Structure-activity relationships for gene activation oestrogenicity: evaluation of a diverse set of aromatic chemicals.

Abstract:

: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 17 beta-estradiol and varied over eight orders of magnitude. Analysis of the data compared to 17 beta-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 17 beta-hydroxyl moiety of the D-ring, especially with an oxygen-to-oxygen distance similar to that between the 3- and 17 beta-hydroxyl groups of 17 beta-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 17 beta-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 17 beta-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 17 beta-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 17 beta-estradiol.

journal_name

Environ Toxicol

journal_title

Environmental toxicology

authors

Schultz TW,Sinks GD,Cronin MT

doi

10.1002/tox.10027

keywords:

subject

Has Abstract

pub_date

2002-02-01 00:00:00

pages

14-23

issue

1

eissn

1520-4081

issn

1522-7278

pii

10.1002/tox.10027

journal_volume

17

pub_type

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