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Interactions between methylsulfonyl PCBs and the glucocorticoid receptor
M Johansson1, S Nilsson, B O Lund
1Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Environmental Health Perspectives
|November 30, 1998
Summary
Persistent organic pollutants called polychlorinated biphenyl (PCB) metabolites can interfere with the human glucocorticoid receptor (GR). Some PCB metabolites act as antagonists, blocking GR function and potentially disrupting hormonal systems.
Area of Science:
- Environmental Chemistry
- Endocrinology
- Toxicology
Background:
- Polychlorinated biphenyls (PCBs) are persistent environmental pollutants.
- PCB metabolites, specifically methylsulfonyl PCBs, are found ubiquitously, including in human milk.
- The interaction of these metabolites with critical hormone receptors, like the glucocorticoid receptor (GR), is not well understood.
Purpose of the Study:
- To investigate the interaction of persistent PCB metabolites with the human glucocorticoid receptor (GR).
- To determine if PCB metabolites can functionally antagonize the GR.
- To explore structure-activity relationships for PCB metabolite binding affinity to the GR.
Main Methods:
- Competitive binding assays using 3H-dexamethasone and human GR.
- Functional assays in GRAF cells expressing human GR and a reporter enzyme.
- Analysis of 24 different methylsulfonyl PCB compounds for GR binding affinity.
Main Results:
- 3-Methylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) competed with dexamethasone for GR binding (IC50 ≈ 1 µM).
- 3-MeSO2-CB149 acted as a competitive antagonist of the human GR in functional assays (IC50 = 2.7 µM).
- Seven other methylsulfonyl PCBs exhibited higher affinity for the GR than 3-MeSO2-CB149, with specific structural features enhancing binding.
Conclusions:
- Certain PCB methyl sulfone metabolites can bind to and antagonize the human glucocorticoid receptor.
- Structural characteristics, including chlorination patterns, influence the affinity of PCB metabolites for the GR.
- These findings highlight the potential for PCB metabolites to act as endocrine disruptors impacting the glucocorticoid system, necessitating further research into their human health relevance.