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EFFECTS OF 2,2′4,4′-TETRABROMODIPHENYL ETHER ON NUCLEAR RECEPTOR REGULATED GENES: IMPLICATIONS FOR THYROID HORMONE DISRUPTION
Citation:
RICHARDSON, V., D. STASKAL, J. J. DILIBERTO, M. J. DEVITO, AND L. S. BIRNBAUM. EFFECTS OF 2,2′4,4′-TETRABROMODIPHENYL ETHER ON NUCLEAR RECEPTOR REGULATED GENES: IMPLICATIONS FOR THYROID HORMONE DISRUPTION. Presented at 26th International Symposium on Halogenated Persistent Organic Pollutants, Oslo, NORWAY, August 21 - 25, 2006.
Description:
2,2′,4,4′-Tetrabromodiphenyl ether (BDE 47) is usually the most common polybrominated diphenyl ether (PBDE) congener found in human tissues and wildlife. Several studies demonstrate that PBDEs may act as endocrine disruptors through interference with thyroid hormone homeostasis. Although exposure risks to humans have not been determined, studies in rodents show that PBDE-mediated decreases in thyroid hormone most profoundly affect the developing animal1-3. Decreased concentrations of thyroid hormones following exposures to PBDEs have previously been linked to the induction of hepatic uridinediphosphate-glucuronosyltransferases (UDPGTs). While UGTs glucuronidate thyroid hormones and play a role in thyroid hormone homeostasis, it is not certain that metabolism alone is responsible for the effects of PBDEs on thyroid hormone concentrations. For example, studies exposing UGT1A-deficient Gunn rats to phenobarbital (PB) or polychlorinated biphenyl (PCB) demonstrated that serum total T4 decreases were not necessarily glucuronidation dependent4,5. This suggests that other mechanisms must be involved in the thyroid hormone decreases. UGTs are also important in the metabolism of xenobiotics and like other xenobiotic metabolism enzymes (XMEs) they are regulated by nuclear receptors such as aryl-hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR). Not only do these nuclear receptors regulate the expression of XMEs they have also been implicated in the regulation of xenobiotic transporters 6,7. The ability of PBDEs to induce UGTs indicates that PBDEs may also activate nuclear receptors that regulate other genes involved in xenobiotic metabolism and transport. This study examined the ability of BDE 47 to activate genes in the AhR, CAR, and PXR pathways which may also be involved in thyroid hormone decreases due to metabolism, transport, and elimination.