Diethylstilboestrol

There is some evidence for chemically mediated endocrine disruption in amphibians. The egg yolk protein, vitellogenin, is inducible in amphibians by exposure to DDT. " Males of the short clawed toad Xenopus laevis given 250 fig/g or 1 fig/g o,p -DDT for seven days have been shown to produce vitellogenin, although the induction was less than that achieved by treatment with 1 fig/g of either 17/1-oestradiol or diethylstilboestrol. Research has also shown that endocrine disrupting chemicals can alter sex ratios in wild populations of certain species PCB congeners and organochlorine compounds have been linked with male domination of sex ratios in polluted compared to unpolluted sites. ... 

Fig. 1. The structures of sugar-transport inhibitors, (a) Phloretin, (b) diethylstilboestrol, (c) 2-A -[4-(l-azi-2,2,2-trifluoroethyl)benzoyl]-l,3-bis-(D-mannos-4-yloxy)-2-propylamine (ATB-BMPA), (d) forskolin, (e) androsten-4-ene-3,17-dione, (0 cytochalasin B.

Glucose transport in the erythrocyte is also potently inhibited by a series of biphenolic compounds, including diethylstilboestrol and related compounds, and phloretin, whose structures are shown in Fig. 1. Diethylstilboestrol inhibits transport with a K of about 5 [35] and phloretin inhibits with a K of about 2 /rM [36]. 

Natural oestrogens generally only retain a significant proportion of their activity if administered intravenously. Several synthetic analogues have been developed which can be administered orally. Most of these substances also display more potent activity than native oestrogen. The most important synthetic oestrogen analogues include ethinyloestradiol and diethylstilboestrol (often simply termed stilboestrol). These are orally active and are approximately 10 and 5 times (respectively) more potent than oestrone. 

Bis-(4-hydroxyphenyl)hexane [5635-50-7] M 270.4, m 187°. Freed from diethylstilboestrol by zone refining. 

Unsaturated aliphatic compounds and heterocyclic compounds may also be metabolized via epoxide intermediates as shown in Figure 4.6 and chapter 5, Figure 14. Note that when the epoxide ring opens, the chlorine atom shifts to the adjacent carbon atom (Fig. 4.6). In the case of the furan ipomeanol and vinyl chloride, the epoxide intermediate is thought to be responsible for the toxicity (see below and chap. 7). Other examples of unsaturated aliphatic compounds, which may be toxic and are metabolized via epoxides, are diethylstilboestrol, allylisopropyl acetamide, which destroys cytochrome P-450, sedormid, and secobarbital. 

The carcinogen diethylstilboestrol induces tumors in those female organs particularly exposed to estrogens, namely, the mammary glands, uterus, and vagina (fig. 6.28). In male hamsters, however, this compound causes kidney tumors. 

Figure 6.28 Metabolism of diethylstilboestrol via an epoxide intermediate. This potentially reactive intermediate may show an affinity for the estradiol receptor and thereby accumulate in oestrogen target organs. This may facilitate reaction with DNA in these organs. Source. From Ref. 10.

Lempert P. Myopia in diethylstilboestrol exposed amblyopic subjects. Br J Ophthalmol 1999 83(1) 126. 

RUdiger, H.W., F. Haenisch, M. Metzler, F. Oesch, and H.R. Glatt. Metabolites of diethylstilboestrol induced sister chromatid exchange in human fibroblasts. Nature 281 392-394, 1979. 

For humans, except for cases where high levels of exposure have occurred (for example, in the therapeutic use of diethylstilboestrol), the data is inconsistent and inconclusive. Information on levels of exposure is lacking and there is no firm evidence for a Hnk between low level exposure and adverse health outcomes in the human population. For all the adverse health outcomes the evidence of association with environmental exposure to endocrine disruptors is weak (except in the case of minor effects on thyroid hormones, where evidence is moderate). In some cases, such as changes in sperm count, a possible connection is scientifically plausible. Further evidence is needed, and especially evidence that Hnks actual exposure levels in humans to effects. ... 

Several papers have discussed either synthetic approaches to, or structure modifications of, substances related to diethylstilboestrol, which may be considered as a diseco-steroid. "" trans-3-(p-methoxystyryl)-2-methylcyclopentan-1-one (316) was prepared (Scheme 21) by reduction of ethyl 2-methyl-3-ethylene-... 

Herbst A L1984 Diethylstilboestrol exposure—1984 [effects of exposure during pregnancy on mother and daughters]. New England Journal of Medicine 311 1433-1435... 

When studied by a traditional, oestrogen-metabolism bioassay method, genistein was seen to be a very weak oestrogen. Its estrogenic potency was estimated at only 10 times the potency of diethylstilboestrol. 

---