Hostname: page-component-8448b6f56d-cfpbc Total loading time: 0 Render date: 2024-04-19T13:41:08.841Z Has data issue: false hasContentIssue false
  • English
  • Français

Prenatal exposure to diethylstilbestrol and long-term impact on the breast and reproductive tract in humans and mice

Published online by Cambridge University Press:  19 December 2011

R. R. Newbold
R. R. Newbold*
Affiliation:
National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), North Carolina, USA
*
*Address for correspondence: R. R. Newbold, National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), P.O. Box 12233, Mail Drop K2-15, Research Triangle Park, NC 27709, USA. (Email newbold1@niehs.nih.gov)
Get access Rights & Permissions [Opens in a new window]

Abstract

The term ‘developmental origins of health and disease’ (DOHaD) originally referred to delayed effects of altered maternal factors (e.g. smoking or poor nutrition) on the developing offspring, but it now also encompasses early life exposure to environmental chemicals, which can cause an unhealthy prenatal environment that endangers the fetus and increases its susceptibility to disease later in life. Prenatal exposure to the pharmaceutical diethylstilbestrol (DES) is a well-known DOHaD example as it was associated in the 1970s with vaginal cancer in daughters who were exposed to this potent synthetic estrogen before birth. Subsequently, numerous long-term effects have been described in breast and reproductive tissues of DES-exposed humans and experimental animals. Data reviewed suggest that the prenatal DES-exposed population should continue to be monitored for potential-increased disease risks as they age. Knowledge of sensitive developmental periods, and the mechanisms of DES-induced toxicities, provides useful information in predicting potential adverse effects of other environmental estrogens.

Keywords

breast cancercritical windowsepigeneticsfibroidshormonal carcinogenesis
Type
Review
Information
Journal of Developmental Origins of Health and Disease , Volume 3 , Issue 2 , April 2012 , pp. 73 - 82
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.)

Footnotes

†

The author is retired but the research was conducted while employed at NIEHS.

References

1. Giusti, RM, Iwamoto, K, Hatch, EE. Diethylstilbestrol revisited: a review of the long-term health effects. Ann Intern Med. 1995; 122, 778–788.CrossRefGoogle ScholarPubMed
2. Herbst, AL, Ulfelder, H, Poskanzer, DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971; 284, 878–879.CrossRefGoogle ScholarPubMed
3. Hatch, EE, Palmer, JR, Titus-Ernstoff, L, Noller, KL, Kaufman, RH, Mittendorf, R, et al. . Cancer risk in women exposed to diethylstilbestrol in utero. JAMA. 1998; 280, 630–634.CrossRefGoogle ScholarPubMed
4. Palmer, JR, Hatch, EE, Rosenberg, CL, Hartge, P, Kaufman, RH, Titus-Ernstoff, L, et al. . Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States). Cancer Causes Control. 2002; 13, 753–758.CrossRefGoogle Scholar
5. Palmer, JR, et al. . Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006; 15, 1509–1514.CrossRefGoogle ScholarPubMed
6. Troisi, R, Potischman, N, Hoover, RN. Exploring the underlying hormonal mechanisms of prenatal risk factors for breast cancer: a review and commentary. Cancer Epidemiol Biomarkers Prev. 2007; 16, 1700–1712.CrossRefGoogle Scholar
7. National Institute of Health (NIH). DES Research Update, NIH Publication No: 00-4722. 1999, Bethesda, MD.Google Scholar
8. Herbst, AL, Bern, HA. Developmental Effects of Diethylstilbestrol (DES) in Pregnancy. 1981; pp. 1–193. Thieme-Stratton, Inc., New York.Google Scholar
9. Center for Disease Control and Prevention (CDC). Department of Health and Human Services Center for Disease Control and Prevention: DES Update, 2003, http://www.cdc.gov/DES/ Google Scholar
10. Diamanti-Kandarakis, E, et al. . Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009; 30, 293–342.CrossRefGoogle ScholarPubMed
11. Newbold, RR. Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmnetal estrogens. Environ Health Perspect. 1995; 103, 83–87.Google Scholar
12. Newbold, RR. Lessons learned from perinatal exposure to diethylstilbestrol. Toxicol Appl Pharmacol. 2004; 199, 142–150.CrossRefGoogle ScholarPubMed
13. Bern, H. The fragile fetus. In Chemically-induced Alterations in Sexual and Functional Development: the Wildlife Connection, Vol. XXI (eds. Colborn T, Clement C), 1992; pp. 9–16. Princeton Scientific Publishing Company, Princeton, NJ.Google Scholar
14. Newbold, R, Kinyamu, H. Epigenetic reproductive toxicants. In Reproductive Toxicology (eds. Kapp RW, Tyl R), 2010; pp. 317–331. Informa Healthcare, New York.Google Scholar
15. Gluckman, P, Hanson, M, Pinal, C. The developmental origins of disease. Matern Child Nutr. 2005; 1, 130–141.CrossRefGoogle Scholar
16. Colborn, T, vom Saal, FS, Soto, AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect. 1993; 101, 378–384.CrossRefGoogle ScholarPubMed
17. Colborn, T, Dumanoski, D, Myers, JP. Our Stolen Future, 1996. Penguin Books USA Inc., New York, pp. 1–306.Google Scholar
18. Hatch, EE, Herbst, A, Hoover, R, Noller, K, Adam, E, Kaufman, R, et al. . Incidence of squamous neoplasia of the cervix and vagina in DES-exposed daughters. Ann Epidemiol. 2000; 10, 467.CrossRefGoogle Scholar
19. Li, S, et al. . Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Res. 1997; 57, 4356–4359.Google ScholarPubMed
20. Li, S, et al. . Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog. 2003; 38, 78–84.CrossRefGoogle ScholarPubMed
21. Newbold, RR, et al. . Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life. Mol Carcinog. 2007; 46, 783–796.CrossRefGoogle ScholarPubMed
22. Tang, WY, et al. . Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology. 2008; 149, 5922–5931.CrossRefGoogle ScholarPubMed
23. Newbold, RR, et al. . Developmental exposure to diethylstilbestrol (DES) alters uterine response to estrogens in prepubescent mice: low versus high dose effects. Reprod Toxicol. 2004; 18, 399–406.CrossRefGoogle ScholarPubMed
24. Melnick, R, Lucier, G, Wolfe, M, Hall, R, Stancel, G, Prins, G, et al. . Summary of the National Toxicology Program's report of the endocrine disruptors low-dose peer review. Environ Health Perspect. 2002; 110, 427–431.CrossRefGoogle ScholarPubMed
25. vom Saal, FS, Akingbemi, BT, Belcher, SM, Birnbaum, LS, Crain, DA, Eriksen, M, et al. . Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol. 2007; 24, 131–138.CrossRefGoogle Scholar
26 Heindel, JJ, Newbold, RR, (eds.). Developmental origins of health and disease: the importance of environmental exposures. In Early Life Origins of Human Health and Disease, 2009; pp. 42–51. Basel, Switzerland, Karger.Google Scholar
27. Soto, AM, Sonnenschein, C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010; 6, 363–370.CrossRefGoogle ScholarPubMed
28 Hogan, MD, Newbold, RR, McLachlan, JA. Extrapolation of teratogenic responses observed in laboratory animals to humans: DES as an illustative example. In Developmental Toxicology: Mechanisms and Risk (eds. McLachlan JA, Pratt RM, Market C), 1987, pp. 257–269. Cold Spring Harbor Laboratory, Cold Spring Harbor: MA, USA.Google Scholar
29. Ekbom, A, Trichopoulos, D, Adami, HO, Hsieh, CC, Lan, SJ. Evidence of prenatal influences on breast cancer risk. Lancet. 1992; 340, 1015–1018.CrossRefGoogle ScholarPubMed
30. Russo, J, et al. . Comparative study of human and rat mammary tumorigenesis. Lab Invest. 1990; 62, 244–278.Google ScholarPubMed
31. Russo, J, Gusterson, BA, Rogers, AE, Russo, IH, Wellings, SR, van Zwieten, MJ. Developmental, cellular, and molecular basis of human breast cancer. J Natl Cancer Inst Monogr. 2000; 27, 17–37.CrossRefGoogle Scholar
32. Rosso, J, Hu, YF, Yang, X, Russo, IH. Anatomy and physiologic morphology. In Rosen's Breast Pathology, (ed. Rosen P), 2008, pp. 1–22. Lippincott, Williams, and Wilkins, New York.Google Scholar
33. Friedrichs, N, Steiner, S, Buettner, R, Knoepfle, G. Immunohistochemical expression patterns of AP2alpha and AP2gamma in the developing fetal human breast. Histopathology. 2007; 51, 814–823.CrossRefGoogle ScholarPubMed
34. Robinson, GW, Karpf, AB, Kratochwil, K. Regulation of mammary gland development by tissue interaction. J Mammary Gland Biol Neoplasia. 1999; 4, 9–19.CrossRefGoogle ScholarPubMed
35. Vandenberg, LN, Maffini, MV, Wadia, PR, Sonnenschein, C, Rubin, BS, Soto, AM. Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland. Endocrinology. 2007; 148, 116–127.CrossRefGoogle ScholarPubMed
36. Lemmen, JG, Broekhof, JL, Kuiper, GG, Gustafsson, JA, van der Saag, PT, van der Burg, B. Expression of estrogen receptor alpha and beta during mouse embryogenesis. Mech Dev. 1999; 81, 163–167.CrossRefGoogle ScholarPubMed
37. Narbaitz, R, Stumpf, WE, Sar, M. Estrogen receptors in mammary gland primordia of fetal mouse. Anat Embryol (Berl). 1980; 158, 161–166.CrossRefGoogle ScholarPubMed
38. Saji, S, Jensen, EV, Nilsson, S, Rylander, T, Warner, M, Gustafsson, JA. Estrogen receptors alpha and beta in the rodent mammary gland. Proc Natl Acad Sci U S A. 2000; 97, 337–342.CrossRefGoogle ScholarPubMed
39. Richert, MM, Schwertfeger, KL, Ryder, JW, Anderson, SM. An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia. 2000; 5, 227–241.CrossRefGoogle ScholarPubMed
40. Rustia, M, Shubik, P. Effects of transplacental exposure to diethylstilbestrol on carcinogenic susceptibility during postnatal life in hamster progeny. Cancer Res. 1979; 39, 4636–4644.Google ScholarPubMed
41. Boylan, ES, Calhoon, RE. Mammary tumorigenesis in the rat following prenatal exposure to diethylstilbestrol and postnatal treatment with 7,12-dimethylbenz[a]anthracene. J Toxicol Environ Health. 1979; 5, 1059–1071.CrossRefGoogle Scholar
42. Boylan, ES, Calhoon, RE. Prenatal exposure to diethylstilbestrol: ovarian-independent growth of mammary tumors induced by 7,12-dimethylbenz[a]anthracene. J Natl Cancer Inst. 1981; 66, 649–652.Google Scholar
43. 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
44. 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
45. Vassilacopoulou, D, Boylan, ES. Mammary gland morphology and responsiveness to regulatory molecules following prenatal exposure to diethylstilbestrol. Teratog Carcinog Mutagen. 1993; 13, 59–74.CrossRefGoogle ScholarPubMed
46. Walker, BE. Tumors in female offspring of control and diethylstilbestrol-exposed mice fed high-fat diets. J Natl Cancer Inst. 1990; 82, 50–54.CrossRefGoogle ScholarPubMed
47. Kawaguchi, H, Miyoshi, N, Miyamoto, Y, Souda, M, Umekita, Y, Yasuda, N, et al. . Effects of fetal exposure to diethylstilbestrol on mammary tumorigenesis in rats. J Vet Med Sci. 2009; 71, 1599–1608.CrossRefGoogle ScholarPubMed
48. Nagasawa, H, Mori, T, Nakajima, Y. Long-term effects of progesterone or diethylstilbestrol with or without estrogen after maturity on mammary tumorigenesis in mice. Eur J Cancer. 1980; 16, 1583–1589.CrossRefGoogle ScholarPubMed
49. Bern, HA, Jones, LA, Mori, T, Young, PN. Exposure of neonatal mice to steroids: longterm effects on the mammary gland and other reproductive structures. J Steroid Biochem. 1975; 6, 673–676.CrossRefGoogle ScholarPubMed
50. Warner, MR, Warner, RL. Effects of exposure of neonatal mice to 17beta-estradiol on subsequent age-incidence and morphology of carcinogen-induced mammary dysplasia. J Natl Cancer Inst. 1975; 55, 289–298.Google ScholarPubMed
51. Mori, T, Bern, HA, Mills, KT, Young, PN. Long-term effects of neonatal steroid exposure on mammary gland development and tumorigenesis in mice. J Natl Cancer Inst. 1976; 57, 1057–1062.CrossRefGoogle ScholarPubMed
52. Mori, T, Nagasawa, H, Bern, HA. Long-term effects of perinatal exposure to hormones on normal and neoplastic mammary growth in rodents: a review. J Environ Pathol Toxicol. 1979; 3, 191–205.Google ScholarPubMed
53. Hovey, RC, Asai-Sato, M, Warri, A, Terry-Koroma, B, Colyn, N, Ginsburg, E, et al. . Effects of neonatal exposure to diethylstilbestrol, tamoxifen, and toremifene on the BALB/c mouse mammary gland. Biol Reprod. 2005; 72, 423–435.CrossRefGoogle ScholarPubMed
54. Ninomiya, K, Kawaguchi, H, Souda, M, Taguchi, S, Funato, M, Umekita, Y, et al. . Effects of neonatally administered diethylstilbestrol on induction of mammary carcinomas induced by 7, 12-dimethylbenz(a)anthracene in female rats. Toxicol Pathol. 2007; 35, 813–818.CrossRefGoogle ScholarPubMed
55. Umekita, Y, Souda, M, Hatanaka, K, Hamada, T, Yoshioka, T, Kawaguchi, H, et al. . Gene expression profile of terminal end buds in rat mammary glands exposed to diethylstilbestrol in neonatal period. Toxicol Lett. 2011; 205, 15–25.CrossRefGoogle ScholarPubMed
56. Tuchmann-Duplessis, H, Haegel, P, (eds.). Illustrated Human Embrology: Organogenesis, Vol. 11, 1982. Spring Verlag, New York.Google Scholar
57. Taylor, HS, Vanden Heuvel, GB, Igarashi, P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod. 1997; 57, 1338–1345.CrossRefGoogle ScholarPubMed
58. Troisi, R, Hatch, EE, Titus-Ernstoff, L, Hyer, M, Palmer, JR, Robboy, SJ, et al. . Cancer risk in women prenatally exposed to diethylstilbestrol. Int J Cancer. 2007; 121, 356–360.CrossRefGoogle ScholarPubMed
59. Titus-Ernstoff, L, Troisi, R, Hatch, EE, Palmer, JR, Wise, LA, Ricker, W, et al. . Mortality in women given diethylstilbestrol during pregnancy. Br J Cancer. 2006; 95, 107–111.CrossRefGoogle ScholarPubMed
60. Boylan, ES. Morphological and functional consequences of prenatal exposure to diethylstilbestrol in the rat. Biol Reprod. 1978; 19, 854–863.CrossRefGoogle ScholarPubMed
61. McLachlan, JA, Newbold, RR, Shah, HC, Hogan, M, Dixon, RL. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril. 1982; 38, 364–371.CrossRefGoogle ScholarPubMed
62. 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
63. Baird, DD, Newbold, RR. Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development. Reprod Toxicol. 2005; 20, 81–84.CrossRefGoogle ScholarPubMed
64. Cook, JD, Davis, BJ, Goewey, JA, Berry, TD, Walker, CL. Identification of a sensitive period for developmental programming that increases risk for uterine leiomyoma in Eker rats. Reprod Sci. 2007; 14, 121–136.CrossRefGoogle ScholarPubMed
65. Henderson, BE, Feigelson, HS. Hormonal carcinogenesis. Carcinogenesis. 2000; 21, 427–433.CrossRefGoogle ScholarPubMed
66. Larson, PS, Ungarelli, RA, de lasMorenas, A, Cupples, LA, Rowlings, K, Palmer, JR, et al. . In utero exposure to diethylstilbestrol (DES) does not increase genomic instability in normal or neoplastic breast epithelium. Cancer. 2006; 107, 2122–2126.CrossRefGoogle ScholarPubMed
67. Szyf, M. The dynamic epigenome and its implications in toxicology. Toxicol Sci. 2007; 100, 7–23.CrossRefGoogle ScholarPubMed
68. Ho, SM, Tang, WY. Techniques used in studies of epigenome dysregulation due to aberrant DNA methylation: an emphasis on fetal-based adult diseases. Reprod Toxicol. 2007; 23, 267–282.CrossRefGoogle ScholarPubMed
69. Prins, GS, Birch, L, Tang, WY, Ho, SM. Developmental estrogen exposures predispose to prostate carcinogenesis with aging. Reprod Toxicol. 2007; 23, 374–382.CrossRefGoogle ScholarPubMed
70. Prins, GS, Tang, WY, Belmonte, J, Ho, SM. Developmental exposure to bisphenol A increases prostate cancer susceptibility in adult rats: epigenetic mode of action is implicated. Fertil Steril. 2008; 89, e41.CrossRefGoogle ScholarPubMed
71. Prins, GS, Tang, WY, Belmonte, J, Ho, SM. Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin Pharmacol Toxicol. 2008; 102, 134–138.CrossRefGoogle ScholarPubMed
72. Fenton, SE, Reed, C, Newbold, RR. Perinatal environmental exposures affect mammary development, function, and cancer risk in adulthood. Annu Rev Pharmacol Toxicol. 2012; 52, 455–479.CrossRefGoogle ScholarPubMed