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Triclosan Alters Thyroid Hormone Homeostasis via Up-regulation of Hepatic Catabolism
Citation:
PAUL, K. B., J. M. HEDGE, M. J. DEVITO, AND K. M. CROFTON. Triclosan Alters Thyroid Hormone Homeostasis via Up-regulation of Hepatic Catabolism. Presented at Annual meeting of the Society of Toxicology, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
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Description:
Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) decreases serum thyroxine (T4) in the weanling rat. Scientific uncertainties include: by what mode of action (MOA) does triclosan decrease T4, and does triclosan induce hypothyroxinemia in dams and neonates? To test the hypothesized MOA that triclosan decreases T4 via activation of the pregnane X and constitutive androstane receptors, and subsequent up-regulation of hepatic catabolism of hormones, weanling female Long-Evans rats received triclosan po (0-1000 mg/kg/day) for 4 days. Pentoxyresorufin-O-deethylase (PROD) and uridine diphosphate glucuronyltransferase (UGT) enzyme activities were measured in liver microsomes. qRT-PCR was used to measure mRNA expression of cytochrome P450s 1a1, 2b2, and 3a, UGTs 1a1, 1a6, and 2b5, sulfotransferases 1c1 and 1b1, and hepatic transporters OATP1a1 and 1a4, MRP2, and MDR1b. PROD activity increased ~800 percent and T4-glucuronidation increased 2-fold at 1000 mg/kg/day. CYP2b2, CYP3a, UGT1a1, and SULT1c1 mRNA expression levels were induced 2-fold, 4-fold, 2.2-fold, and 2.6-fold at 300 mg/kg/day, respectively. No changes were observed in mRNA levels for any transporters. These data support the hypothesized MOA for that triclosan-induced hypothyroxinemia. To determine if this MOA applies to dams and neonates, pregnant Long Evans rats received triclosan po (0-300 mg/kg/day) in corn oil from gestational day (GD) 6 to postnatal day (PND) 21. Serum and liver were obtained from pups on PND4, 14, and 21, and dams on PND22. Maternal weight-gain (GD19-PND13) decreased ~10% with 300 mg/kg/d treatment. Serum T4 was reduced in dams by ~30 percent at 300 mg/kg/day, with no T4 effects observed for PND4, PND14, or PND21 pups. This work suggests susceptibility differences between weanling directly exposed and neonates exposure via dams. This abstract does not necessarily reflect the policy of the US EPA.