It is proposed that various pathologies can be explained, at least in part, by overproduction and lack of degradation of H2O2 (tumorigenesis, myxedematous cretinism, and thyroiditis) and by failure of the H2O2 generation or its positive control system (congenital hypothyroidism).

DNA double-strand breaks (DSBs) are considered as one of the primary causes of cancer but their induction by hydrogen peroxide (H 2 O 2 ) is still controversial. In this work, we studied whether the high levels of H 2 O 2 produced in the thyroid to oxidize iodide could induce DNA modifications. Scores of DNA damage, in terms of strand breaks, were obtained by comet assay (alkaline condition for single-strand breaks (SSBs) and neutral condition for DSBs). We demonstrated that in a rat thyroid cell line (PCCl3), non-lethal concentrations of H 2 O 2 (0.1-0.5 mmol/l) as well as irradiation (1-10 Gy) provoked a large number of SSBs (w2-3 times control DNA damage values) but also high levels of DSBs (1.2-2.3 times control DNA damage values). We confirmed the generation of DSBs in this cell line and also in human thyroid in primary culture and in pig thyroid slices by measuring phosphorylation of histone H2AX. L-Buthionine-sulfoximine, an agent that depletes cells of glutathione, decreased the threshold to observe H 2 O 2 -induced DNA damage. Moreover, we showed that DNA breaks induced by H 2 O 2 were more slowly repaired than those induced by irradiation. In conclusion, H 2 O 2 causes SSBs and DSBs in thyroid cells. DSBs are produced in amounts comparable with those observed after irradiation but with a slower repair. These data support the hypothesis that the generation of H 2 O 2 in thyroid could also play a role in mutagenesis particularly in the case of antioxidant defense deficiency.

Despite the high sequence similarity shared between DUOX1 and DUOX2, the two isoforms present distinct regulations, tissue expression and catalytic functions. The phenotypic characterization of novel DUOX/DUOXA invalidated animal models will be very useful for defining their medical importance in pathological conditions.

Iodide oxidation and binding to proteins require a thyroperoxidase and an ill defined H2O2-generating system. The NADP+ supply and, thus, NADPH oxidation are the limiting steps of the pentose phosphate pathway. The purpose of this work was to test the hypothesis that H2O2 generation is a limiting step of iodination and NADPH oxidation and, therefore, of the pentose phosphate pathway. H2O2 produced by dog thyroid slices was measured with the homovanillic fluorescence assay. Our data show that H2O2 generation is stimulated by both the cAMP cascade [as activated by TSH, forskolin and (Bu)2cAMP] and the Ca2(+)-phosphatidylinositol cascade (as activated by carbamylcholine, ionomycin, and 12-O-tetradecanoylphorbol-13-acetate). We used several physiological and pharmacological agents that modulate iodide organification. In all cases there was a strict parallelism between effects on H2O2 generation, iodide binding to proteins, and pentose phosphate pathway activity. Moreover, in TSH- or carbamylcholine-stimulated slices, glucose or Ca2+ depletion, which greatly depressed H2O2 generation, also greatly decreased iodide organification and the activity of the pentose phosphate pathway. The glutathione peroxidase-catalyzed H2O2 reduction in the cytosol, which involves NADPH oxidation and, therefore, increases the NADP supply, also enhances the activity of the pentose phosphate pathway. All of these data strongly support the hypothesis that H2O2 generation in dog thyroid controls iodination of proteins; through the NADPH oxidation resulting from H2O2 production and reduction, hydrogen peroxide also regulates the activity of the pentose phosphate pathway.

GH-secreting pituitary adenomas can be hypo-, iso-or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 23:113 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso-and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso-and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso-and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.