Interactions between methylsulfonyl PCBs and the glucocorticoid receptor

Persistent polychlorinated biphenyl (PCB) metabolites were studied with res pect to their interaction with the human glucocorticoid receptor (GR). 3-Me thylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) was shown t o compete with H-3-dexamethasone for binding to the GR, with an IC50 (conce ntration that inhibits 50%) of approximately 1 mu M. Using GRAF cells expre ssing human GR, glucocorticoid responsive element, and a reporter enzyme, w e demonstrated that 3-MeSO2-CB149 functionally acts as an antagonist at the GR (IC50 = 2.7 mu M). In accordance with the receptor binding, the antagon ism mainly appeared to be of a competitive nature. When studying the compet itive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR f rom mouse liver cytosol, seven compounds had a higher affinity to GR than 3 -MeSO2-CB149. Structure-activity relationship studies indicated that the pr esence of three chlorine atoms in the ortho-position and chlorine and methy l sulfone groups on either end of the molecule (4 and 4'-position) increase d 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 milli The results stress the need for studying endocrine disrupters that affect hormonal systems other than sex and thyroidogenic hormones.