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PCB-153 AND BDE-47 INCREASE THYROXINE T4) CATABOLISM IN RAT AND HUMAN HEPATOCYTES
Citation:
RICHARDSON, V. AND M. DeVito. PCB-153 AND BDE-47 INCREASE THYROXINE T4) CATABOLISM IN RAT AND HUMAN HEPATOCYTES. Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
The data demonstrates that basal activity for T4G formation in rat hepatocytes is approximately 50-times higher than that of human hepatocytes.
Description:
Previous studies demonstrate that in vivo exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) decrease serum thyroxine (T4) levels in rats. This decrease is thought to occur through the induction of hepatic metabolizing enzymes resulting in enhanced catabolism of T4. There is some evidence that the T4 decrease occurs in humans, but the mechanism is unclear. Using primary rat and human hepatocytes, we compared the effects of PCB-153 and BDE-47 on T4 catabolism. 48 hours after plating, fresh human or Sprague-Dawley rat hepatocytes were treated with PCB-l53 or BDE-47 at a concentration of30uM in 0.1% DMSO. 72 hours after dosing, cell culture media was replaced with media containing [I25]-T4 at median serum concentrations observed in rats and humans; 0.05uM and 0.1uM, respectively. 24 hours after [II25]-T4 administration, media was collected, T4 and its metabolites were separated by UPLC, and fractions collected and quantified on a gamma counter. The predominant metabolite found in media of control and treated hepatocytes was T4-glucuronide (T4G). Results show a higher basal activity of T4G formation in unexposed rat hepatocytes as compared to unexposed human hepatocytes (5.2 vs.O.l fmol T4G/min/mg protein). Following PCB-153 treatment, T4G formation in rat hepatocytes increased 3.8-fold while increasing 10.8-fold in human hepatocytes. BDE-47 increased T4G formation in rat and human hepatocytes by 1.6-and l3.3-fold, respectively. The data demonstrates that basal activity for T4G formation in rat hepatocytes is approximately 50-times higher than that of human hepatocytes. Additionally, PCB-153 and BDE-47 increase T4G formation in rat and human hepatocytes, with greater increases in humans. As a possible screening tool for risk assessment, these results highlight the utility of primary hepatocytes in evaluating potential species differences in the effects of thyroid hormone disruptors. (This abstract of a proposed presentation, does not reflect USEPA or NIH policy.)