Journal Article

Structural Requirements for the Interaction of 91 Hydroxylated Polychlorinated Biphenyls with Estrogen and Thyroid Hormone Receptors

Sundaram Arulmozhiraja, Fujio Shiraishi, Tameo Okumura, Mitsuru Iida, Hidetaka Takigami, John S. Edmonds and Masatoshi Morita

in Toxicological Sciences

Volume 84, issue 1, pages 49-62
Published in print March 2005 | ISSN: 1096-6080
Published online December 2004 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfi063
Structural Requirements for the Interaction of 91 Hydroxylated Polychlorinated Biphenyls with Estrogen and Thyroid Hormone Receptors

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Estrogenic and thyroid activities of 91 monohydroxylated PCBs were measured with two-hybrid assays using yeast cells containing the human estrogen receptor ERα or human thyroid receptor TRα. Estrogenic activity of 30 of the 91 compounds, including all compounds active in the yeast two-hybrid assay, were also measured by a reporter gene assay employing Chinese hamster ovary cells. The mammalian cell assay was more sensitive than the yeast assay but the rank order of estrogenicities of the compounds were in broad agreement for the two assays. Results for estrogenicity and thyroid activity were analyzed by inspection and those for estrogenicity by a theoretical treatment. Inspection indicated para-hydroxyl was more likely to be estrogenically active than meta-, which was more likely to be active than ortho-; one ortho-chlorine was important for activity but additional ortho-chlorines did not increase activity; and 2 lateral chlorines or 2,4,6-chloro- substitution of the non-phenol ring were favorable. In contrast, thyroid activity appeared not to depend strongly on the position of the hydroxyl group although ortho-hydroxyls occurred in the most active compounds. Activity was usually associated with at least one ortho-chlorine, with 2 chlorines in the phenolic ring and, importantly, two chlorines in the non-phenolic ring, and with 1 or 2 chlorines ortho to the hydroxyl group. Examination of the torsion angle between the rings, in the theoretical examination of estrogenicity, suggested that perpendicular orientation (i.e., rigidity) was not essential for activity. Intramolecular hydrogen bonding of the phenolic groups to adjacent chlorines or to the π-electron cloud of the non-phenol ring possibly decreased activity—the hydroxyl should be free of intramolecular interactions for maximum activity. It was difficult to predict the estrogenic activity of a congener from its obtained potential energy curve (PEC). In general, estrogenically active congeners had large values for the sum of the atomic charges on the carbon atoms of the hydroxylated ring, and on the oxygen atom. Hydroxyl substitution at the para-position allowed the compounds to become more polarizable in the x-axis (molecular axis), whereas OH substitution at the ortho-position made the congeners less polarizable in the same direction. However, no general statement about polarizability and estrogenic activity was possible.

Keywords: hydroxylated polychlorinated biphenyls; hydro-xylated PCBs; estrogenicity; thyroid hormone activity; yeast two-hybrid assay; Chinese hamster ovary cell assay; structure-activity relationships

Journal Article.  9013 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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