Abstract
The site and specificity of the tissue response to a toxicant are of central importance; it is in this area of Diethylstilbestrol (DES) toxicity that the estrogen receptor would appear to play its primary role. Compilation of the various sites of DES toxicity in humans and experimental animals indicates that lesions appear predominantly in estrogen responsive target tissues suggesting that the presence of the estrogen receptor in such target tissues may help govern the tissue specificity of the toxic insult. DES and many of its oxidative metabolites interact with high affinity with the estrogen receptor. Such an interaction may be responsible for localizing DES to target tissues. Autoradiographic and biochemical studies have supported the localization of radiolabeled DES in susceptible tissues. The intracelullar mechanism of receptor binding of DES and certain metabolites could then result in mobilization of these compounds to the nucleus. Experimental evidence has shown that DES and a number of its metabolites are able to translocate receptor to the nucleus of uterine cells. Such an action by the receptor results in an increased probability of potential chemical interactions with the genome. The actual induction of a chemical lesion in the target cell may, at this point, proceed by non-receptor mediated mechanisms. For example, studies using in vitro cell culture systems which contain no estrogen receptors have shown that DES can induce neoplastic cell transformation, mutagenesis, irreversible binding to DNA and protein and unscheduled DNA synthesis. These results raise the possibility that a part of DES toxicity may follow pharmacologic principles established for chemical carcinogens. Following induction of the molecular lesion, the role of the receptor continues in this process by mediating increased protein synthesis and mitogenesis in responsive target tissues which ultimately permits a more extensive expression of the toxic effects. It has been demonstrated that DES is a potent mitogen in vivo in both uterine and pituitary tissues, subsequently, the lesion will perpetuate itself through this receptor mediated biological response. This is particularly important since a number of DES induced reproductive tract tumors are expressed only after additional estrogen exposure. While other tumors have been shown to be estrogen sensitive and will regress without continued estrogen stimulation. Therefore, it should be considered that the presence of the estrogen receptor and the estrogen receptor mediated biological responsiveness of a particular tissue are most important in explaining the specificity of DES toxicity.
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References
Barnes, A.B., Colton, T. and Gunderson, J. (1980) Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. New Engl J Med 302: 609–613.
Bengtsson, G. and Ullberg, S. (1963) The autoradiographic distribution pattern after administration of diethylstilbestrol compared with that of natural oestrogens. Acta Endocrinol (Copenh) 43: 561–570.
Berger, M.J. and Goldstein, D.P. (1980) Impaired reproductive performance in DES-exposed women. Obstet Gynecol 55: 25–29.
Clark, J.H. and McCormack, S.A. (1977) Clomid or Nafoxidine administered to neonatal rats causes reproductive tract abnormalities. Science 197: 164–165.
DeCherney, A.H., Cholst, I. and Naftolin, F. (1981) Structure and function of the fallopian tube following exposure to diethylstilbestrol ( DES) during gestation. Fertil Steril 36: 741–743.
Degen, G.H., Eling, T.E. and McLachlan, J.A. (1982) Oxidative metabolism of diethylstilbestrol by prostaglandin synthetase. Caner Res 42: 919–923.
Dieckmann, W.J., Davis, M.E., Rynkiewicz, L.M. and Pottinger, R.E. (1953) Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obst Gynecol 66: 1062–1081.
Dodds, E.C., Golberg, L., Lawson, W. and Robinson, R. (1938) Oestrogenic activity of certain synthetic compounds. Nature 141: 247–250.
Forsberg, J-G. (1967) The development of atypical epithelium in the mouse uterine cervix and vaginal fornix after neonatal oestradiol treatment. Br J Exp Pathol 50: 187–194.
Gill, W.B., Schumacher, G.F.B. and Bibbo, M. (1976) Structural and functional abnormalities in the sex organs of male offspring of mothers treated with diethylstilbestrol ( DES ). J Reprod Med 16: 147–153.
Gorski, J. and Gannon, F. (1976) Current models of steroid hormone action: a critique. Ann Rev Physiol 38: 425–450.
Haney, A.F., Hammond, C.B., Saules, M.R. and Creasman, W.T. (1979) Diethylstilbestrol-induced upper genital tract abnormalities. Fert Steril 31: 142–146.
Herbst, A.L. and Bern, H.A. (1981) Developmental Effects of Diethylstilbestrol (DES) in Pregnancy. Thieme-Stratton, Inc. New York.
Herbst, A.L., Ulfelder, H. and Poskanzer, D.C. (1971) Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284: 878–881.
Kaufman, R.H., Binder, G.L. and Gray, P.M. (1977) Upper genital tract changes associated with exposure in utero to diethylstilbestrol. Am J Obstet Gyneco 128: 51–59.
King, W.J. and Greene, G.L. (1984) Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 307: 745–747.
Korach, K.S. (1981) Selected Biochemical Actions of Ovarian Hormones. Environ Hlth. Perspect 38: 39–45.
Korach, K.S. (1982) Biochemical and estrogenic activity of some diethylstilbestrol metabolites and analogs in the mouse uterus. In: Leavitt, W.W. (ed.): Hormones and Cancer, Plenum Press, New York, p 39.
Korach, K.S., Metzler, M. and McLachlan, J.A. (1978) Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs. Proc Natl Acad Sci 75: 468–4717.
Korach, K.S., Metzler, M. and McLachlan, J.A. (1979) Diethylstilbestrol metabolites and analogs: new probes for the study of hormone action. J Biol Chem 254: 8963–8972.
Lamartiniere, C.A., Dieringer, G.S. and Lucier, G.W. (1979) Altered sexual differentiation of hepatic UDP glucuronyltransferase by neonatal hormone treatment. Biochem J 180: 313–320.
Leavitt, W.W., Evans, R.W. and Hendry, W.J. (1982) Etiology of DES-induced uterine tumors in the Syrian hamster. In: Leavitt, W.W. (ed.): Hormones and Cancer, Plenum Press, New York, p 63–86.
Liehr, J.G., DaGue, B.B., Ballatore, A.M. and Henkin, J. (1983) Diethylstilbestrol (DES) quinone: a reactive intermediate in DES metabolism. Biochem Pharmacol 32: 3711–3717.
Maydl, R., Newbold, R.R., Metzler, M. and McLachlan, J.A. (1983) Diethylstilbestrol metabolism by the fetal genital tract. Endocrinology 113: 146–151.
McLachlan, J.A. (1977) Prenatal exposure to diethylstilbestrol in mice: toxicological studies. J Toxicol Environ Hlth 2: 527–537.
McLachlan, J.A., Newbold, R.R. and Bullock, B.C. (1980) Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res 40: 3988–3999.
McLachlan, J.A., Newbold, R.R., Shah, H.C., Hogan, M.D., and Dixon, R.L. (1982) Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril 38 (3): 364–371.
McLachlan, J.A., Wong, A., Degen, G.H. and Barrett, J.C. (1982) Morphologic and neoplastic transformation of Syrian hamster embryo fibroblasts by diethylstilbestrol and its analogs. Cancer Res 42: 3040–3046.
Metzler, M. (1981) The metabolism of diethylstilbestrol. CRC Crit Rev Biochem 10: 171–212.
Metzler, M. and McLachlan, J.A. (1978) Peroxidase-mediated oxidation, a possible pathway for metabolic activation of diethylstilbestrol. Biochem Biophys Res Commun 85: 874–884.
Newbold, R.R. and McLachlan, J.A. (1982) Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Res 42: 2003–2011.
Newbold, R.R., Bullock, B.C. and McLachlan, J.A. (1983a) Exposure to diethylstilbestrol during pregnancy permanently alters the ovary and oviduct. Biol Reprod 28: 735–744.
Newbold, R.R., Tyrey, S., Haney, A.F. and McLachlan, J.A. (1983b) Developmentally arrested oviduct: a structural and functional defect in mice following prenatal exposure to diethylstilbestrol. Teratology 27: 417–426.
Peckham, B., Barash, H., Emlen, J., Kiekhofer, W. and Ladinsky, J. (1963) Changes in vaginal cellular activity elicited by varying doses of natural and synthetic estrogens. Exp Cell Res 30: 339–343.
Schmidt, G., Fowler, W.C., Talbert, L.M. and Edelman, D.A. (1980) Reproductive history of women exposed to diethylstilbestrol in utero. Fertil Steril 33: 21–26.
Smith, O.W. and Smith, G.S. (1949) Use of diethylstilbestrol to prevent fetal loss from complications of late pregnancy N Engl J Med 241: 562–565.
Stumpf, W.E., Narbeitz, R. and Sar, M. (1980) Estrogen receptors in the fetal mouse. J Steroid Biochem 12: 55–60.
Weishors, W.V., Lieberman, M.E. and Gorski, J. (1984) Nuclear localization of unoccupied oestrogen receptors. Nature 307: 747–749.
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Korach, K.S., McLachlan, J.A. (1985). The Role of the Estrogen Receptor in Diethylstilbestrol Toxicity. In: Chambers, P.L., Cholnoky, E., Chambers, C.M. (eds) Receptors and Other Targets for Toxic Substances. Archives of Toxicology, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-69928-3_4
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DOI: https://doi.org/10.1007/978-3-642-69928-3_4
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