Manganese ion as a goitrogen in the female mouse.

Kawada, Jun; Nishida, Mikio; Yoshimura, Yoshiyuki; Yamashita, Kikuji

doi:10.1507/endocrj1954.32.635

Cited by 21 publications

(7 citation statements)

References 22 publications

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“…There was a clear sex-specific difference in the phenotype of Slc30a10 Ϫ/Ϫ mice; thyroxine levels and normalized body weights were lower in males. Sex-specific differences in the effects of manganese on thyroid function were also described in the report by Kawada et al (41). Unlike our study, in that of Kawada et al (41), female mice were sensitive.…”

Section: Figure 5 Measurements Of Additional Anterior Pituitary Hormsupporting

confidence: 74%

“…In 1983, the same authors (40) demonstrated that rats treated with manganese for a longer period (1 mg MnSO 4 ⅐H 2 O/100 g daily for 5 weeks) had decreases in body weight, and serum thyroxine and thyroid-stimulating hormone levels. In 1985, Kawada et al (41) reported that ingestion of 200 mg/liter MnCl 2 ⅐4H 2 O for 7 weeks induced goiter in female mice. In that study, manganese-treated animals also exhibited a mild reduction in serum thyroxine levels (41).…”

Section: Figure 5 Measurements Of Additional Anterior Pituitary Hormmentioning

confidence: 99%

“…In 1985, Kawada et al (41) reported that ingestion of 200 mg/liter MnCl 2 ⅐4H 2 O for 7 weeks induced goiter in female mice. In that study, manganese-treated animals also exhibited a mild reduction in serum thyroxine levels (41). Finally, a study by the National Toxicology Program demonstrated that mice fed very high manganese (15,000 g manganese/g) for 2 years developed thyroid follicular dilatation and hyperplasia (42).…”

Section: Figure 5 Measurements Of Additional Anterior Pituitary Hormmentioning

confidence: 99%

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Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice

Hutchens¹,

Liu²,

Jursa

et al. 2017

Journal of Biological Chemistry

118

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Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell-surface-localized manganese efflux transporter, cause a heritable manganese metabolism disorder resulting in elevated manganese levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of function at the organism level, we generated knock-out mice. During early development, knock-outs were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knock-out mice failed to gain weight, were smaller, and died prematurely (by ∼6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were ∼20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knock-outs were largely unaffected, but their thyroid exhibited extensive alterations. Because hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knock-outs had markedly reduced thyroxine levels (∼50-80%) and profoundly increased thyroid-stimulating hormone levels (∼800-1000-fold), indicating that knock-out mice develop hypothyroidism. Importantly, a low-manganese diet produced lower tissue manganese levels in the knock-outs and rescued the phenotype, suggesting that manganese toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of manganese-induced disease and identifies knock-out mice as a new model for studying thyroid biology.

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Section: Figure 5 Measurements Of Additional Anterior Pituitary Hormsupporting

confidence: 74%

Section: Figure 5 Measurements Of Additional Anterior Pituitary Hormmentioning

confidence: 99%

Section: Figure 5 Measurements Of Additional Anterior Pituitary Hormmentioning

confidence: 99%

See 1 more Smart Citation

Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice

Hutchens¹,

Liu²,

Jursa

et al. 2017

Journal of Biological Chemistry

118

View full text Add to dashboard Cite

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“…Levels of plasma manganese were elevated in individuals with goiter in another study (49). In rodents, administration of manganese was reported to reduce serum levels of thyroxine or induce goiter (42,50,51). Thus, there is precedent for our discovery of manganese-induced thyroid defects in Slc30a10 knockout mice.…”

Section: Zip14 Depletion Rescues Hypothyroidism In Slc30a10 Knockoutsmentioning

confidence: 98%

Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production

Liu

Hutchens

Jursa

et al. 2017

Journal of Biological Chemistry

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SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in the blood and brain and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10 but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced single and double knockout mice and compared their phenotypes with that of single knockouts. Compared with wild-type controls, single and double knockouts had higher manganese levels in the blood and brain but not in the liver. In contrast, single knockouts had elevated manganese levels in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with single knockouts, single and double knockouts had lower thyroid manganese levels and normal thyroid function. Moreover, intrathyroid thyroxine levels of single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction.

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“…The authors concluded that manganese uptake by the thyroid is controlled by serum TSH and thyroid hormone concentrations. Another study examined the role of manganese in goiter development (Kawada et al, 1985). Mice were fed excessive amounts of manganese while iodine concentrations in the diet remained at normal levels.…”

Section: Manganese Thyroid Hormone and Dopamine 3a Manganese And Thmentioning

confidence: 99%

Effects of manganese on thyroid hormone homeostasis: Potential links

Soldin

Aschner

2007

NeuroToxicology

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Manganese (Mn) is an essential trace nutrient that is potentially toxic at high levels of exposure. As a constituent of numerous enzymes and a cofactor, manganese plays an important role in a number of physiologic processes in mammals. The manganese-containing enzyme, manganese superoxide dismutase (Mn-SOD), is the principal antioxidant enzyme which neutralizes the toxic effects of reactive oxygen species. Other manganese-containing enzymes include oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases and glutamine synthetase. Environmental or occupational exposure to high levels of manganese can cause a neuropathy resembling idiopathic Parkinson's disease, commonly referred to as manganism. Manganism and Parkinson's disease are both characterized by motor deficits and damage to nuclei of the basal ganglia, particularly the substantia nigra, with altered dopamine (and its metabolites) contributing to these disorders. Dopamine, a major neurotransmitter plays a crucial role in the modulation of the cognitive function, working memory and/or attention of the prefrontal cortex and the hippocampus. Dopamine is also a known inhibitory modulator of thyroid stimulating hormone (TSH) secretion. The involvement of dopamine and dopaminergic receptors in neurodevelopment, as well as TSH modulation, led us to hypothesize that excessive manganese exposure may lead to adverse neurodevelopmental outcomes due to the disruption of thyroid homeostasis via the loss of dopaminergic control of TSH regulation of thyroid hormones. This disruption may alter thyroid hormone levels, resulting in some of the deficits associated with gestational exposure to manganese. While the effects of manganese in adult populations are relatively well documented, comprehensive data on its neurodevelopmental effects are sparse. Given the importance of this topic, we review the potential participation of thyroid hormone dyshomeostasis in the neurodevelopmental effects of manganese positing the hypotheses that manganese may directly or indirectly affect thyroid function by injuring the thyroid gland or dysregulating dopaminergic modulation of thyroid hormone synthesis.

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Manganese ion as a goitrogen in the female mouse.

Abstract: Effect of excessive ingestion of manganese (Mn) on the mouse thyroid was

Cited by 21 publications

References 22 publications

Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice

Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice

Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production

Effects of manganese on thyroid hormone homeostasis: Potential links

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