ToxSci Advance Access published online on October 31, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn230
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EFFECTS OF PERINATAL PBDE EXPOSURE ON HEPATIC PHASE I, PHASE II, PHASE III AND DEIODINASE 1 GENE EXPRESSION INVOLVED IN THYROID HORMONE METABOLISM IN MALE RAT PUPS
* Experimental, US EPA, ORD, NHEERL, 109 TW Alexander Dr., MD B143-01, Research Triangle Park, NC 27711, diliberto.janet{at}epa.gov, birnbaum.linda{at}epa.gov, ross.david{at}epa.gov, kodavanti.prasada{at}epa.gov, richardson.vicki{at}epa.gov
# Neurotoxicology Divisions, US EPA, ORD, NHEERL, 109 TW Alexander Dr., MD B143-01, Research Triangle Park, NC 27711, diliberto.janet{at}epa.gov, birnbaum.linda{at}epa.gov, ross.david{at}epa.gov, kodavanti.prasada{at}epa.gov, richardson.vicki{at}epa.gov
UNC Curriculum in Toxicology, US EPA, MD B143-01, 109 TW Alexander Dr., Research Triangle Park, NC 27711
Corresponding Author: David Taylor Szabo, US EPA, 109 TW Alexander Dr., MD B143-01, Research Triangle Park, NC 27711, Szabo.David{at}epa.gov, Phone: 919.951.4171, Fax: 919.541.9464
Received July 15, 2008; revision received October 3, 2008; accepted October 7, 2008
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Abstract |
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Previous studies demonstrated that perinatal exposure to PBDEs, a major class of brominated flame retardants, may affect thyroid hormone (TH) concentrations by inducing hepatic uridinediphosphate-glucoronosyltransferases (UGTs). This study further examines effects of the commercial penta mixture, DE-71®, on genes related to TH metabolism at different developmental time points in male rats. DE-71® is predominately composed of PBDE congeners 47, 99, 100, 153, 154 with low levels of brominated dioxin and dibenzofuran contaminants. Pregnant Long-Evans rats were orally administered 1.7 (low), 10.2 (mid), or 30.6 (high) mg/kg/day of DE-71® in corn oil from gestational day (GD) 6 to postnatal day (PND) 21. Serum and liver were collected from male pups at PND 4, 21, and 60. Total serum thyroxine (T4) decreased to 57% (mid) and 51% (high) on PND 4, and 46% (mid) dose and 25% (high) on PND 21. Cyp1a1, Cyp2b1/2, and Cyp3a1 enzyme and mRNA expression, regulated by AhR, CAR, and PXR, respectively, increased in a dose dependent manner. UGT-T4 enzymatic activity significantly increased, while age and dose dependent effects were observed for Ugt1a6, 1a7 and 2b mRNA. Sult1b1 mRNA expression increased while that of transthyretin (Ttr) decreased as did both the deiodinase I (D1) enzyme activity and mRNA expression. Hepatic efflux transporters Mdr1, Mrp2 and Mrp3 and influx transporter Oatp1a4 mRNA expression increased. In this study the most sensitive responses to PBDEs following DE-71® exposure were CYP2B and D1 activities and Cyb2b1/2, d1, Mdr1, Mrp2, and Mrp3 gene expression. All responses were reversible by PND 60. In conclusion, deiodination, active transport, and sulfation, in addition to glucuronidation, may be involved in disruption of TH homeostasis due to perinatal exposure to DE-71® in male rat offspring.
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