ToxSci Advance Access published online on October 1, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn206
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A Concentration Addition Model for the Activation of the Constitutive Androstane Receptor by Xenobiotic Mixtures
1 William S. Baldwin, Clemson University, Inst of EnvironToxicology, Biological Sciences, 509 Westinghouse Rd., PO Box 709, Pendleton, SC 29670, Baldwin{at}clemson.edu.
2 Jonathan Roling, Bridgewater State College, Biological Sciences, 24 Park Avenue, Room 114, Bridgewater, MA 02325, jonathan.roling{at}usm.edu.
Received July 25, 2008; revision received September 17, 2008; accepted September 20, 2008
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Abstract |
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The effects of contaminants are typically studied in individual exposures; however, environmental exposures are rarely from a single contaminant. Therefore, the study of chemical mixtures is important in determining the effects of xenobiotics. The constitutive androstane receptor (CAR) responds to endobiotics and xenobiotics, and in turn induces detoxification enzymes involved in their elimination. First, we compared several androgens as inverse agonists, including androgens allegedly used by BALCO to enhance athletic performance. CAR inverse agonists ranked in order of potency were dihydroandrosterone > tetrahydrogestrinone (THG) > androstanol > norbolethone. Therefore, we used dihydroandrosterone as an inverse agonist during transactivation assays. Next, we examined the effects of several pesticides, plasticizers, steroids, and bile acids on CAR activation. Our data demonstrates that several pesticides and plasticizers, including DEHP, nonylphenol, cypermethrin, and chlorpyrifos activate CAR. Both full and partial CAR activators were discovered, and EC50 values and Hillslopes were determined for use in the concentration addition models. Concentration addition models with and without restraint values to account for partial activators were developed. Measured results from transactivation assays with a mixture of 2-5 chemicals indicate that the concentration addition model without restraints correctly predicts activity unless all of the chemicals in the mixture are partial activators, and then restraint values be considered. Overall, our data indicates that it is important to consider that we are exposed to a milieu of chemicals, and the efficacy of each individual chemical is not the sole factor in determining CAR's activity in mixture modeling.