Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line

Zhang, Danhui; Kanthasamy, Anumantha G.; Anantharam, Vellareddy

doi:10.1016/j.taap.2010.03.023

Cited by 60 publications

(51 citation statements)

References 48 publications

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“…First, olfactory Mn instillation significantly down-regulated TH by 78% in iron-adequate rats ( Figure 5A; P< 0.001) and by 70% in iron-deficient rats (P< 0.001; n = 4 per group), which is in agreement with Zhang et al [42], who showed that chronic manganese exposure (0.1-1 µM for 24 h) induced a dose-dependent decrease in TH activity of dopaminergic neuronal cell line. Sriram et al [43] also reported that rats exposed to aerosolized welding fumes (manual metal arc-hard surfacing; containing high Mn) of 0.5 mg/rat for 7 weeks caused loss of TH protein in the striatum and midbrain.…”

Section: Tyrosine Hydroxylase Is Altered Upon Olfactory Mn Exposures supporting

confidence: 90%

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2015

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and anti-oxidant capacities. In particular, manganese superoxide dismutase (MnSOD) catalyzes dismutation of superoxide anion to hydrogen peroxide and molecular oxygen [11]. Manganese is also involved in bone formation and metabolism of amino acids, cholesterol and carbohydrates [12]. While Mn deficiency is rarely observed in humans, Mn exposure is significantly associated with neurobehavioral deficits. Manganese neurotoxicity resembles Parkinson's disease and has been well-documented in people drinking contaminated water, workers employed in mining and Mn ore processing and agricultural workers exposed to Mncontaining pesticide [13]. The use of methylcyclopentadienyl manganese tricarbonyl (MMT), an octane enhancer in gasoline, continues to be a huge concern about potential neurological damage due to inhalable Mn particles after combustion [14] Mn intoxication has also been observed in children under long-term parenteral nutrition and patients with chronic liver diseases [15].Advances in molecular physiology and toxicology have revealed that Mn neurotoxicity is, at least, mediated by dopaminergic dysfunction [16][17][18][19]. The dopaminergic neurotransmission is also impaired by iron deficiency. There is an accumulating body of evidence indicating that iron deficiency reduces dopamine receptor 1 (D 1 R) and D 2 R levels [20][21][22][23]. In addition, extracellular dopamine level is increased in irondeficient animals, which is related to a reduced uptake by AbstractWhile exposures to excessive amounts of metals increase brain damage, our recent study demonstrated that manganese (Mn) exposure corrected neurobehavioral problems resulting from iron deficiency in young rats. To further characterize the dose-dependent effect of intranasal manganese on motor coordination under iron deficiency, weanling rats were fed iron-deficient (5 mg iron/kg diet) or iron-adequate control diet (50 mg/kg) for 5 weeks and manganese chloride (MnCl2) solution was intranasally instilled through the right nostril twice a week for 3 weeks. Iron-deficient rats displayed lower blood hematocrit than controls, reflecting an iron-deficient anemic condition. Mn instillation did not alter hematocrit but modestly decreased body weight. In the rotarod test, Mn-instilled rats decreased motor coordination compared with water-instilled control rats (17% decrease in the time of the first drop; P=0.042). Iron-deficiency also decreased rotarod performance. However, upon Mn instillation, iron-deficient rats stayed longer on the bar by 30% than controls (P=0.006). Interestingly, the improvement in motor coordination was associated with manganese dose. Since both iron and Mn support tyrosine hydroxylase (TH), a critical enzyme in dopamine production, we tested if TH expression was modified by Mn instillation under iron deficiency. TH levels in the striatum were increased in iron deficiency and decreased upon Mn instillation, indicating that TH is unrelated with improved motor coordination in response to olfactory Mn under iron deficiency. Taken together, th...

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Section: Tyrosine Hydroxylase Is Altered Upon Olfactory Mn Exposures supporting

confidence: 90%

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2015

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“…47 Conversely, other studies using differentiated N27 dopaminergic cells exposed to low Mn concentration did not demonstrate alteration of Ser40 phosphorylation. 49 However, Mn caused a decrease of TH activity in a manner dependent of PKCd and PP2A activity. 49 Therefore, it is evident that Mn may affect TH activity; however, the effect of Mn on TH level, activity, and phosphorylation deserves to be studied in dopaminergic neurons from intact tissue exposed in vivo in order to clarify the TH modulation in situ by Mn.…”

Section: Alteration In Mapk and Akt Signaling Induced By Manganesementioning

confidence: 96%

“…49 However, Mn caused a decrease of TH activity in a manner dependent of PKCd and PP2A activity. 49 Therefore, it is evident that Mn may affect TH activity; however, the effect of Mn on TH level, activity, and phosphorylation deserves to be studied in dopaminergic neurons from intact tissue exposed in vivo in order to clarify the TH modulation in situ by Mn. Abbreviations: CaMK, calciumand calmodulin-stimulated protein kinase; ERK, extracellular signalregulated protein kinase; MK-2, MAPK-activated protein kinase; PDPK, proline-directed protein kinase; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PP2A, protein phosphatase 2A.…”

Section: Alteration In Mapk and Akt Signaling Induced By Manganesementioning

confidence: 96%

Effect of Manganese on Signaling Pathways

Peres¹,

Córdova²,

Lopes³

et al. 2014

Manganese in Health and Disease

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A complex intercellular and intracellular signaling network modulates the main neural functions. Regulation of protein kinases and protein phosphatases activities modify the phosphorylation state of target proteins that direct a diversity of cell fates, including gene expression, neural cell migration, differentiation or proliferation, cell survival or death, and synaptic plasticity. Regardless of all these aspects, modulation of intracellular signaling pathways by toxicants has only recently become part of the molecular toxicology research. Manganese (Mn) exposure causes a neurological syndrome, manganism, which resembles Parkinson's disease. The mechanisms of Mn neurotoxicity are not completely clear but may involve mitochondrial dysfunctions, induction of oxidative stress, and alterations in dopaminergic system, especially in the basal ganglia. The modulation of intracellular cell signaling elements by Mn and the cell fates of these effects is an issue that requires attention. In this chapter, we will present cell signaling pathways dependent of protein kinases (e.g. PKA, PKC, MAPKs, AKT, and GSK3β) and protein phosphatases (e.g. PP1 and PP2A) that have been reported to be altered in response to Mn exposure. Since only a few studies have addressed these aspects in vivo, a series of data obtained in vitro from cell cultures exposed to Mn will also be presented, aiming to help us identify the possible sites of Mn action in cell signaling networks involved in the patophysiology of Mn neurotoxicity.

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“…In addition, abusers of the Mn-containing Bazooka (a cocaine-based drug) are also leading to Mn neurotoxicity [14]. The recent introduction of an Mn-containing fuel additive, methylcyclopentadienyl Mn tricarbonyl, to gasoline has also raised concerns over potential chronic exposures to Mn [15]. Inhaled Mn can bypass the gut and enter into the brain in two ways: by olfactory (nasal airway) neural pathways that provide a direct path to brain tissue, and by pulmonary uptake with long residence time that could provide a source of continuing exposure [16].…”

Section: Exposure To Mnmentioning

confidence: 99%

“…Adverse neurological effects of Mn also occurred in people who drank Mncontaminated water in many countries [15]. Although the World Health Organization discontinued Drinking Water Guideline [31] as 500 ug/L in 1958 and 400 ug/L in 2004, the latter guideline was criticized as still too high to adequately protect public health.…”

Section: Exposure To Mnmentioning

confidence: 99%

A Current Review for Biological Monitoring of Manganese with Exposure, Susceptibility, and Response Biomarkers

Kim

Lee

Bang

et al. 2015

Journal of Environmental Science and Health, Part C

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People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes manganism, a motor syndrome similar to Parkinson disease, via interference of the several neurotransmitter systems, particularly the dopaminergic system in areas. At cellular levels, Mn preferentially accumulates in mitochondria and increases the generation of reactive oxygen species, which changes expression and activity of manganoproteins. Many studies have provided invaluable insights into the causes, effects, and mechanisms of the Mn-induced neurotoxicity. To regulate Mn exposure, many countries have performed biological monitoring of Mn with three major biomarkers: exposure, susceptibility, and response biomarkers. In this study, we review current statuses of Mn exposure via various exposure routes including food, high susceptible population, effects of genetic polymorphisms of metabolic enzymes or transporters (CYP2D6, PARK9, SLC30A10, etc.), alterations of the Mn-responsive proteins (i.e., glutamine synthetase, Mn-SOD, metallothioneins, and divalent metal trnsporter1), and epigenetic changes due to the Mn exposure. To minimize the effects of Mn exposure, further biological monitoring of Mn should be done with more sensitive and selective biomarkers.

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Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line

Cited by 60 publications

References 48 publications

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Effect of Manganese on Signaling Pathways

A Current Review for Biological Monitoring of Manganese with Exposure, Susceptibility, and Response Biomarkers

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