Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and chlorinated paraffins (CPs) in rats-testing interactions and mechanisms for thyroid hormone effects.
The effects of the polybrominated diphenyl ether (PBDE) congener 2,2'4, 4'-tetrabromodiphenylether (DE-47), and technical preparations of polychlorinated biphenyls (PCBs; Aroclor 1254) and chlorinated paraffins (CPs; Witaclor 171P) on thyroid hormone (TH) levels were examined in rats. To study possible interactive effects, also combinations of the three compounds were used. Thus, female Sprague-Dawley rats, 7 weeks old, were treated with approximately isomolar doses (ca. 30 micromol/kg bw per day) of DE-47 (6.0 mg/kg per day), Aroclor 1254 (4.0 mg/kg per day) and Witaclor 171P (6.8 mg/kg per day), alone or in combinations, daily for 14 days by gastric intubation. DE-47 was also administered in a higher (18 mg/kg per day) and lower (1.0 mg/kg per day) dose. In order to test possible mechanisms behind the TH effects, microsomal enzyme (cytochrome P-450 isozymes and uridine diphosphoglucuronyl transferase-UDPGT) activity (indicating both metabolic activation and/or biliary clearance), ex vivo-binding of 125I-T4 to plasma proteins (suggesting effects on peripheral TH transport) and light microscope morphology of the thyroid gland were studied. The observed degree of TH reduction after Aroclor 1254 and DE-47 exposure corresponded with a decrease in the ex vivo binding of 125I-T4 to the plasma TH-transporter transthyretin (TTR), and with induction of the microsomal phase I enzymes (ethoxy- and methoxy-resorufin dealkylases, EROD and MROD). The phase II enzyme UDPGT was also elevated, but only moderately. The thyroid morphology showed an activation of the epithelia, but no degenerative alternations, that was correlated to exposure to Aroclor 1254. In our model, the observed effects match the hypothesis that the T4 decrease is chiefly due to disturbances in serum transport, caused by binding of in vivo-formed Aroclor 1254 and DE-47 metabolites to TTR. However, decreased plasma TH levels due to increased glucuronidation activity may also be of some importance. The thyroid gland hyperactivity is probably a feed-back consequence of the T4 decrease, in spite of the lack of TSH alterations. In the mixed DE-47 and Witaclor 171P group synergistic effects were indicated on free T4 (FT4) and EROD induction levels, results that may suggest that such effects should be considered in risk assessment of mixtures of persistent organohalogens.
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, P.O. Box 594, Uppsala, Sweden.
Sara
S
Hallgren
Per Ola
PO
Darnerud
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D020111:Chlorodiphenyl (54% Chlorine) / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D055768:Halogenated Diphenyl Ethers; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010232:Paraffin / Q000633:toxicity*; D010647:Phenyl Ethers / Q000633:toxicity*; D011075:Polybrominated Biphenyls; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology; D013974:Thyroxine / Q000097:blood*
D001798:Blood Proteins; D055768:Halogenated Diphenyl Ethers; D006842:Hydrocarbons, Brominated; D010647:Phenyl Ethers; D011075:Polybrominated Biphenyls; C511295:2,2',4,4'-tetrabromodiphenyl ether; D020111:Chlorodiphenyl (54% Chlorine); D010232:Paraffin; D019363:Cytochrome P-450 CYP1A1; D014453:Glucuronosyltransferase; D013974:Thyroxine