Mechanisms of divalent metal toxicity in affective disorders

Menon, Archita Venugopal; Chang, JuOae; Kim, Jonghan

doi:10.1016/j.tox.2015.11.001

Cited by 66 publications

(25 citation statements)

References 288 publications

(272 reference statements)

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“…The localization of SLC30A10 to the bile duct epithelium in human liver (19) and to the apical domain of polarized HepG2 cells (25) suggests that SLC30A10 is required for Mn export into bile. As for cellular Mn uptake, the plasma membrane protein divalent metal-ion transporter-1 (DMT1) is frequently cited as the primary Mn 2+ importer (26)(27)(28). Although DMT1 can certainly transport Mn (29), a study of intestine-specific DMT1-null mice demonstrated that it is dispensable for Mn absorption (30).…”

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confidence: 99%

SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

Jenkitkasemwong

Akinyode

Paulus

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

110

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Solute carrier family 39, member 14 (SLC39A14) is a transmembrane transporter that can mediate the cellular uptake of zinc, iron, and manganese (Mn). Studies of knockout () mice have documented that SLC39A14 is required for systemic growth, hepatic zinc uptake during inflammation, and iron loading of the liver in iron overload. The normal physiological roles of SLC39A14, however, remain incompletely characterized. Here, we report that mice spontaneously display dramatic alterations in tissue Mn concentrations, suggesting that Mn is a main physiological substrate for SLC39A14. Specifically, mice have abnormally low Mn levels in the liver coupled with markedly elevated Mn concentrations in blood and most other organs, especially the brain and bone. Radiotracer studies using Mn reveal that mice have impaired Mn uptake by the liver and pancreas and reduced gastrointestinal Mn excretion. In the brain of mice, Mn accumulated in the pons and basal ganglia, including the globus pallidus, a region susceptible to Mn-related neurotoxicity. Brain Mn accumulation in mice was associated with locomotor impairments, as assessed by various behavioral tests. Although a low-Mn diet started at weaning was able to reverse brain Mn accumulation in mice, it did not correct their motor deficits. We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues. The inability of Mn depletion to correct the motor deficits in mice suggests that the motor impairments represent lasting effects of early-life Mn exposure.

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confidence: 99%

SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

Jenkitkasemwong

Akinyode

Paulus

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Furthermore, the cytotoxicity of soluble metals resulting from intracellular dissolution of metal NPs should be rigorously examined. Numerous studies have demonstrated biochemical alterations and behavioural dysfunction in animals and humans caused by exposure to various metals (Chang et al, 2014;Kim, 2015a, 2015b;Menon et al, 2016). Measuring the soluble metal concentrations of NP-exposed cells and cell culture media would provide important information about the potential effect of NP dissolution on metal toxicity.…”

Section: Discussionmentioning

confidence: 99%

Role of fatty acid composites in the toxicity of titanium dioxide nanoparticles used in cosmetic products

et al. 2016

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-It has been recognized that the use of nanoparticles (NPs) in the cosmetic industry results in products with better efficacy and functionality. However, recent advances in molecular toxicology have revealed that NP exposure can promote cytotoxicity and oxidative damage, which has raised health concerns in the use of NPs in personal care products. Nevertheless, the mechanistic basis for the toxicity and safety of cosmetic NPs is poorly understood. The goal of the study was to determine the cytotoxicity and intracellular distribution of titanium dioxide (TiO 2 ) NPs containing fatty acid composites (palmitoleic acid, palmitic acid, stearic acid and oleic acid) commonly used in cosmetic products. Two types of cells, human fibroblast skin cells and adenocarcinoma lung cells, were exposed to either bare TiO 2 NPs or TiO 2 NPs mixed with fatty acids for up to 48 hr. NMR analysis confirmed that the fatty acid composites remained in the NPs after wash. The cytotoxicity of TiO 2 NPs was determined by cell viability measurement using quantitative confocal microscopy, and the localization of two different forms of TiO 2 NPs were assessed using electron spectroscopic imaging with transmission electron microscopy. TiO 2 NPs containing fatty acids posed significantly reduced cytotoxicity (80-88% decreases) than bare NPs in both cell types. Furthermore, there was less intracellular penetration of the NPs containing fatty acid composites compared with bare NPs. These results provide important insights into the role of fatty acids in protecting the cells from possible toxicity caused by NPs used in the production of cosmetic products.

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“…; Han and Kim ; Menon et al . ). For example, iron deficiency in children causes increased anxiety and depression along with social and attention problems (Lozoff et al .…”

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confidence: 97%

“…Iron plays an established role in proper brain function and emotional behavior (Delinard et al 1981;Beard et al 1993;Han and Kim 2015;Menon et al 2016). For example, iron deficiency in children causes increased anxiety and depression along with social and attention problems (Lozoff et al 2000).…”

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confidence: 99%

Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity

Han

Chang

Kim

2016

Journal of Neurochemistry

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The divalent metal transporter 1 (DMT1) is a major iron transporter required for iron absorption and erythropoiesis. Loss of DMT1 function results in microcytic anemia. While iron plays an important role in neural function, the behavioral consequences of DMT1 deficiency are largely unexplored. The goal of this study was to define the neurobehavioral and neurochemical phenotypes of homozygous Belgrade (b/b) rats that carry DMT1 mutation and explore potential mechanisms of these phenotypes. The b/b rats (11–12 wk old) and their healthy littermate heterozygous (+/b) Belgrade rats used as controls, were subject to elevated plus maze tasks. The b/b rats spent more time in open arms, entered open arms more frequently and traveled more distance in the maze than +/b controls, suggesting increased impulsivity. Impaired emotional behavior was associated with down-regulation of GABA in the hippocampus in b/b rats. Also, b/b rats showed increased GABAA receptor α1 and GABA transporter, indicating altered GABAergic function. Furthermore, metal analysis revealed that b/b rats have decreased total iron, but normal non-heme iron, in the brain. Interestingly, b/b rats exhibited unusually high copper levels in most brain regions, including striatum and hippocampus. Quantitative PCR analysis showed that both copper importer Ctr1 and exporter Atp7a were up-regulated in the hippocampus from b/b rats. Finally, b/b rats exhibited increased 8-isoprostane levels and decreased GSH/GSSG ratio in the hippocampus, reflecting elevated oxidative stress. Combined, our results suggest that copper loading in DMT1 deficiency could induce oxidative stress and impair GABA metabolism, which promote impulsivity-like behavior.

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Mechanisms of divalent metal toxicity in affective disorders

Cited by 66 publications

References 288 publications

SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

Role of fatty acid composites in the toxicity of titanium dioxide nanoparticles used in cosmetic products

Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity

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