Effects of a mixture of polychlorinated biphenyls (Aroclor 1254) on the transcriptional activity of thyroid hormone receptor.
Polychlorinated biphenyls (PCBs) are environmental contaminants which may affect thyroid function. PCBs may reduce serum thyroid hormone (TH) concentrations by either displacing T4 from TH transport proteins or increasing its hepatic metabolism. The reduced serum T4 causes neurological and growth defects in animals exposed to PCBs during the perinatal period, which can partially be reverted by T4 administration. In addition to a hypothyroid-like syndrome, a direct action of PCBs on TH-sensitive genes has been postulated. In the present study the effects of Aroclor 1254 (ARO), a mixture of PCBs, on transcription of TH-dependent genes were investigated. A reporter plasmid containing the TH-responsive element (TRE) of malic enzyme (ME) gene was used in transient transfections to assess the responsiveness to ARO. ARO (10 microM) reduced the CAT activity by about 50% and competed with T3 to reduce the induction of transcription. Cotransfection of TH receptor (TR) and a wild type TRE was required to reveal ARO inhibitiry effect, which was abolished by a mock reaction not containing TR or by a mutated TRE. ARO reduced the 125I-T3 binding to TR by 30%, but did not affect the interaction of TR with a 32P-labeled TRE in gel shift assay. ARO is likely to produce a conformational change in in vitro translated TR, leading to its increased proteolysis by trypsin. These results demonstrate that ARO interacts with TR, thereby affecting the transcription of TH-sensitive genes, and provide a molecular basis to further explain the complex effects of PCBs on TH disruption.
Bogazzi
F
F
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy. f.bogazzi@endoc.med.unipi.it
Raggi
F
F
Ultimieri
F
F
Russo
D
D
Campomori
A
A
McKinney
J D
JD
Pinchera
A
A
Bartalena
L
L
Martino
E
E
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004785:Environmental Pollutants / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta; D013974:Thyroxine / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism
D013956:Antithyroid Agents; D004785:Environmental Pollutants; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D020111:Chlorodiphenyl (54% Chlorine); D002795:Choline O-Acetyltransferase; D013974:Thyroxine