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Structure–activity relationships for gene activation oestrogenicity: Evaluation of a diverse set of aromatic chemicals
Author(s) -
Schultz T. Wayne,
Sinks Glendon D.,
Cronin Mark T. D.
Publication year - 2002
Publication title -
environmental toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.813
H-Index - 77
eISSN - 1522-7278
pISSN - 1520-4081
DOI - 10.1002/tox.10027
Subject(s) - moiety , chemistry , hydrogen bond , ring (chemistry) , stereochemistry , xenoestrogen , benzene , molecule , organic chemistry , biology , cancer , estrogen receptor , breast cancer , genetics
Structure–activity relationships for oestrogenicity were developed based on 120 aromatic chemicals evaluated in the Saccharomyces cerevisiae ‐based Lac ‐Z reporter assay. Relative gene activation was compared to 17β‐estradiol and varied over eight orders of magnitude. Analysis of the data compared to 17β‐estradiol identified three structural criteria that were related to xenoestrogen activity and potency: (1) the hydrogen‐bonding ability of the phenolic ring mimicking the A‐ring, (2) a hydrophobic centre similar in size and shape to the B‐ and C‐rings, and (3) a hydrogen‐bond donor mimicking the 17β‐hydroxyl moiety of the D‐ring, especially with an oxygen‐to‐oxygen distance similar to that between the 3‐ and 17β‐hydroxyl groups of 17β‐estradiol. Binding data were segregated into activity clusters including strong, moderate, weak, and detectable gene expression, and those compounds that were inactive. The hydrogen‐bonding ability of hydroxy group in the 3‐position on 17β‐estradiol was observed to be essential for gene activation. Compounds with a 4‐hydroxyl substituted benzene ring and a hydrophobic moiety of size and shape equivalent to the B‐ring of 17β‐estradiol were generally observed to be weakly active compounds. Moderately active compounds have a 4‐hydroxyl substituted benzene ring with a hydrophobic moiety equivalent in size and shape to the B‐ and C‐ring of 17β‐estradiol, or have a high hydrogen‐bond donor capacity owing to the presence of halogens on a nonphenolic ring. Strongly active compounds, similar to 4,4′‐diethylethylene bisphenol (DES), possess the same hydrophobic ring structure as described for moderately active compounds and an additional hydroxyl group with an oxygen‐to‐oxygen distance close to that exhibited by the 3‐ and 17‐hydroxyl groups of 17β‐estradiol. © 2002 by Wiley Periodicals, Inc. Environ Toxicol 17: 14–23, 2002