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EFFECTS OF 2,2',4,4'-TETRABROMODIPHENYL ETHER ON CAR AND PXR REGULATED GENE EXPRESSION IN WEANLING FEMALE RATS
Citation:
Richardson, V. M., K M. Crofton, AND M J. DeVito. EFFECTS OF 2,2',4,4'-TETRABROMODIPHENYL ETHER ON CAR AND PXR REGULATED GENE EXPRESSION IN WEANLING FEMALE RATS. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
EFFECTS OF 2,2',4,4,'-TETRABROMODIPHENYL ETHER ON CAR AND PXR REGULATED GENE EXPRESSION IN WEANLING FEMALE RATS. V M RICHARDSON1, K M CROFTON2, AND M J DEVITO1. USEPA, ORD/NHEERL/ETD1/NTD2,RTP, NC, USA. The polybrominated diphenyl ether (PBDEs) mixture DE-71 (PBDEs) cause endocrine disruption by altering thyroid function via the induction of hepatic uridinediphosphate-glucoronosyltransferases, (UGTs). DE-71 also induces ethoxyresorufin-O-deethylase (EROD), and pentoxyresorufin-O-deethylase (PROD). These studies suggest that DE-71 is a mixed inducer of Ah receptor (AhR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulated genes. There are no definitive conclusions on the ability of PBDE-47, a major congener in DE-71, to act as a CAR/PXR agonist. This study examined the ability of PBDE-47 and DE-71 to activate genes in the AhR, CAR and PXR pathways by quantitative real-time PCR. Female Long-Evans rats (28 day old) were orally administered 3, 10, 30 or 100 mg PBDE-47/kg/day or 30 mg DE-71/kg/day for 4 days. Animals were sacrificed 24 hours after the final dose and livers were collected and stored at -80�C until analyzed. PBDE-47 caused a dose-dependent increase in PROD activity starting at 10mg/kg/day, and only a slight increase in EROD activity at the highest dose (100mg/kg/day). Neither PBDE-47 nor DE-71 affected CAR, PXR, RXR, Mrp2, Oatp2, or UGT2B mRNA expression. DE-71 significantly increased AhR, CYP2B1, CYP2B2, UGT1A6 and UGT1A7 mRNA levels, while significantly decreasing Mdr1A, and UGT1A1 mRNA levels. PBDE-47 significantly increased AhR mRNA at 100mg/kg/day. Significant increases were also seen in CYP2B1 and 2B2 mRNA at 30 and 100mg/kg/day PBDE-47. DE-71 induced CYP1A1 over 90-fold, while PBDE 47 only induced CYP1A1 12 fold at the highest dose tested. CYP2B1 was induced 350-fold by DE-71 and 1100-fold by 100 mg PBDE-47/kg/day. The data indicate that PBDE-47 and DE-71 alter AhR and CAR/PXR regulated genes, although PBDE-47 is more efficacious as a CAR/PXR activator than DE-71. The AhR activated genes suggests that PBDE-47 may be a weak AhR agonist or contains minor dioxin-like contaminants. (This abstract does not necessarily reflect USEPA policy).