Synthetic Estrogens and the Relation Between their Structure and their Activity.

Solmssen, U.

doi:10.1021/cr60118a004

Cited by 92 publications

(40 citation statements)

References 85 publications

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“…This work included the first demonstration of the weak estrogenic activity of bisphenol A (BPA) based on activity in a vaginal cornification assay (Dodds and Lawson, 1936). From these early efforts, a large body of work has been devoted to explaining and predicting the estrogenic activity of substances based on structure-activity relationships that preceded the discovery of the ER (for early reviews see Grundy, 1957;Solmssen, 1945).…”

Section: History Of Estrogen Structure-activity Investigationsmentioning

confidence: 99%

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Owens

Ashby

2002

Critical Reviews in Toxicology

110

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A current issue for regulatory agencies is endocrine-related modes of action such as those mediated by the estrogen, androgen, and thyroid nuclear receptors. At the national and international levels, the consensus recommendation for the assessment of such modes of action is a tiered series of in vitro and in vivo protocols. The tiered framework begins with screens for structural alerts and then moves to rapid, mechanistic in vitro screening assays, and then to in vivo screening bioassays. The objective of these screens is to identify substances that may warrant testing for endocrine-mediated adverse effects. The final framework tier as needed is to test these substances in long-term bioassays for adverse endocrine-mediated reproductive and/or developmental effects. The subject of this review, the rodent uterotrophic bioassay, is intended to be a rapid in vivo screening bioassay for possible estrogen agonists and based on the response of the estrogen-sensitive uterus. The central metric of bioassay is a statistically significant increase in the weight of the uterus after 3 consecutive days of test substance administration. The extensive background literature is summarized in this review on the mode of action underlying the bioassay and the uterine response to estrogens. The review includes the bioassay's history of development and how its employment has changed and evolved over time. The review describes two major uterotrophic bioassay versions, the intact, immature female and the mature, ovariectomized female, and the protocol factors likely to influence relevance, reproducibility, and reliability of bioassay. The emphasis of the review is the ability of the uterotrophic bioassay to identify the substances of current interest: weak estrogen agonists with binding affinities relative to the natural 17beta-estradiol in the log 0 to log -3 range. Using selected model substances having RBAs in this target range, the bioassay's performance in a hierarchical, tiered approach is evaluated, including the predictive capability of the uterotrophic bioassay based on available reproductive and developmental testing data. The review concludes that the uterotrophic bioassay is reliable and can identify substances that may act via an estrogen-mode of action, supporting the validity of the uterotrophic bioassay and its regulatory use as an in vivo mechanistic screening bioassay for estrogen agonists and antagonists.

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Section: History Of Estrogen Structure-activity Investigationsmentioning

confidence: 99%

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Owens

Ashby

2002

Critical Reviews in Toxicology

110

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“…hydroxyl group has generally been observed to be necessary for hormonal activity (Solmssen, 1945). It was not surprising, therefore, that pretreatment of immature rats with CCI 4 reduced the uterotropic activity of o,p'-DDT (Welch et al, 1969a), since this pretreatment should reduce the rate of metabolism of o,p'-DDT.…”

Section: Chlorinated Hydrocarbons 331mentioning

confidence: 99%

Estrogenlc activities of chlorinated hydrocarbons

Nelson¹,

Struck²,

James³

1978

Journal of Toxicology and Environmental Health

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Some DDT analogs are estrogenic, particularly o,p'-DDT, which comprises approximately 15-20% of the commercial DDT mixture. Whether this compound or its metabolites are active has not been established. In fact, the data obtained thus far are more confusing than enlightening. For example, CCl4 pretreatment of immature female rats has been reported to inhibit or enhance estrogenic activity of o,p'-DDT, and SKF-525A pretreatment has been reported to enhance or not alter the estrogenic effect. Although o,p'-DDT inhibits binding of estradiol to the estrogen receptor from rat or human at low levels (approximately 1-10 micrometer) in vitro, higher levels are required to inhibit nuclear binding of [3H] estradiol in incubated whole uteri. Futhermore, o,p'-DDT appears to be neither estrogenic nor antiestrogenic in an in vitro estrogen assay. Methoxychlor appears to be "activated" by metabolism, and it is probable that phenolic metabolites are responsible for its estrogenic activity. Since chlorinated hydrocarbons often enhance the metabolism of steroids and may reduce circulating levels of steroids, interactions of the exogenous hormonally active agents with steroid receptors may be self-potentiating in vivo.

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“…In fact, the differing effects of oestro¬ gen :androgen interaction on the reproductive tract and the RES may be due to differences in the binding properties of the cell membrane proteins in these two target areas. It has been stated that steroid activity of any given type depends on chemical specificity (Solmssen, 1945;Schueler, 1946;Gordon, 1950;Höhn, 1952). This suggests that these hormones function in metabolism by forming essential links with other substances, presumably proteins, and evidence has been produced showing that the circulating oestrogens become more firmly bound to protein than the other steroids .…”

Section: Stilbenesmentioning

confidence: 99%

The Effects of Oestrogen: Androgen Interaction on the Reticulo-Endothelial System and Reproductive Tract

Nicol¹,

Vernon‐Roberts²,

Quantock³

1966

Journal of Endocrinology

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1) Oestrone, oestriol, 17\g=b\-oestradiol,ethinyloestradiol, oestradiol monobenzoate, diethylstilboestrol, 4-hydroxy-\g=a\,\g=b\-diethyldibenzyl(HDB), dienoestrol, hexoestrol, triphenylethylene and tri-p-anisylchloroethylene (TACE) stimulated the reticulo-endothelial system (RES) in intact male and in ovariectomized female mice.(2) Testosterone propionate inhibited the vaginal smear response to all the above oestrogenic compounds. It also inhibited the RE stimulation produced by oestrone, oestriol, ethinyloestradiol, oestradiol monobenzoate, triphenylethylene and TACE but had no effect on RE stimulation by diethylstilboestrol, HDB, dienoestrol or hexoestrol; it markedly potentiated the stimulant effect of 17\g=b\-oestradiol on the RES.(3) The effect on the RES of oestrogen : androgen interaction does not appear to be dependent on the type of androgen used.

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Synthetic Estrogens and the Relation Between their Structure and their Activity.

Cited by 92 publications

References 85 publications

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Estrogenlc activities of chlorinated hydrocarbons

The Effects of Oestrogen: Androgen Interaction on the Reticulo-Endothelial System and Reproductive Tract

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