Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs

Abstract

The diethylstilbestrol (DES) metabolite (8-dienestrol), which had been identified in mouse, rat, monkey, and human urine, and two proposed metabolic intermediates (diethylstilbestrol a,a'-epqxide and a,a'-dihydroxy DES) were synthesized and their estrogenic activities determined. In addition, three DES analogs, a-dienestrol, DES-dihydroxy diethyl phenanthrene (DES-phenanthrene), and 14a-ethyl, 4a-hydroxyphenyl)indanyl-5-ol (indanyl-DES), were studied. Estrogenic activities of the compounds in vivo were determined by the immature mouse uterine weight bioassay; in vitro, their estradiol receptor binding activity (competitive equilibrium binding, sucrose gradient analysis, and association rate inhibition assays) was determined. Results of the mouse uterine weight bioassay gave the following order of estrogenicity: DES > a-dienestrol Diethylstilbestrol (DES) is a nonsteroidal estrogen first synthesized and described by Dodds in 1938 (1). It has significant oral activity as an estrogenic substance and invokes a strong hormonal response equivalent to an injected dose of the steroidal estradiol-17fl.In recent years, reports by Herbst and colleagues (2) have linked in utero exposure to DES with subsequent developmernt of vaginal clear cell adenocarcinoma in a number of female offspring. A detailed review by Gunning of the human studies has been published (3). Investigations in our laboratory (4, 5) have been concerned with the development of an animal model system for studying this effect of in utero exposure.Pharmacokinetic studies with radiolabeled DES in the laboratory mouse model (6) have shown that this compound is localized in the fetal reproductive tract and associated struc-

Morphometric studies of neonatal estrogen imprinting in the mature mouse prostate

“…A recent study of DES and estradiol effects in male hamsters described severe disruption of reproductive function with neonatal DES (Khan et al 1998) which was attributed to lasting damage to the target tissue resulting in aberrant response to normal endocrine signals. Alternatively, DES effects may possibly be mediated by other mechanisms in addition to its interaction with estrogen receptors, like production of toxic metabolites (Korach et al 1978).…”

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: A review of rodent and human data

“…Obviously, the interpretation of those data is difficult due to differences in age at treatment, dose and age at study. Korach et al (1978) showed that uterus weight was doubled after injection of 5 µg/kg day of E2 between PND 23 and 26.…”

“…It does not bind α-fetoprotein, an estrogen-binding plasma protein, and can thus bind ERs in the fetal tissues much more actively than endogenous estrogens (McLachlan and Newbold, 1987). Korach et al (1978) GD: gestational day; PND: postnatal day; VO: vaginal opening; HP: hypothalamic-pituitary.…”

The immature mouse is a suitable model for detection of estrogenicity in the uterotropic bioassay.

“…Rats are commonly used in toxicologic testing, and many studies have been performed in this species (8)(9)(10)(11)(12)(13). Because of our experience with the CD-1 mouse and our previously published data on the uterotropic responses in this strain (14)(15)(16)(17)(18), we compared uterine responses in this mouse strain with responses in the Sprague-Dawley rat. We investigated the sensitivity of both species to varying doses of 17β-estradiol by comparing uterine wet weight increase and a number of morphologic and biochemical end points that are known estrogenic responses in both species (19)(20)(21)(22)(23)(24).…”