Logo of envhperEnvironmental Health PerspectivesBrowse ArticlesAbout EHPGeneral InformationAuthorsMediaProgramsPartnerships
Environ Health Perspect. 2003 Apr; 111(4): 389–394.
PMCID: PMC1241417
Research Article

Cancer and developmental exposure to endocrine disruptors.


Developing organisms have increased susceptibility to cancer if they are exposed to environmental toxicants during rapid growth and differentiation. Human studies have demonstrated clear increases in cancer after prenatal exposure to ionizing radiation, and there is suggestive evidence that brain tumors and leukemia are associated with parental exposures to chemicals. Animal experiments have demonstrated increased tumor formation induced by prenatal or neonatal exposure to a variety of chemicals, including direct-acting carcinogens and drugs. Recently, natural estrogens have been classified as known human carcinogens. Prenatal exposure to natural and synthetic estrogens is associated with increases in breast and vaginal tumors in humans as well as uterine tumors in animals. Synthetic halogenated chemicals increase liver tumors after early life-stage exposure. Recently, a prototypical endocrine-disrupting compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin, has been shown to be a developmental toxicant of the mammary gland in rodents. Dioxin alters multiple endocrine systems, and its effects on the developing breast involve delayed proliferation and differentiation of the mammary gland, as well as an elongation of the window of sensitivity to potential carcinogens. Implications of these new findings suggest that causes of endocrine-related cancers or susceptibility to cancer may be a result of developmental exposures rather than exposures existing at or near the time of tumor detection.

Full Text

The Full Text of this article is available as a PDF (461K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Abbott BD, Birnbaum LS, Perdew GH. Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo. Dev Dyn. 1995 Oct;204(2):133–143. [PubMed]
  • Abbott BD, Perdew GH, Buckalew AR, Birnbaum LS. Interactive regulation of Ah and glucocorticoid receptors in the synergistic induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin and hydrocortisone. Toxicol Appl Pharmacol. 1994 Sep;128(1):138–150. [PubMed]
  • Alexander FE, Patheal SL, Biondi A, Brandalise S, Cabrera ME, Chan LC, Chen Z, Cimino G, Cordoba JC, Gu LJ, et al. Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. Cancer Res. 2001 Mar 15;61(6):2542–2546. [PubMed]
  • Anderson LM, Diwan BA, Fear NT, Roman E. Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models. Environ Health Perspect. 2000 Jun;108 (Suppl 3):573–594. [PMC free article] [PubMed]
  • Bertazzi A, Pesatori AC, Consonni D, Tironi A, Landi MT, Zocchetti C. Cancer incidence in a population accidentally exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. Epidemiology. 1993 Sep;4(5):398–406. [PubMed]
  • Birnbaum LS. Endocrine effects of prenatal exposure to PCBs, dioxins, and other xenobiotics: implications for policy and future research. Environ Health Perspect. 1994 Aug;102(8):676–679. [PMC free article] [PubMed]
  • Birnbaum Linda S, Cummings Audrey M. Dioxins and endometriosis: a plausible hypothesis. Environ Health Perspect. 2002 Jan;110(1):15–21. [PMC free article] [PubMed]
  • Birnbaum LS, Tuomisto J. Non-carcinogenic effects of TCDD in animals. Food Addit Contam. 2000 Apr;17(4):275–288. [PubMed]
  • Boice JD, Jr, Miller RW. Childhood and adult cancer after intrauterine exposure to ionizing radiation. Teratology. 1999 Apr;59(4):227–233. [PubMed]
  • Brunström B, Lund BO, Bergman A, Asplund L, Athanassiadis I, Athanasiadou M, Jensen S, Orberg J. Reproductive toxicity in mink (Mustela vison) chronically exposed to environmentally relevant polychlorinated biphenyl concentrations. Environ Toxicol Chem. 2001 Oct;20(10):2318–2327. [PubMed]
  • Chhabra RS, Bucher JR, Haseman JK, Elwell MR, Kurtz PJ, Carlton BD. Comparative carcinogenicity of 5,5-diphenylhydantoin with or without perinatal exposure in rats and mice. Fundam Appl Toxicol. 1993 Aug;21(2):174–186. [PubMed]
  • Chhabra RS, Eustis S, Haseman JK, Kurtz PJ, Carlton BD. Comparative carcinogenicity of ethylene thiourea with or without perinatal exposure in rats and mice. Fundam Appl Toxicol. 1992 Apr;18(3):405–417. [PubMed]
  • Cooper RL, Stoker TE, Tyrey L, Goldman JM, McElroy WK. Atrazine disrupts the hypothalamic control of pituitary-ovarian function. Toxicol Sci. 2000 Feb;53(2):297–307. [PubMed]
  • Das PC, McElroy WK, Cooper RL. Alteration of catecholamines in pheochromocytoma (PC12) cells in vitro by the metabolites of chlorotriazine herbicide. Toxicol Sci. 2001 Jan;59(1):127–137. [PubMed]
  • Den Hond Elly, Roels Harry A, Hoppenbrouwers Karel, Nawrot Tim, Thijs Lutgarde, Vandermeulen Corinne, Winneke Gerhard, Vanderschueren Dirk, Staessen Jan A. Sexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek's hypothesis revisited. Environ Health Perspect. 2002 Aug;110(8):771–776. [PMC free article] [PubMed]
  • Desaulniers D, Leingartner K, Russo J, Perkins G, Chittim BG, Archer MC, Wade M, Yang J. Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat. Environ Health Perspect. 2001 Jul;109(7):739–747. [PMC free article] [PubMed]
  • Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br J Radiol. 1997 Feb;70:130–139. [PubMed]
  • Flaws JA, Sommer RJ, Silbergeld EK, Peterson RE, Hirshfield AN. In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces genital dysmorphogenesis in the female rat. Toxicol Appl Pharmacol. 1997 Dec;147(2):351–362. [PubMed]
  • Freedman DM, Stewart P, Kleinerman RA, Wacholder S, Hatch EE, Tarone RE, Robison LL, Linet MS. Household solvent exposures and childhood acute lymphoblastic leukemia. Am J Public Health. 2001 Apr;91(4):564–567. [PMC free article] [PubMed]
  • Gray LE, Jr, Ostby JS. In utero 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters reproductive morphology and function in female rat offspring. Toxicol Appl Pharmacol. 1995 Aug;133(2):285–294. [PubMed]
  • Gray LE, Wolf C, Mann P, Ostby JS. In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive development of female Long Evans hooded rat offspring. Toxicol Appl Pharmacol. 1997 Oct;146(2):237–244. [PubMed]
  • Greaves MF. Aetiology of acute leukaemia. Lancet. 1997 Feb 1;349(9048):344–349. [PubMed]
  • Groce DF, Kimbrough RD. Stunted growth, increased mortality, and liver tumors in offspring of polybrominated biphenyl (PBB) dosed sherman rats. J Toxicol Environ Health. 1984;14(5-6):695–706. [PubMed]
  • 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 Apr 15;284(15):878–881. [PubMed]
  • Halakivi-Clarke L, Cho E, Onojafe I, Liao DJ, Clarke R. Maternal exposure to tamoxifen during pregnancy increases carcinogen-induced mammary tumorigenesis among female rat offspring. Clin Cancer Res. 2000 Jan;6(1):305–308. [PubMed]
  • Hilakivi-Clarke L, Cho E, Onojafe I, Raygada M, Clarke R. Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring. Oncol Rep. 1999 Sep-Oct;6(5):1089–1095. [PubMed]
  • Hsieh CC, Tzonou A, Zavitsanos X, Kaklamani E, Lan SJ, Trichopoulos D. Age at first establishment of chronic hepatitis B virus infection and hepatocellular carcinoma risk. A birth order study. Am J Epidemiol. 1992 Nov 1;136(9):1115–1121. [PubMed]
  • Hushka LJ, Williams JS, Greenlee WF. Characterization of 2,3,7,8-tetrachlorodibenzofuran-dependent suppression and AH receptor pathway gene expression in the developing mouse mammary gland. Toxicol Appl Pharmacol. 1998 Sep;152(1):200–210. [PubMed]
  • Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Wade CE, Dittenber DA, Kalnins RP, Frauson LE, Park CN, Barnard SD, et al. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol Appl Pharmacol. 1978 Nov;46(2):279–303. [PubMed]
  • Lamartiniere Coral A, Cotroneo Michelle S, Fritz Wayne A, Wang Jun, Mentor-Marcel Roycelynn, Elgavish Ada. Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr. 2002 Mar;132(3):552S–558S. [PubMed]
  • Lin FH, Stohs SJ, Birnbaum LS, Clark G, Lucier GW, Goldstein JA. The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hepatic estrogen and glucocorticoid receptors in congenic strains of Ah responsive and Ah nonresponsive C57BL/6J mice. Toxicol Appl Pharmacol. 1991 Mar 15;108(1):129–139. [PubMed]
  • Lucier GW, Tritscher A, Goldsworthy T, Foley J, Clark G, Goldstein J, Maronpot R. Ovarian hormones enhance 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated increases in cell proliferation and preneoplastic foci in a two-stage model for rat hepatocarcinogenesis. Cancer Res. 1991 Mar 1;51(5):1391–1397. [PubMed]
  • Markey CM, Luque EH, Munoz De Toro M, Sonnenschein C, Soto AM. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod. 2001 Oct;65(4):1215–1223. [PubMed]
  • McLachlan JA, Newbold RR, Bullock BC. Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res. 1980 Nov;40(11):3988–3999. [PubMed]
  • Meinert R, Schüz J, Kaletsch U, Kaatsch P, Michaelis J. Leukemia and non-Hodgkin's lymphoma in childhood and exposure to pesticides: results of a register-based case-control study in Germany. Am J Epidemiol. 2000 Apr 1;151(7):639–650. [PubMed]
  • Miller RK. Perinatal toxicology: its recognition and fundamentals. Am J Ind Med. 1983;4(1-2):205–244. [PubMed]
  • Newbold RR, Banks EP, Bullock B, Jefferson WN. Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res. 2001 Jun 1;61(11):4325–4328. [PubMed]
  • Newbold RR, Bullock BC, McLachlan JA. Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis. Cancer Res. 1990 Dec 1;50(23):7677–7681. [PubMed]
  • Newbold RR, Hanson RB, Jefferson WN, Bullock BC, Haseman J, McLachlan JA. Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis. 2000 Jul;21(7):1355–1363. [PubMed]
  • Pershagen G. Childhood cancer and malignancies other than lung cancer related to passive smoking. Mutat Res. 1989 Feb;222(2):129–135. [PubMed]
  • Peters FM, Preston-Martin S, Yu MC. Brain tumors in children and occupational exposure of parents. Science. 1981 Jul 10;213(4504):235–237. [PubMed]
  • Rice JM, Rehm S, Donovan PJ, Perantoni AO. Comparative transplacental carcinogenesis by directly acting and metabolism-dependent alkylating agents in rodents and nonhuman primates. IARC Sci Publ. 1989;(96):17–34. [PubMed]
  • Rogan WJ, Gladen BC, McKinney JD, Carreras N, Hardy P, Thullen J, Tingelstad J, Tully M. Polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) in human milk: effects on growth, morbidity, and duration of lactation. Am J Public Health. 1987 Oct;77(10):1294–1297. [PMC free article] [PubMed]
  • Russo IH, Russo J. Developmental stage of the rat mammary gland as determinant of its susceptibility to 7,12-dimethylbenz[a]anthracene. J Natl Cancer Inst. 1978 Dec;61(6):1439–1449. [PubMed]
  • Safe S, Wang F, Porter W, Duan R, McDougal A. Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms. Toxicol Lett. 1998 Dec 28;102-103:343–347. [PubMed]
  • Sasco AJ. Epidemiology of breast cancer: an environmental disease? APMIS. 2001 May;109(5):321–332. [PubMed]
  • Schoenig GP, Goldenthal EI, Geil RG, Frith CH, Richter WR, Carlborg FW. Evaluation of the dose response and in utero exposure to saccharin in the rat. Food Chem Toxicol. 1985 Apr-May;23(4-5):475–490. [PubMed]
  • Shu XO, Stewart P, Wen WQ, Han D, Potter JD, Buckley JD, Heineman E, Robison LL. Parental occupational exposure to hydrocarbons and risk of acute lymphocytic leukemia in offspring. Cancer Epidemiol Biomarkers Prev. 1999 Sep;8(9):783–791. [PubMed]
  • Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001 May;16(5):972–978. [PubMed]
  • Stjernfeldt M, Berglund K, Lindsten J, Ludvigsson J. Maternal smoking during pregnancy and risk of childhood cancer. Lancet. 1986 Jun 14;1(8494):1350–1352. [PubMed]
  • Strohsnitter WC, Noller KL, Hoover RN, Robboy SJ, Palmer JR, Titus-Ernstoff L, Kaufman RH, Adam E, Herbst AL, Hatch EE. Cancer risk in men exposed in utero to diethylstilbestrol. J Natl Cancer Inst. 2001 Apr 4;93(7):545–551. [PubMed]
  • Taylor JM, Weinberger MA, Friedman L. Chronic toxicity and carcinogenicity to the urinary bladder of sodium saccharin in the in utero-exposed rat. Toxicol Appl Pharmacol. 1980 Jun 15;54(1):57–75. [PubMed]
  • Tomatis L. Overview of perinatal and multigeneration carcinogenesis. IARC Sci Publ. 1989;(96):1–15. [PubMed]
  • Van den Berg M, Birnbaum L, Bosveld AT, Brunström B, Cook P, Feeley M, Giesy JP, Hanberg A, Hasegawa R, Kennedy SW, et al. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect. 1998 Dec;106(12):775–792. [PMC free article] [PubMed]
  • Walker BE, Kurth LA. Multi-generational carcinogenesis from diethylstilbestrol investigated by blastocyst transfers in mice. Int J Cancer. 1995 Apr 10;61(2):249–252. [PubMed]
  • Warner Marcella, Eskenazi Brenda, Mocarelli Paolo, Gerthoux Pier Mario, Samuels Steven, Needham Larry, Patterson Donald, Brambilla Paolo. Serum dioxin concentrations and breast cancer risk in the Seveso Women's Health Study. Environ Health Perspect. 2002 Jul;110(7):625–628. [PMC free article] [PubMed]
  • Weiss HA, Potischman NA, Brinton LA, Brogan D, Coates RJ, Gammon MD, Malone KE, Schoenberg JB. Prenatal and perinatal risk factors for breast cancer in young women. Epidemiology. 1997 Mar;8(2):181–187. [PubMed]
  • Yu W, Sipowicz MA, Haines DC, Birely L, Diwan BA, Riggs CW, Kasprzak KS, Anderson LM. Preconception urethane or chromium(III) treatment of male mice: multiple neoplastic and non-neoplastic changes in offspring. Toxicol Appl Pharmacol. 1999 Jul 15;158(2):161–176. [PubMed]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Science


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...