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Evaluating Thyroxine Metabolism and Transport in Primary Rat and Human Hepatocytes Following BDE 47 Exposure
Citation:
Richardson, V. AND Chris Mazur. Evaluating Thyroxine Metabolism and Transport in Primary Rat and Human Hepatocytes Following BDE 47 Exposure. ISSX, Orlando, FL, October 18 - 22, 2015.
Impact/Purpose:
To present at ISSX 2015
Description:
Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in various consumer products including polyurethane foam, electronics, and textile coating. 2,2’,4,4’-Tetrabromodiphenyl ether (BDE 47) is the predominant PBDE congener accounting for half of the body burden in human and wildlife tissues. PBDEs act as endocrine disruptors through interference with thyroid hormone (TH) homeostasis. Although consequences of exposure to humans have not been determined, PBDE-mediated decreases in TH profoundly affect developing rodents. Decreased concentrations of THs following exposures to PBDEs have previously been linked to the induction of hepatic uridinediphosphate-glucuronosyltransferases (UGTs). While UGTs metabolize THs and play a role in TH homeostasis, it is not certain that metabolism alone is responsible for the effects of PBDEs on circulating TH concentrations. PBDEs have also been shown to increase the expression of genes involved not only in TH metabolism but also TH transport. In this study, we used sandwich-cultured hepatocytes (SCHs) to examine the effects of BDE 47 on hepatic metabolism and uptake of thyroxine (T4) and the role these mechanisms may play in TH disruption. SCHs from human or Sprague-Dawley rats were treated (72 hours) with BDE 47 (0 or 30 uM). Medium was removed and replaced with 0.05 or 0.1 uM T4 (rat or human median serum concentration). Media was collected to measure T4-glucuronide (T4G) after 24 hours and cells were collected after 20-30 minutes to measure T4 uptake. Medium and cells were then prepared for analysis by liquid chromatography. T4G in the medium of untreated rat SCHs was about 20-times greater than in the medium of untreated human SCHs. Following BDE 47 exposure, T4G in the medium of rat SCHs was unchanged; however, T4G in the medium of human SCHs increased nearly 2-fold. T4 uptake into rat and human SCHs was unchanged following BDE 47 exposure. The data does not fully support the hypothesis that BDE 47 increases hepatic metabolism and active transport of T4 in rat and human hepatocytes; however it does show significant species differences in hepatic UGT activity toward T4. This study also highlights the utility of primary hepatocytes in screening potential TH disruptors. (This abstract does not reflect US EPA policy.)