Impaired gene expression due to iodine excess in the development and differentiation of endoderm and thyroid is associated with epigenetic changes.

Abstract

BACKGROUND\nThyroid hormone synthesis is essential for the control of development, growth and metabolism in vertebrates and depends on sufficient dietary iodine intake. Importantly, both iodine deficiency and iodine excess (IE) impair thyroid hormone synthesis, causing serious health problems especially during fetal/neonatal development. While it is known that IE disrupts thyroid function by inhibiting thyroid gene expression, its effects on thyroid development are less clear. Accordingly, this study sought to investigate the effects of IE during the embryonic development/differentiation of endoderm and thyroid gland.\n\n\nMETHODS\nWe used the murine embryonic stem (ES) cell model of in vitro directed differentiation to assess the impact of IE on the generation of endoderm and thyroid cells. Additionally, we subjected endoderm and thyroid explants obtained during early gestation to IE, and evaluated gene and protein expression of endodermal markers in both models.\n\n\nRESULTS\nES cells were successfully differentiated into endoderm cells and, subsequently, into thyrocytes expressing the specific thyroid markers Tshr, Slc5a5, Tpo and Tg. IE exposure decreased the mRNA levels of the main endoderm markers Afp, Crcx4, Foxa1, Foxa2 and Sox17 in both ES cell-derived endoderm cells and embryonic explants. Interestingly, IE also decreased the expression of the main thyroid markers in ES cell-derived thyrocytes and thyroid explants. Finally, we demonstrated that DNA methyltransferase expression was increased by IE exposure, and this was accompanied by hypermethylation and hypoacetylation of histone H3, pointing to an association between the gene repression triggered by IE and the observed epigenetic changes.\n\n\nCONCLUSIONS\nThese data establish that IE treatment is deleterious for embryonic endoderm and thyroid gene expression.