Biochemical changes during goiter induction by methylmercaptoimidazol and inhibition by δ-iodolactone in rat

Abstract

Background: We have demonstrated that the administration of δ-iodolactone (i.e., 5-iodo-delta lactone) of arachidonic acid (IL-δ), a mediator in thyroid autoregulation, prevents goiter induction by methylmercaptoimidazol (MMI) in rats. Other studies have shown that transforming growth factor beta-1 (TGF-β1) mimics some of the actions of excess iodide, but its participation in autoregulation is disputed. The present studies were performed to test the hypotheses that IL-δ decreases thyroid growth by inhibition of cell proliferation and/or by stimulation of apoptosis due to oxidative stress, that TGF-β is stimulated by an excess of iodide and by IL-δ, and that c-Myc and c-Fos expression are upregulated during goiter induction and downregulated during goiter inhibition. Methods: Rats were treated with MMI alone or together with iodide or IL-δ. Thyroid weight, cell number, cell proliferation, apoptosis, and oxidative stress were determined. Proliferating cell nuclear antigen (PCNA), TGF-β1, TGF-β3, c-Myc, and c-Fos were measured by Western blot. Results: MMI caused a progressive increase in thyroid weight accompanied by an increase in cell number, asymmetry of the ploidy histograms, and PCNA, c-Fos, and c-Myc expression. In addition, an early increase of apoptosis was observed. Peroxides as well as glutathione peroxidase and catalase activities were also increased in goitrous animals. The inhibitory action of IL-δ on goiter formation was accompanied by the inhibition of cell proliferation evidenced by a significant decrease in cell number, PCNA expression, and asymmetry of the ploidy histograms. A transient stimulation of apoptosis after 7 days of treatment was also observed. MMI administration stimulated TGF-β1 but not TGF-β3 synthesis. IL-δ alone caused a slight increase of TGF-β3 but not TGF-β1, whereas potassium iodide (KI) stimulated both isoforms and MMI reversed KI effect on TGF-β1 expression but not on TGF-β3. Conclusions: The goiter inhibitory action of IL-δ is due to the inhibition of cell proliferation and the transient stimulation of apoptosis. This latter action does not involve oxidative stress. TGF-β1 does not play a role in the autoregulatory pathway mediated by IL-δ. Iodide stimulates TGF-β3 without the need of being organified. These results suggest that there may be more than one pathway involved in the autoregulatory mechanism.