title: Biochemical changes during goiter induction by methylmercaptoimidazol and inhibition by delta-iodolactone in rat.
abstract: BACKGROUND
  We have demonstrated that the administration of delta-iodolactone (i.e., 5-iodo-delta lactone) of arachidonic acid (IL-delta), a mediator in thyroid autoregulation, prevents goiter induction by methylmercaptoimidazol (MMI) in rats. Other studies have shown that transforming growth factor beta-1 (TGF-beta1) 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-delta decreases thyroid growth by inhibition of cell proliferation and/or by stimulation of apoptosis due to oxidative stress, that TGF-beta is stimulated by an excess of iodide and by IL-delta, 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-delta. Thyroid weight, cell number, cell proliferation, apoptosis, and oxidative stress were determined. Proliferating cell nuclear antigen (PCNA), TGF-beta1, TGF-beta3, 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-delta 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-beta1 but not TGF-beta3 synthesis. IL-delta alone caused a slight increase of TGF-beta3 but not TGF-beta1, whereas potassium iodide (KI) stimulated both isoforms and MMI reversed KI effect on TGF-beta1 expression but not on TGF-beta3.
  
  
  CONCLUSIONS
  The goiter inhibitory action of IL-delta is due to the inhibition of cell proliferation and the transient stimulation of apoptosis. This latter action does not involve oxidative stress. TGF-beta1 does not play a role in the autoregulatory pathway mediated by IL-delta. Iodide stimulates TGF-beta3 without the need of being organified. These results suggest that there may be more than one pathway involved in the autoregulatory mechanism.
authors.affiliation: Nuclear Biochemistry Division, Department of Radiobiology, National Atomic Energy Commission, Buenos Aires, Argentina.
authors.forename: Lisa
authors.initials: L
authors.lastname: Thomasz
authors.forename: Romina
authors.initials: R
authors.lastname: Oglio
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Randi
authors.forename: Marina
authors.initials: M
authors.lastname: Fernandez
authors.forename: María A
authors.initials: MA
authors.lastname: Dagrosa
authors.forename: Romulo L
authors.initials: RL
authors.lastname: Cabrini
authors.forename: Guillermo J
authors.initials: GJ
authors.lastname: Juvenal
authors.forename: Mario A
authors.initials: MA
authors.lastname: Pisarev
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000627:therapeutic use*; D002374:Catalase / Q000032:analysis; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005979:Glutathione Peroxidase / Q000032:analysis; D006042:Goiter / Q000139:chemically induced / Q000517:prevention & control*; D008713:Methimazole / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010545:Peroxides / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D053782:Transforming Growth Factor beta3 / Q000032:analysis
chemical_list: C026915:6-iodo-5-hydroxy-eicosatrienoic acid, delta-lactone; D001095:Arachidonic Acids; D010545:Peroxides; D018809:Proliferating Cell Nuclear Antigen; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D008713:Methimazole; D002374:Catalase; D005979:Glutathione Peroxidase