Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission

Bouabid, Salim; Tinakoua, Anass; Lakhdar-Ghazal, Nouria; Benazzouz, Abdelhamid

doi:10.1111/jnc.13442

Cited by 105 publications

(57 citation statements)

References 182 publications

(196 reference statements)

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“…Two possible routes for manganese to enter the brain from the blood stream are currently being discussed: (1) directly via the blood brain barrier (BBB) and (2) via the brain cerebrospinal fluid (CSF) barrier, followed by translocation to the brain. According to some authors, the latter route might be of particular importance, at least at elevated manganese plasma concentrations . It is assumed that the transport from the blood into the brain is mediated inter alia by the transferrin/transferrin receptor‐mediated endocytosis pathway.…”

Section: Manganese In the Human Bodymentioning

confidence: 99%

“…Currently unknown transporters might also be involved. In addition, following inhalation, manganese may directly enter the brain via the olfactory nerve, thereby bypassing the BBB and CSF barrier …”

Section: Manganese In the Human Bodymentioning

confidence: 99%

“…Basically, it is thought that manganese exposure exceeding a level regulated by homeostatic mechanisms causes an accumulation of the metal in certain brain regions, in particular in the basal ganglia, such as striatum, globus pallidus, and substantia nigra. The basal ganglia are involved, for example, in the coordination of cognitive functions, emotions, and motor functions . Upon uptake, intracellular manganese predominantly accumulates in the Golgi apparatus, in mitochondria and in the nucleus …”

Section: Possible Health Effectsmentioning

confidence: 99%

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Dietary Manganese Exposure in the Adult Population in Germany—What Does it Mean in Relation to Health Risks?

Sachse

Kolbaum

Ziegenhagen

et al. 2019

Molecular Nutrition Food Res

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Manganese is both an essential nutrient and a potential neurotoxicant. Therefore, the question arises whether the dietary manganese intake in the German population is on the low or high side. Results from a pilot total diet study in Germany presented here reveal that the average dietary manganese intake in the general population in Germany aged 14–80 years is about 2.8 mg day−1 for a person of 70 kg body weight. This exposure level is within the intake range of 2–5 mg per person and day as recommended by the societies for nutrition in Germany, Austria, and Switzerland. No information on the dietary exposure of children in Germany can be provided so far. Although reliable information on health effects related to oral manganese exposure is limited, there is no indication from the literature that these dietary intake levels are associated with adverse health effects either by manganese deficiency or excess. However, there is limited evidence that manganese taken up as a highly bioavailable bolus, for example, uptake via drinking water or food supplements, could pose a potential risk to human health—particularly in certain subpopulations—when certain intake amounts, which are currently not well defined, are exceeded.

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Section: Manganese In the Human Bodymentioning

confidence: 99%

Section: Manganese In the Human Bodymentioning

confidence: 99%

Section: Possible Health Effectsmentioning

confidence: 99%

See 1 more Smart Citation

Dietary Manganese Exposure in the Adult Population in Germany—What Does it Mean in Relation to Health Risks?

Sachse

Kolbaum

Ziegenhagen

et al. 2019

Molecular Nutrition Food Res

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“…Manganese toxicity is associated with neurological dysfunction and Parkinson's disease (Chartlet 2012, O'Neal & Zhang 2015, Bouabid 2016, Sarkar 2018. Excess manganese exposures in animals have been shown to disrupt mitochondrial function, induce neuroinflammation, obstruct neurotransmission, and damage the basal ganglia of the midbrain (Bouabid 2016, Sarkar 2018. Extensive neuronal death and tissue damage in the midbrain impairs motor function control and can be reliably measured in animals using various motor behavioral tests (Brooks & Dunnett 2009).…”

Section: Introductionmentioning

confidence: 99%

Manganese-induced Parkinsonism in mice is reduced using a novel contaminated water sediment exposure model

Freeman

O’Neal

Zhang

et al. 2019

Preprint

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AbstractThe effects of heavy metals on human health have become an important area of study. For instance, acute manganese toxicity is known to induce Parkinsonism. Heavy metals including manganese enter the aquatic environment from both anthropogenic and natural processes. These metals accumulate within water sediments and their behavior is then dependent upon the sediment composition and phase. These metal-sediment interactions remain to be explored within in-vivo animal studies. To study the effect of these interactions, herein we successfully developed an exposure model in mice that encapsulates the aquatic microenvironment of heavy metals before exposure. Male and female C57/BL6 mice were exposed to manganese contaminated sediment via their drinking water (Sed_Mn) or to manganese placed directly into their drinking water with no prior sediment interaction (Mn) for six weeks. Sediment interaction did not alter total manganese in drinking water (mg/L) or weekly manganese consumption (mg) in males (54.9±1.5 mg) or females (44.6±1.0 mg) over the six-week exposure period. We analyzed motor impairment, a common feature in Parkinson’s disease, using the beam traversal, cylinder, and accelerating rotarod behavioral tests. We observed Parkinson’s like deficits in motor control in both treatment groups as early as four weeks of exposure in males but not in females. Intriguingly, mice given water incubated with manganese spiked sediment (Sed_Mn) performed better overall compared to mice given manganese directly in water (Mn) despite having similar exposure in males and females. Male Sed_Mn mice compared to Mn mice had a 146% reduction in time to cross the beam traversal test (p<0.05), a 10% increase in rearing activity in the cylinder test (p<0.05), and a 14% increase in time remaining on the rotarod (not significant). Female Sed_Mn mice compared to Mn mice had no change in the time to cross the beam traversal test, a 36% increase in rearing activity in the cylinder test (p<0.05), and a 35% increase in time on the rotarod (p<0.05). Our study indicates that metal-sediment interactions may alter metal toxicity in mammals and introduces a new exposure model to test the toxicity of metal contaminants of drinking water.

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“…[5][6][7][8] Chronic occupational or environmental exposure to high levels of Mn can lead to its accumulation in basal ganglia 9,10 and result in manganism, which is characterized by Parkinson-like motor dysfunction. 6,11 Additionally, with extensive commercial application of Mn (eg, Mn-containing pesticide, gasoline antiknock agent [methylcyclopentadienyl manganese tricarbonyl], and industry waste water contamination), reports of cognitive impairments among adults and children induced by excessive Mn exposure have increased. 7,8 However, the precise molecular mechanisms of Mn-induced neurotoxicity, particularly cognitive dysfunction, remain unclear.…”

mentioning

confidence: 99%

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

Yang

Ma²,

Wei

et al. 2019

Environmental Toxicology

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Manganese (Mn) plays a critical role in individual growth and development, yet excessive exposure can result in neurotoxicity, especially cognitive impairment. Neuronal apoptosis is considered as one of the mechanisms of Mn‐induced neurotoxicity. Recent evidence suggests that cAMP‐PKA‐CREB signaling regulates apoptosis and is associated with cognitive function. However, whether this pathway participates in Mn‐induced neurotoxicity is not completely understood. To fill this gap, in vitro cultures of PC12 cells were exposed to 0, 400, 500, and 600 μmol/L Mn for 24 hours, respectively. Another group of cells were pretreated with 10.0 μmol/L rolipram (a phosphodiesterase‐4 [PDE4] inhibitor) for 1 hour followed by 500 μmol/L Mn exposure for 24 hours. Flow cytometry, immunofluorescence staining, enzyme‐linked immunosorbent assay, and Western blot analysis were used to detect the apoptosis rate, protein levels of PDE4, cAMP signaling, and apoptosis‐associated proteins, respectively. We found that Mn exposure significantly inhibited cAMP signaling and protein expression of Bcl‐2, while increasing apoptosis rate, protein levels of PDE4, Bax, activated caspase‐3, and activated caspase‐8 in PC12 cells. Pretreatment of rolipram ameliorated Mn‐induced deficits in cAMP signaling and apoptosis. These findings demonstrate that cAMP‐PKA‐CREB signaling pathway‐induced apoptosis is involved in Mn‐induced neurotoxicity.

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Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission

Cited by 105 publications

References 182 publications

Dietary Manganese Exposure in the Adult Population in Germany—What Does it Mean in Relation to Health Risks?

Dietary Manganese Exposure in the Adult Population in Germany—What Does it Mean in Relation to Health Risks?

Manganese-induced Parkinsonism in mice is reduced using a novel contaminated water sediment exposure model

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

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