You are here:
Triclosan Decreases Rat Thyroxine: Mode-of-Action, Developmental Susceptibility and Human Relevance
Citation:
Paul, K. B., J. M. HEDGE, S. SIMMONS, M. DeVitro, AND K. M. CROFTON. Triclosan Decreases Rat Thyroxine: Mode-of-Action, Developmental Susceptibility and Human Relevance. Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
The data suggest that the initial key event of the MOA may be different between rats and humans, but the downstream effects may be similar between species.
Description:
Triclosan (TCS) decreases serum thyroxine (T4) in the rat. In vivo and in vitro approaches were used to address three uncertainties: by what mode-of-action (MOA) does TCS decrease T4; does TCS decrease T4 developmentally; and, are effects observed in rats relevant to humans? To test the hypothesized MOA that TCS decreases T4 via activation of the pregnane X and constitutive androstane receptors (PXR, CAR), and subsequent up-regulation of hepatic catabolism ofT4, weanling female Long-Evans rats received TCS po (0-1000 mg/kg/day) for 4 days. Pentoxyresorufin-O-deethylase (PROD) and uridine diphosphate glucuronyltransferase (VGT) enzyme activities were measured in liver microsomes. qRT-PCR was used to measure mRNA expression of CYPs, VGTs, and sulfotransferases. PROD and VGT activities increased 8-and 2fold at 1000 mg/kg/day. Cyp2b2, Cyp3al, Ugtlal and Sultlc1 mRNA expression levels were induced 2-to 4-fold at 300 mg/kg/day. To test this MOA in dams and offspring, pregnant Long Evans rats received TCS po (0-300 mg/kg/day) from gestational day (GD) 6 to postnatal day (PND) 21. Serum T4 decreased 30% in GD20 dams and fetuses, PND4 pups and PND22 dams at 300 mg/kg/day. Hepatic PROD activity increased 3-fold in PND22 dams and PND4 pups, and VGT activity was 1.S-fold in PND22 dams at 300 mg/kg/day. Reductions of 30% in T4 for dams and GD20 and PND4 offspring with concomitant increases in PROD and VGT activity suggest TCS may reduce T4 during development by a similar MOA to weanlings. To assess human relevance of the MOA, cell lines (Puracyp, Inc.) containing a CYP3A promoter-luciferase gene fusion were used to test activation of PXR in luciferase-based reporter assays. TCS moderately activated human PXR, but did not activate rat PXR. The data suggest that the initial key event of the MOA may be different between rats and humans, but the downstream effects may be similar between species. This abstract does not necessarily reflect the policy of the US EPA