(Massachusetts Institute of Technology and Woods Hole Oceanographic Institution, 1999-12)
Hestermann, Eli V.
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.
