Reactive Oxygen Species and Thyroid Diseases

Sato, Masahiro

doi:10.1007/978-3-642-30018-9_150

Cited by 11 publications

(11 citation statements)

References 86 publications

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“…The mitochondrial electron transport chain generates superoxide radicals (O 2 − ). SODs promptly convert O 2 − into H 2 O 2 and O 2 48 , 49 . Although ROS are key second messengers in several signal transduction pathways 50 , 51 , an excess of them can lead to oxidative stress characterized by increased cellular macromolecule damage, as often occurs in aging 52 .…”

Section: Discussionmentioning

confidence: 99%

An extremely high dietary iodide supply forestalls severe hypothyroidism in Na+/I− symporter (NIS) knockout mice

Ferrandino

Kaspari

Reyna-Neyra

et al. 2017

Sci Rep

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The sodium/iodide symporter (NIS) mediates active iodide (I−) accumulation in the thyroid, the first step in thyroid hormone (TH) biosynthesis. Mutations in the SLC5A5 gene encoding NIS that result in a non-functional protein lead to congenital hypothyroidism due to I− transport defect (ITD). ITD is a rare autosomal disorder that, if not treated promptly in infancy, can cause mental retardation, as the TH decrease results in improper development of the nervous system. However, in some patients, hypothyroidism has been ameliorated by unusually large amounts of dietary I−. Here we report the first NIS knockout (KO) mouse model, obtained by targeting exons 6 and 7 of the Slc5a5 gene. In NIS KO mice, in the thyroid, stomach, and salivary gland, NIS is absent, and hence there is no active accumulation of the NIS substrate pertechnetate (99mTcO4 −). NIS KO mice showed undetectable serum T4 and very low serum T3 levels when fed a diet supplying the minimum I− requirement for rodents. These hypothyroid mice displayed oxidative stress in the thyroid, but not in the brown adipose tissue or liver. Feeding the mice a high-I− diet partially rescued TH biosynthesis, demonstrating that, at high I− concentrations, I− enters the thyroid through routes other than NIS.

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Section: Discussionmentioning

confidence: 99%

An extremely high dietary iodide supply forestalls severe hypothyroidism in Na+/I− symporter (NIS) knockout mice

Ferrandino

Kaspari

Reyna-Neyra

et al. 2017

Sci Rep

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“…DUOX2-mediated H 2 O 2 acts as a thyroperoxidase (TPO) co-substrate, rapidly oxidising iodine and resulting in its covalent binding to the tyrosine residues of thyroglobulin in the follicular lumen. This produces monoiodotyrosine (MIT) and diiodotyrosine (DIT), in the thyroglobulin molecule, which undergo coupling to give the THs triiodothyronine (T 3 ) and thyroxine (T 4 ) (Carvalho and Dupuy, 2013; Muzza and Fugazzola, 2017; Sugawara, 2014). A negative feedback loop is in charge of thyroid size and function.…”

Section: Introductionmentioning

confidence: 99%

Zebrafishduoxmutations provide a model for human congenital hypothyroidism

2019

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Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone (TH) synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidases DUOX1 and DUOX2. Indeed, mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2 . In this study, we investigated the phenotypes associated with two nonsense mutant alleles, sa9892 and sa13017 , of the single duox gene in zebrafish. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function, beginning from an early larval stage, when T 4 levels are already noticeably absent in the mutants. Loss of T 4 production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia/external goiter and infertility. Remarkably, all of these defects associated with chronic congenital hypothyroidism could be rescued with T 4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advanced stages of development.

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“…DUOX2-mediated H 2 O 2 acts as a thyroperoxidase (TPO) co-substrate, rapidly oxidising iodine and resulting in the covalent binding of iodide to the tyrosine residues of thyroglobulin in the follicular lumen. This produces monoiodotyrosine (MIT) and diiodotyrosine (DIT), in the thyroglobulin molecule, which undergo coupling to give the THs triiodothyronine (T 3 ) and thyroxine (T 4 ) (Carvalho and Dupuy, 2013;Muzza and Fugazzola, 2017;Sugawara, 2014). A negative feedback loop is in charge of thyroid size and function.…”

Section: Introductionmentioning

confidence: 99%

Zebrafishduoxmutations provide a model for human congenital hypothyroidism

Chopra

Ishibashi

Amaya

2018

Preprint

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Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidase, DUOX1 and DUOX2. Indeed mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2. In this study, we investigated the phenotypes associated with two nonsense mutant alleles of the single duox gene in zebrafish, sa9892 and sa13017. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine the external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function, beginning from the early larval stage, when T 4 levels are already noticeably absent in the mutants. Loss of T 4 production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia / external goiter, and infertility. Remarkably all of these defects associated with chronic congenital hypothyroidism could be rescued with T 4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advance stages of development.

show abstract

Reactive Oxygen Species and Thyroid Diseases

Cited by 11 publications

References 86 publications

An extremely high dietary iodide supply forestalls severe hypothyroidism in Na+/I− symporter (NIS) knockout mice

An extremely high dietary iodide supply forestalls severe hypothyroidism in Na+/I− symporter (NIS) knockout mice

Zebrafishduoxmutations provide a model for human congenital hypothyroidism

Zebrafishduoxmutations provide a model for human congenital hypothyroidism

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