Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis

Ye, Qi; Kim, Jonghan

doi:10.1016/j.etap.2015.06.016

Cited by 21 publications

(25 citation statements)

References 65 publications

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“…In addition, the hematocrit and total iron levels in lungs, liver, and blood also showed no significant change (Tables 2, 3). Similar results were observed in mice after intranasal instillation of Mn for 3 weeks (Ye et al, 2015a); iron status in the liver and brain were unaltered upon Mn instillation. However, Mn exposure by drinking water for 5 weeks significantly decreased iron levels in the liver (Alsulimani et al, 2015).…”

Section: Figsupporting

confidence: 83%

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats

et al. 2016

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-Manganese (Mn) is used in industrial metal alloys and can be released into the atmosphere during methylcyclopentadienyl manganese tricarbonyl combustion. Increased Mn deposition in the brain after long-term exposure to the metal by inhalation is associated with altered dopamine metabolism and neurobehavioral problems, including impaired motor skills. However, neurotoxic effects of short-term exposure to inhaled Mn are not completely characterized. The purpose of this study is to define the neurobehavioral and neurochemical effects of short-term inhalation exposure to Mn at a high concentration using rats. Male Sprague-Dawley rats were exposed to MnCl 2 aerosol in a nose-only inhalation chamber for 3 weeks (1.2 μm, 39 mg/m 3 ). Motor coordination was tested on the day after the last exposure using a rotarod device at a fixed speed of 10 rpm for 2 min. Also, dopamine transporter and dopamine receptor protein expression levels in the striatum region of the brain were determined by Western blot analysis. At a rotarod speed of 10 rpm, there were no significant differences in the time on the bar before the first fall or the number of falls during the two-minute test observed in the exposed rats, as compared with controls. The Mn-exposed group had significantly higher Mn levels in the lung, blood, olfactory bulb, prefrontal cortex, striatum, and cerebellum compared with the control group. A Mn concentration gradient was observed from the olfactory bulb to the striatum, supporting the idea that Mn is transported via the olfactory pathway. Our results demonstrated that inhalation exposure to 39 mg/m 3 Mn for 3 weeks induced mild lung injury and modulation of dopamine transporter expression in the brain, without altering motor activity.

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Section: Figsupporting

confidence: 83%

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats

et al. 2016

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“…The striatum was chosen for several reasons. Firstly, Mn levels were consistently lower in H67D mice among all Mn doses, suggesting a pronounced effect of H67D on Mn transport (Figure 2); secondly, the striatum is a brain region sensitive to Mn neurotoxicity 43 ; thirdly, the striatum showed significant neurochemical changes in response to both HFE deficiency and intranasal Mn exposure 30 . Neither Mn instillation nor H67D mutation affected the expression of DMT regardless of the existence of IRE.…”

Section: Resultsmentioning

confidence: 98%

“…These results indicate that loss of HFE function could enhance absorption as well as clearance of Mn. In addition, we found that HFE-knockout mice are resistant to memory deficits and emotional dysfunction induced by chronic intranasal Mn instillation compared with Mn-treated wild-type mice, suggesting that HFE deficiency could modify Mn-associated neurobehavioral problems 30, 31 . However, it is yet to be determined whether H67D mutation, a prevalent mutation in HH patients, alters Mn deposition in the brain and consequently modifies neurotoxicity after acute olfactory exposure.…”

Section: Introductionmentioning

confidence: 85%

Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure

Kim

2016

Metallomics

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Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability, and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene HFE. Mutations in the HFE gene are the major cause of the iron overload disorder hereditary hemochromatosis, one of prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and resultant neurotoxic effects after olfactory Mn exposure. Mice carrying H67D HFE mutation that is homologous to H63D mutation in humans and their control wild-type mice were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg/kg) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in blood, liver and most brain regions, especially in the striatum, while mice fed iron overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but unchanged in H67D mice. Together, our results suggest that H67D mutation provides decreased susceptibility to Mn accumulation in the brain and associated neurotoxicity induced by inhaled Mn.

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“…Supporting this observation, Hfe-deficient mice that display iron overload increase brain Mn uptake after intranasal administration of Mn radioisotope [102]. This increase in Mn uptake from the olfactory route under Hfe deficiency altered the neurotoxicity of Mn post intranasal exposure [185].…”

Section: Olfactory Uptakementioning

confidence: 73%

“…Consistent to this observation, Rosemarie et al found an association between anxiety and environmental Mn exposure [256]. In contrast, Ye et al found intranasal exposure to MnCl2 reduced the anxiety [185]. This difference in anxiety response to Mn exposure in both studies could be due to different route of administration.…”

Section: Discussionmentioning

confidence: 85%

Effect of hemochromatosis on manganese neurotoxicity

Alsulimani¹

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ABSTRACT:Manganese (Mn) is an essential element for normal brain function, but excess levels of Mn in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. While Mn is known to share iron transporters for cellular uptake, deficiency in the Hfe (hemochromatosis), a cellular iron regulatory protein, affects the activities of iron transporters and impairs iron metabolism. Previously it was shown that Mn uptake into the brain is increased after intranasal exposure to Mn in Hfe-deficient mice, a mouse model of iron overload hereditary hemochromatosis. However, there is limited information about the effect of Hfe deficiency on Mn toxicity after exposure by other routes. Mn exposure is common through ingestion and inhalation in both environmental and occupational settings. Because Hfe deficiency alters iron transporters, and since Mn shares iron transporters, I hypothesize that Hfe deficiency increases Mn toxicity by modulating Mn uptake from the absorption site and deposition into the target organ for Mn toxicity which is the brain after gastric exposure in drinking water and pulmonary exposure to Mn particles. Specific aims are focused on the effect of Hfe deficiency on 1) the expression levels of metal transporters in the brain, gut and lung including alveolar macrophages, 2) levels of Mn, 3) Mn-associated neurobehavioral impairments, and 4) mechanisms of Mn neurotoxicity. This research will enhance the knowledge of Mn exposure and uptake in Hfe-related hemochromatosis, a prevalent iron disorder in the world.

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Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis

Cited by 21 publications

References 65 publications

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats

Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure

Effect of hemochromatosis on manganese neurotoxicity

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