T-screen to quantify functional potentiating, antagonistic and thyroid hormone-like activities of poly halogenated aromatic hydrocarbons (PHAHs).
The present study investigates chemical thyroid hormone disruption at the level of thyroid hormone receptor (TR) functioning. To this end the (ant)agonistic action of a series of xenobiotics was tested in the newly developed T-screen. This assay makes use of a GH3 rat pituitary cell line, that specifically proliferates when exposed to 3,3',5-triiodo-L-thyronine (T3). The growth stimulatory effect is mediated via T3-receptors. (Ant)agonistic and potentiating action of compounds was studied in absence and presence of T3 at its EC50 level (0.25 nM). The compounds tested included the specific TR-antagonist amiodarone, as well as a series of brominated diphenyl ethers (BDEs), including specifically synthesized BDEs with a structural resemblance to 3,5-diiodo-L-thyronine (T2), T3 and T4 (3,3',5,5'-tetraiodo-L-thyronine). The results obtained reveal that only BDE206 and amiodarone are specific antagonists. Interestingly some compounds which did not respond in the T-screen in absence of T3, potentiated effects when tested in combination with T3. This points at possibilities for disruption at the TR in vivo, where exposure generally occurs in presence of T3. Altogether the results of the present study show that the newly developed T-screen can be used as a valuable tool for identification and quantification of compounds active in disturbing thyroid hormone homeostasis at the level of TR-functioning.
Schriks
Merijn
M
Department of Toxicology, Toxicology Section, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. merijn.schriks@wur.nl
Vrabie
Cozmina M
CM
Gutleb
Arno C
AC
Faassen
Elisabeth J
EJ
Rietjens
Ivonne M C M
IM
Murk
Albertinka J
AJ
D000638:Amiodarone / Q000633:toxicity; D000818:Animals; D001681:Biological Assay; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006727:Hormone Antagonists / Q000633:toxicity*; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D010647:Phenyl Ethers / Q000633:toxicity; D010911:Pituitary Neoplasms; D011075:Polybrominated Biphenyls / Q000633:toxicity; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013963:Thyroid Hormones / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D006727:Hormone Antagonists; D006846:Hydrocarbons, Halogenated; D010647:Phenyl Ethers; D011075:Polybrominated Biphenyls; D011084:Polycyclic Aromatic Hydrocarbons; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D000638:Amiodarone