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Maria Johansson,¹ Stefan Nilsson,² and Bert-Ove Lund¹

¹Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden
²Karo Bio AB, Huddinge, Sweden

Abstract

Persistent polychlorinated biphenyl (PCB) metabolites were studied with respect to their interaction with the human glucocorticoid receptor (GR) . 3-Methylsulphonyl-2,5,6,2´,4´,5´-hexachlorobiphenyl (3-MeSO₂-CB149) was shown to compete with ³H-dexamethasone for binding to the GR, with an IC₅₀ (concentration that inhibits 50%) of approximately 1 µM. Using GRAF cells expressing human GR, glucocorticoid responsive element, and a reporter enzyme, we demonstrated that 3-MeSO₂-CB149 functionally acts as an antagonist at the GR (IC₅₀ = 2.7 µM) . In accordance with the receptor binding, the antagonism mainly appeared to be of a competitive nature. When studying the competitive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR from mouse liver cytosol, seven compounds had a higher affinity to GR than 3-MeSO₂-CB149. Structure-activity relationship studies indicated that the presence of three chlorine atoms in the ortho-position and chlorine and methyl sulfone groups on either end of the molecule (4 and 4´-position) increased the affinity to GR. The relevance of this finding for human health is not known, but PCB methyl sulfones are ubiquitous pollutants present in mother's milk. The results stress the need for studying endocrine disruptors that affect hormonal systems other than sex and thyroidogenic hormones. Key words: endocrine disruptor, glucocorticoid receptor, methyl sulphone, PCB, polychlorinated biphenyls, xenobiotic. Environ Health Perspect 106:769-772 (1998) . [Online 12 November 1998]

http://ehpnet1.niehs.nih.gov/docs/1998/106p769-772johansson/ abstract.html

Address correspondence to B.-O. Lund, Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, BMC Box 573, SE-751 23 Uppsala, Sweden.

We are grateful to Lars-Göran Bladh and Sanja Juric for technical assistance, Christina Larsson for synthesis of methyl sulfones, Anne-Cathrine Adlercreutz for secreterial assistance, and the Swedish Environmental Protection Agency for economical support.

Received 18 May 1998 ; accepted 17 July 1998.