The Estrogen Receptor Relative Binding Affinities of 188 Natural and Xenochemicals: Structural Diversity of Ligands

Abstract

We have utilized a validated (standardized) estrogen receptor (ER) competitive-binding assay to determine the ER affinity for a large, structurally diverse group of chemicals. Uteri from ovariectomized Sprague-Dawley rats were the ER source for the competitive-binding assay. Initially, test chemicals were screened at high concentrations to determine whether a chemical competed with [3H]-estradiol for the ER. Test chemicals that exhibited affinity for the ER in the first tier were subsequently assayed using a wide range of concentrations to characterize the binding curve and to determine each chemical's IC50 and relative binding affinity (RBA) values. Overall, we assayed 188 chemicals, covering a 1 x 10(6)-fold range of RBAs from several different chemical or use categories, including steroidal estrogens, synthetic estrogens, antiestrogens, other miscellaneous steroids, alkylphenols, diphenyl derivatives, organochlorines, pesticides, alkylhydroxybenzoate preservatives (parabens), phthalates, benzophenone compounds, and a number of other miscellaneous chemicals. Of the 188 chemicals tested, 100 bound to the ER while 88 were non-binders. Included in the 100 chemicals that bound to the ER were 4-benzyloxyphenol, 2,4-dihydroxybenzophenone, and 2,2'-methylenebis(4-chlorophenol), compounds that have not been shown previously to bind the ER. It was also evident that certain structural features, such as an overall ring structure, were important for ER binding. The current study provides the most structurally diverse ER RBA data set with the widest range of RBA values published to date.

Structure−Activity Relationships for a Large Diverse Set of Natural, Synthetic, and Environmental Estrogens

“…All assays were repeated at least twice; the IC50 values of positive chemicals are the means of the replicate values. The standard deviation of IC50 for each chemical was reported (23), and only the mean RBA value was used for this study. The purity of chemicals as well as their effect on RBAs was also studied by Blair et al (23).…”

Emerging contaminants in surface waters and their relevance for the production of drinking water in Europe

“…Laboratory research has shown that a large number of different chemicals can exert estrogenic effects (Blair et al 2000;Legler et al 2000;Nishihara et al 2000;Houtman et al 2004b), including the natural estrogenic hormones 17b-estradiol, estriol and estrone, the synthetic estrogenic hormone and contraceptive pill ingredient 17a-ethynylestradiol, and phytoestrogens like isoflavonoides and coumestrol. Furthermore, various pesticides and industrial compounds, such as alkylphenols, alkylphenolethoxylates, and bisphenol A, which are applied as surfactants, plasticizers, and raw materials for the production of polycarbonate plastic, are estrogenic.…”

Ozone treatment prevents the toxicity of an environmental mixture of estrogens on rat fetal testicular development

“…EE2>E2>E3>E1 [29]. It is important to note that the present experiments were designed to evaluate the impact of the overall estrogenic activity of the MIX and the contribution of each individual compound is impossible to measure.…”