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ENDOCRINE AND DIABETES

The Thyroid Disruptor 1,1,1-Trichloro-2,2-Bis(p-Chlorophenyl)-Ethane Appears to Be an Uncompetitive Inverse Agonist for the Thyrotropin Receptor

Departments of Neurosciences (M.R., M.T.D., F.G., G.U.C., R.M.) and Psychiatry, Neurobiology, Pharmacology, and Biotechnology (M.L.T.) and Department of Endocrinology, Centre of Excellence for the Study of Damage to the Nervous and Endocrine Systems Produced by Environmental, Alimentary, and Pharmacological Agents, AmbiSEN (A.D., P.A., A.P., P.V., M.T.), University of Pisa, Pisa, Italy

In this study, we aimed at establishing whether two previously identified thyroid disruptors, the insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and Aroclor 1254 (a complex mixture of polychlorinated water), may inhibit thyrotropin (TSH) receptor (TSHr) activity. DDT and Aroclor 1254 were shown to inhibit both the basal and bovine TSH (bTSH)-stimulated accumulation of cAMP in Chinese hamster ovary (CHO)-K1 cells stably transfected with the TSHr. Furthermore, both DDT and Aroclor 1254 did indeed prevent cAMP accumulation, as induced by the constitutive activity of a point mutant TSHr(I486M) transiently transfected in African green monkey kidney fibroblast (COS)-7 cells. Neither trypsin digestion of the extracellular domain (ECD) nor deletion of the ECD in a mutant TSHr trunk transiently transfected in COS-7 cells counteracted the inhibitory activity of DDT and Aroclor 1254. DDT exerted a weak inhibitory activity against forskolin in both CHO-K1 and COS-7 cells, whereas it was nil against the agonists dopamine and 5'-(N-ethyl-carboxamido)-adenosine (NECA) in CHO cells stably transfected with the dopamine D₁ receptor and in COS-7 cells transiently transfected with the adenosine type 2a receptor (A₂a) receptor. Furthermore, DDT was inactive against the stimulation by isoproterenol of the endogenously expressed ₂ adrenergic receptor in COS-7 cells. Conversely, Aroclor 1254 inhibited completely forskolin activity in CHO-K1 cells but not in COS-7 cells. Furthermore, it did not prevent accumulation of cAMP as induced by NECA in A₂a transfected cells. The analog of DDT, diphenylethylene, was inactive against bTSH-induced increase in cAMP in CHO-K1 cells stably transfected with the TSHr. We interpreted these results as indicating that DDT and possibly Aroclor 1254 may have an uncompetitive inverse agonist activity for the TSHr.

Address correspondence to: Dr. Roberto Maggio, Department of Experimental Medicine, University of L'Aquila, Via Vetoio (Coppito 2), 67010 L'Aquila-Coppito, Italy. E-mail: roberto.maggio{at}univaq.it