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Xenoestrogenic gene expression: structural features of active polycyclic aromatic hydrocarbons
T Wayne Schultz1, Glendon D Sinks
1Department of Comparative Medicine, College of Veterinary Medicine, The University of Tennessee, Knoxville 37996-4500, USA. tschultz@utk.edu
Environmental Toxicology and Chemistry
|April 16, 2002
Summary
This study assessed the estrogenicity of polycyclic aromatic hydrocarbons (PAHs) using a reporter assay. A 2D structural alignment rule successfully predicted estrogenicity for most PAHs, with exceptions noted for certain nitrogen-heterocyclic and dihydroxylated compounds.
Area of Science:
- Environmental Chemistry
- Toxicology
- Molecular Biology
Background:
- Polycyclic Aromatic Hydrocarbons (PAHs) are environmental contaminants with potential endocrine-disrupting effects.
- Estrogenic activity of PAHs is a significant concern due to potential health impacts.
- Understanding structure-activity relationships is crucial for predicting and mitigating PAH estrogenicity.
Purpose of the Study:
- To quantify the relationship between the molecular structure of PAHs and their estrogenic gene expression.
- To evaluate the applicability of a known 2D structural alert for estrogenicity to a series of PAHs.
- To identify structural features that lead to false positives or negatives in estrogenicity predictions for PAHs.
Main Methods:
- Estrogenicity was assessed using a Saccharomyces cerevisiae-based Lac-Z reporter assay.
- Results were quantified as the logarithm of the inverse of the 50% molar beta-galactosidase activity (log[EC50(-1)]).
- A series of PAHs were evaluated for estrogenic activity and their structures analyzed.
Main Results:
- A 2D structural alignment criterion, based on superpositioning a hydroxylated aromatic system on the phenolic A-ring of 17-beta-estradiol, correctly identified estrogenicity in 22 of 29 evaluated PAHs.
- Estrogenic potency generally correlated with the size of the hydrophobic backbone of the PAHs.
- Seven compounds, including dihydroxylated naphthalenes and aromatic nitrogen-heterocyclic compounds, were incorrectly classified (false positives).
Conclusions:
- The 2D structural alignment criterion is a useful initial screen for PAH estrogenicity but has limitations.
- Specific structural features, such as a second hydroxyl group on the C-ring or catechol-like structures in dihydroxylated naphthalenes, reduce or abolish estrogenicity.
- For nitrogen-heterocyclic compounds, the relative positions of the hydroxyl group and the in-ring nitrogen atom are critical for determining estrogenic activity.