Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals

doi:10.1016/0959-8049(93)90597-9

European Journal of Cancer

Volume 29, Issue 1, 1993, Pages 149-155

https://doi.org/10.1016/0959-8049(93)90597-9 Get rights and content

Abstract

Diethylstilboestrol (DES) exerts several toxic effects in experimental animals, by mechanisms which are still unclear. The genotoxicity of the drug has been attributed to a quinone metabolite and is mainly clastogenic, including sister chromatid exchange, unscheduled DNA synthesis, chromosomal aberrations, disruption of mitotic spindle and aneuploidy. There is evidence that genotoxic effects may occur also transplacentally. Intrauterine and early postnatal exposure to DES can cause a variety of dysplasias. In the offspring of female mice exposed to DES during pregnancy, histological changes are observed in the vaginal and cervical epithelium, the endometrium, the ovary, the testis and the epididymis. Prenatal exposure of rats to DES led to decreased litter size and to urethrovaginal cloaca, penile and testicular hypoplasia, and cryptorchidism. Vaginal ridging, vaginal adenosis, testicular hypoplasia and cryptorchidism have been observed in rhesus monkeys following prenatal exposure. There is sufficient evidence that diethylstilboestrol is carcinogenic in experimental animals, after either prenatal or postnatal exposure. Mice show a similar type of carcinogenicity to that observed in humans, target organs being vagina, cervix, uterus, ovary, mammary gland and testis. In rats, prenatal exposure to DES produces mostly mammary and pituitary tumours, but also some tumours of the vagina. Hamsters develop tumours of vagina, cervix, endometrium, epididymis, testis, liver and kidney. DES induces ovarian papillary carcinomas in dogs, and malignant uterine mesotheliomas in squirrel monkeys. Some experimental evidence points to the possibility of a transgenerational carcinogenic effect, since prenatal treatment of mice with DES is followed by an increased incidence of uterine and ovarian carcinomas in the second-generation descendants. Experimental results could have been used to predict the adverse effects of DES observed in humans in the early 1970s: DES had been reported to be carcinogenic in mice in the 1930s, while experiments in the 1960s had provided evidence that exposure during pregnancy could result in an increased cancer risk in the progeny.

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Neonatal treatment of hamsters with diethylstilbestrol (DES) induces uterine hyperplasia/dysplasia/neoplasia (endometrial adenocarcinoma) in adult animals. We subsequently determined that the neonatal DES exposure event directly and permanently disrupts the developing hamster uterus (initiation stage) so that it responds abnormally when it is stimulated with estrogen in adulthood (promotion stage). To identify candidate molecular elements involved in progression of the disruption/neoplastic process, we performed: (1) immunoblot analyses and (2) microarray profiling (Affymetrix Gene Chip System) on sets of uterine protein and RNA extracts, respectively, and (3) immunohistochemical analysis on uterine sections; all from both initiation stage and promotion stage groups of animals. Here we report that: (1) progression of the neonatal DES-induced hyperplasia/dysplasia/neoplasia phenomenon in the hamster uterus involves a wide spectrum of specific gene expression alterations and (2) the gene products involved and their manner of altered expression differ dramatically during the initiation vs. promotion stages of the phenomenon.
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Concerns about environmental exposure to endocrine disruptors have first been raised in the 70s, when emerged that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, was associated with somatic effects in adulthood, including female genital abnormalities, vaginal cancer, and male urogenital disorders. DES had been largely used from 1948 to 1971 in the management of conditions as threatened abortions, pre-eclampsia, prior premature labor, prostatic and breast cancer, pregnancy complications in diabetic women [9–11]. It is estimated that 2 to 4.8 million human offspring were exposed to DES [12].
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Feature articleDiethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals

Abstract

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Feature article
Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals

Autoradiographic distribution studies of injected ³²P-labelled polydiethylstilbestrol phosphate

Metabolism of ¹⁴C-diethylstilbestrol in sheep

Depletion patterns of radioactivity and tissue residues in beef cattle after withdrawal of oral ¹⁴C-diethylstilbestrol

Fate of radiocarbon in beef steers implanted with ¹⁴C-diethylstilbestrol