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Developmental Triclosan Exposure Decreases Maternal,Fetal, and Early Neonatal Thyroxine: Dynamic and Kinetic Data Support for a Mode-of-Action
Citation:
Paul, K., J. M. HEDGE, R. Bansal, T. Zoeller, T. Zoeller, R. Peter, M. J. DeVito, AND K. M. CROFTON. Developmental Triclosan Exposure Decreases Maternal,Fetal, and Early Neonatal Thyroxine: Dynamic and Kinetic Data Support for a Mode-of-Action. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 300(1-2):31-45, (2012).
Impact/Purpose:
This work tests the mode-of-action (MOA) hypothesis that perinatal triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via activation of pregnane X and/or constitutive androstane receptors (PXR, CAR), resulting in up-regulation of hepatic catabolism and elimination of T4. T4 reductions of 30% for dams and GD20 and PND4 offspring with concomitant increases in PROD and UGT activity suggest TCS may reduce T4 developmentally via up-regulated hepatic catabolism. Serum and liver TCS concentrations demonstrated greater fetal than postnatal internal exposure, consistent with the lack of T4changes in PND14 and PND21 offspring. These data support the MOA hypothesis: nuclear receptor mediated up-regulation of hepatic catabolism by TCS, particularly in dams, contributes to maternal and early neonatal hypothyroxinemia,
Description:
This work tests the mode-of-action (MOA) hypothesis that perinatal triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via activation of pregnane X and/or constitutive androstane receptors (PXR, CAR), resulting in up-regulation of hepatic catabolism and elimination of T4. Time-pregnant Long-Evans rats received TCS po (0-300 mg/kg/day) from gestational day (GD) 6 through postnatal day (PND) 21. Serum and liver were collected from dams (GD20, PND22) and offspring (GD20, PND4, PND14, PND21). Serum T4, triiodothyronine (T3), and thyroid stimulating hormone (TSH) concentrations were measured by radioimmunoassay. Ethoxy-O-deethylase (EROD), pentoxyresorufin-O-deethylase (PROD) and uridine diphosphate glucuronyltransferase (UGT) enzyme activities were measured in liver microsomes. Custom Taqman® qPCR arrays were employed to measure hepatic mRNA expression of select cytochrome P4S0s, UGTs, sulfotransferases, transporters, and thyroidhormone responsive genes. TCS was quantified by LC/MS/MS in serum and liver. Serum T4 decreased approximately 30% in GD20 dams and fetuses, PND4 pups and PND22 dams (300 mg/kg/day). Hepatic PROD activity increased 2-to 3-fold in PND4 pups and PND22 dams, and UGT activity was 1.S-fold higher in PND22 dams (300 mg/kg/day). Minor up-regulation of Cyp2b and Cyp3a expression in dams was consistent with CAR and/or PXR activation. T4 reductions of 30% for dams and GD20 and PND4 offspring with concomitant increases in PROD and UGT activity suggest TCS may reduce T4 developmentally via up-regulated hepatic catabolism. Serum and liver TCS concentrations demonstrated greater fetal than postnatal internal exposure, consistent with the lack of T4 changes in PND 14 and PND21 offspring. These data support the MOA hypothesis: nuclear receptor mediated up-regulation of hepatic catabolism by TCS, particularly in dams, contributes to maternal and early neonatal hypothyroxinemia. This abstract does not necessarily reflect the USEPA policy.
