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Developmental Profile and effects of perinatal PBDE exposure in Hepatic Phase I, II, III and deiodinase I gene expression involved in thyroid hormone metabolism in male rat pups
Citation:
SZABO, D., V. RICHARDSON, D. G. ROSS, J. J. DILIBERTO, PRASADA RAO S. KODAVANTI, AND L. S. BIRNBAUM. Developmental Profile and effects of perinatal PBDE exposure in Hepatic Phase I, II, III and deiodinase I gene expression involved in thyroid hormone metabolism in male rat pups. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 107(1):27-39, (2009).
Impact/Purpose:
This is part of a multi-divisional effort looking at the effects of perinatal exposure to a commercial PBDE mixture. This portion of the study focused on the effects on hepatic metabolism, especially in regard to thyroid perturbations. PBDEs are ubiquitous environmental pollutants which have been shown to have endocrine disrupting effects and cause developmental reproductive and neurotoxicity. This paper strongly suggests that among the most sensitive responses to PBDEs are effects on enzymes, under the control of specific nuclear receptors, which can alter thyroid homeostasis. Their effects appear similar to those of many PCBs suggesting the need for a cumulative risk approach.
Description:
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. Pregnant Long-Evans rats were orally administered 0 (control), 1.7 (low), 10.2 (mid) or 30.6 (high) mg/kg/day of DE-71® from gestational day (GD) 6 to postnatal day (PND) 21. Serum and liver samples were collected for analysis from male pups at PNDs 4, 21, and 60. Total serum thyroxine (T4) concentrations decreased to 57% (mid) and 51% (high) on PND 4 and 46% (mid) dose and 80% (high) on PND 22. Total serum triiodothyronine (T3) concentrations did not change. Cyp1a1, Cyp2b1/2, and Cyp3a1 mRNA expression, known to be regulated by AhR, CAR, and PXR, respectively, increased in a dose-dependent manner at PNDs 4 and 21 as did CYP1A1, CYP2B, and CYP3A enzyme activity. Only CYP1A1 enzyme activity remained increased at PND60. UGT-T4 enzyme activity significantly increased at PNDs 4 and 21 only at the highest dose. Age and dose-dependent effects were observed for Ugt1a6, 1a7 and 2b mRNA expression but not Ugt1a1. No change was observed for any UGT mRNA isoforms measured at PND 60. Hepatic deiodinase I (D1) activity and mRNA expression decreased with DE-71® exposure at PNDs 4 and 21. Sulfotransferase isoform1b1 (Sult1b1) mRNA expression increased at PNDs 4 and 21 at the high dose although overall SULT activity was unchanged. Transthyretin (Ttr) mRNA levels at PND 21 were reduced at the high dose only. Hepatic efflux transporters Mdr1, Mrp2 and Mrp3 mRNA expression increased at PNDs 4 and 21. At PND 60, Mrp2 decreased significantly at the high dose. The hepatic influx transporter Oatp1a4 increased at PND 22 with the high dose. Other influx transporters, Ntcp and Oat2, showed no effect. This study demonstrates perinatal exposure to the PBDE mixture, DE-71®, causes alterations in gene expression and enzyme activity which are dose- and time- dependent but are not necessarily correlated with significant decreases in circulating TH. The most sensitive responses to PBDEs following DE-71 exposure were CYP2B and D1 activities and Cyb2b1/2, d1, Mdr1, Mrp2, and Mrp3. All responses were reversible by PND 60. In conclusion, deiodination, active transport, and sulfation in addition to glucuronidation, may be involved in the disruption of TH homeostasis due to perinatal exposure to DE-71® in male rat offspring.
