Mechanisms of action for aryl hydrocarbon receptor ligands in the PLHC-1 cell line
Hestermann, Eli V.
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Aryl hydrocarbon receptor (AHR) expression and activity was characterized in the teleost hepatoma cell line, PLHC-1. This work was carried out in order to gain insights into mechanisms of halogenated aromatic hydrocarbon (HAH) toxicity. The results improve our ability to characterize the risks posed by HAH exposure as well as further demonstrate the application of cultured cells to questions of AHR function. Cell proliferation, the cell cycle, and DNA sequences for an AHR2 and β-actin were all characterized in PLHC-1. Serum withdrawal of early-passage cells reduced AHR expression and consequently TCDD-induced induction of cytochrome P4501A (CYF1A), which is mediated by the AHR. Serum in cell culture medium was found to reduce bioavailability ofAHR agonists and significantly alter relative potencies of CYP1A induction, raising the possibility of artificial differences in measured potencies among cell types and laboratories. A quantitative pharmacological approach was used to show that both AHR binding affinity and intrinsic efficacy ofligands contribute to observed CYF1A induction potencies. These data also demonstrate the existence of "spare receptors" in this system. Non-additive effects of low-efficacy ligands call into question the utility of the "toxic equivalency factor" approach currently used for HAH risk assessment.
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution December 1999
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