209–212.Google ScholarPubMed
47.Land, CE, Tokunaga, M, Koyama, K, et al. Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950–1990. Radiat Res. 2003; 160, 707–717.CrossRefGoogle ScholarPubMed
48.Ho, S-M, Tang, WY, Belmonte de Frausto, J, Prins, GS. Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res. 2006; 66, 5624–5632.CrossRefGoogle ScholarPubMed
49.Weinberg, RA. The Biology of Cancer, 2006. Taylor & Francis, New York.CrossRefGoogle Scholar
50.Sonnenschein, C, Soto, AM. Theories of carcinogenesis: an emerging perspective. Semin Cancer Biol. 2008; 18, 372–377.CrossRefGoogle ScholarPubMed
51.Maffini, MV, Soto, AM, Calabro, JM, Ucci, AA, Sonnenschein, C. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci. 2004; 117, 1495–1502.CrossRefGoogle ScholarPubMed
52.Robboy, SJ, Welch, WR, Young, RH, et al. Topographic relation of cervical ectropion and vaginal adenosis to clear cell adenocarcinoma. Obstet Gynecol. 1982; 60, 546–551.Google ScholarPubMed
53.Newbold, RR, McLachlan, JA. Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Res. 1982; 42, 2003–2011.Google ScholarPubMed
54.Kurita, T, Mills, A, Cunha, GR. Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis. Development. 2004; 131, 1639–1649.CrossRefGoogle ScholarPubMed
55.Cunha, GR. 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, 361–370.CrossRefGoogle ScholarPubMed
56.Yin, Y, Lin, C, Ma, L. MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol. Mol Endocrinol. 2006; 20, 1535–1546.CrossRefGoogle ScholarPubMed
57.Weber-Hall, SJ, Phippard, DJ, Niemeyer, CC, Dale, TC. Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland. Differentiation. 1994; 57, 205–214.CrossRefGoogle ScholarPubMed
58.Phippard, DJ, Weber-Hall, SJ, Sharpe, PT, et al. Regulation of Msx-1, Msx-2, Bmp-2 and Bmp-4 during foetal and postnatal mammary gland development. Development. 1996; 122, 2729–2737.CrossRefGoogle ScholarPubMed
59.Fleming, JM, Long, EL, Ginsburg, E, et al. Interlobular and intralobular mammary stroma: genotype may not reflect phenotype. BMC Cell Biol. 2008; 9, 46.CrossRefGoogle Scholar
60.Martin, LJ, Boyd, NF. Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res. 2008; 10, 201–214.CrossRefGoogle ScholarPubMed
61.Provenzano, PP, Inman, DR, Eliceiri, KW, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008; 6, 11.CrossRefGoogle ScholarPubMed
62.Paszek, MJ, Weaver, VM. The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia. 2004; 9, 325–342.CrossRefGoogle ScholarPubMed
63.Paszek, MJ, Zahir, N, Johnson, KR, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005; 8, 241–254.CrossRefGoogle ScholarPubMed
64.Diamanti-Kandarakis, E, Bourguignon, JP, Giudice, LC, et al. Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocr Rev. 2009; 30, 293–342.CrossRefGoogle ScholarPubMed