ECE2007 Poster Presentations (1) (659 abstracts)
The endocrine disruptor DDT appears to be an uncompetitive inverse agonist for activating TSHr mutants, FSH receptor and LH receptor
Lucia Montanelli 1 , Eleonora Ferrarini 1 , Antonio Dimida 1 , Mario Rossi 2 , Patrizia Agretti 1 , Franco Giorgi 2 , Giovanni Umberto Corsini 2 , Aldo Pinchera 1 , Paolo Vitti 1 , Roberto Maggio 2 & Massimo Tonacchera 1
1Department of Endocrinology of University of Pisa, Pisa, Italy; 2Department of Neurosciences of University of Pisa, Pisa, Italy.
The insecticide DDT has been shown to inhibit both the basal and the TSH stimulated accumulation of cAMP in CHO stably transfected with the TSHr (CHO-TSHr). Aim of this study was to evaluate whether the DDT has a similar effect on cells transfected with TSHr mutants displaying a high level of constitutive activity. In addition we investigate the effect of DDT on cells transfected with wtFSHr and wtLHr which share a high degree of amino-acid homology sequence with wtTSHr. In contrast with wtTSHr, wtFSHr and wtLHr do not show constitutive activity. Three TSHr mutants transiently transfected in COS cells were evaluated: S281L located in the ectodomain, I486M in the first extracellular loop and P639S in the sixth helix of the transmembrane domain. After incubation with DDT at increasing concentrations (10, 30 and 100 mcM), basal cAMP of the mutants was measured. Conversely, CHO cells stably expressing the wtFSHr and wtLHr (CHO-FSHr, CHO-LHr) were incubated with increasing concentrations of DDT (0.1, 1, 10 and 100 mcM), in presence of FSH (100 mU/ml) and hCG (1 mU/ml), respectively, and cAMP production was measured. The constitutive activity of the three activating TSHr mutants was inhibited and the maximal inhibition was obtained with the highest concentration of DDT. Similarly, DDT inhibited FSH and hCG induced cAMP activity in the two cell lines. At the highest concentration of DDT the inhibition was of 39% and 92% in CHO-FSHr and CHO-LHr, respectively. In conclusion DDT inhibited the constitutive activity of all activating TSHr mutants and the FSH and hCG stimulated accumulation of cAMP in CHO-FSHr and CHO-LHr. These effects are similar to those displayed by DDT on CHO-TSHr. Our data suggest that DDT might be an uncompetitive inverse agonist.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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