Using three-dimensional quantitative structure-activity relationships to examine estrogen receptor binding affinities of polychlorinated hydroxybiphenyls.

Abstract

Certain phenyl-substituted hydrocarbons of environmental concern have the potential to disrupt the endocrine system of animals, apparently in association with their estrogenic properties. Competition with natural estrogens for the estrogen receptor is a possible mechanism by which such effects could occur. We used comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (QSAR) paradigm, to examine the underlying structural properties of ortho-chlorinated hydroxybiphenyl analogs known to bind to the estrogen receptor. The cross-validated and conventional statistical results indicate a high degree of internal predictability for the molecules included in the training data set. In addition to the phenolic (A) ring system, conformational restriction of the overall structure appears to play an important role in estrogen receptor binding affinity. Hydrophobic character as assessed using hydropathic interaction fields also contributes in a positive way to binding affinity. The CoMFA-derived QSARs may be useful in examining the estrogenic activity of a wider range of phenyl-substituted hydrocarbons of environmental concern.ImagesFigure 1.Figure 2.

Internal exposure to pollutants and body size in Flemish adolescents and adults: Associations and dose–response relationships

“…PCBs have xeno-estrogenic activity, mainly through their hydroxylated metabolites (Waller et al, 1995;Arulmozhiraja et al 2005), and can also have estrogenic effects by inhibiting the metabolism of endogenous oestradiol (Kester et al 2002). In the boys participating in this study , serum concentrations of marker PCBs showed a positive association with serum levels of endogenous sex hormones.…”

Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife

“…In addition, several biological or toxic effects have been described for PCBs, for example, which are probably not related to an Ah receptormediated mechanism of action. Among others, these effects include a decrease in dopamine levels (2,3), alterations in retinoid and thyroid hormone levels (4,5), and binding to the estrogen receptor (6). These effects show distinctly different structure-activity relationships for PCBs than those observed for Ah receptor binding involving multiple ortho chlorine substitution or hydroxylated metabolites.…”

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

“…These are generally focused on identification of structural characteristics for chemicals within similar two-dimensional (2D) structural frameworks, including E 2 derivatives (6), DES derivatives (8), PCBs (9), phytoestrogens (10), alkylphenols (11), raloxifenes (12), and others. Modern computer-based tools have enabled the development of quantitative structureactivity relationship (QSAR) models for identifying steric and electrostatic features of a molecule in three-dimensional (3D) space for estrogenic activity (8,(13)(14)(15)(16)(17)(18)(19). Recent crystallographic structures of the human ER R subtype (hERR) with a number of ligands, including E 2 , DES, raloxifene, and 4-OH-tamoxifene, have also been reported (20,21).…”