Topic: DNA damage at the origin of cancer
Title: Iodine deficiency activates antioxidant genes and causes DNA damage in the thyroid gland of rats and mice.
Authors: Maier J, van Steeg H, van Oostrom C, Paschke R, Weiss RE & Krohn K.
Reference: Biochimica Biophysica Acta 1773: 990-999, 2007
Stimulation of the thyroid enhances H 2 O 2 generation by thyroid cells. H 2 O 2 causes damage which could explain mutagenesis and nodule formation.
The objective of the study was to quantify DNA oxidation and damage, and induction of enzymes involved in H 2 O 2 detoxification in the thyroid of iodine deficient rats and mice.
Material & Methods: Animals were submitted to an iodine deficient and iodine sufficient diet for about 2 months. DNA damage in the thyroid was evaluated by the Comet assay, spontaneous mutation rate by a deficient lac Z promoter reactivation, and various gene expressions by PCR.
Iodine deficiency was demonstrated in rats and mice by a decrease in urinary iodide and serum T4 mRNA expression, an increase in serum TSH and thyroid weight. An increase of expression of TPO and NIS, and transiently of the detoxification enzymes SOD (transient), glutathione peroxidase 4 and peroxiredoxin 3 & 5 in mice thyroids was shown. The expression of another detoxification enzyme was decreased (glutathione peroxidase 3). DNA damage as evaluated by the Comet assay was increased, more so for oxidative damage. However, the spontaneous mutation rate was not increased.
The data suggest that iodine deficiency induces a transient oxidative stress and oxidative DNA damage, but does not increase the mutation rate. The authors suggest a compensatory more efficient DNA repair.
It is well known that the thyrocyte produces H 2 O 2 as a substrate for thyroperoxidase and iodine oxidation. Moreover, Corvilain et al. have shown that the generation of H 2 O 2 by an activated thyrocyte was of the same order of magnitude as that of an activated leucocyte (Endocrinology, 1991). While the activated leucocyte, however, lives a few hours, the human thyrocyte lives seven years (Coclet et al. in Clin. Endocrinol., 1989). Thyroidal H 2 O 2 can induce cellular necrosis. Selenium deficiency (i.e. antioxidant deficiency) plays a necessary role in the destruction of the thyroid in myxoedematous cretinism (Contempr- et al. in Endocrinolgy, 2004).
Besides its acute stressing, apoptotic and necrosing role, H 2 O 2 is also a well known as a DNA damaging agent and therefore a putative mutagen. We (and others) have hypothesized in several publications that H 2 O 2 could be responsible for the high incidence of nodules (i.e. neoformations), most of them benign, occurring in the thyroid gland. However, there was no concrete evidence in favour of this hypothesis. Recently two articles have shown: a) that H 2 O 2 induces in the thyroid, as well as in other tissues, considerable DNA damage (evidenced by the Comet assay). The ensuing DNA damage is rapidly repaired, albeit incompletely (see Chico-Galdo V, Mol. Cell Endo. 257:6, 2006); b) in a previous article, Maier et al. have demonstrated a higher level of global DNA damage (by the Comet assay), DNA oxidation and spontaneous mutation frequency in normal thyroid tissue than in other tissues (see Endocrinology 147:3391, 2006).
In the present article, Maier et al. bring direct evidence of this scheme in an in vivo experimental physiological experiment, with the stimulating condition being iodine deficiency. The authors demonstrate the oxidative DNA damage in vivo ! The higher uracil content of thyroid DNA could be a precondition for C – T transitions often detected in somatic mutations in nodular tissue.
There is one discrepancy with the scheme: there was no measured increased mutation rate in the stimulated thyroids. This might be due to a compensatory activation of DNA repair, or a too high sensitivity of the assay system, etc. Nevertheless, the present study will certainly lead clinicians to try antioxidant diets (i.e. selenium) as a prevention tool in patients with thyroid nodules. Selenium supplements seem to provide an efficient prevention against thyroiditis (see Gartner in JCEM, 2002 & Duntas in Eur J Endocrinol, 2003). Present article should therefore elicit new clinical studies.
Summary and commentary prepared by Jacques Dumont (related to Chapters 1 & 18 of TDM)