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Decreased TH expression and phosphorylation levels by manganese-mediated depletion of c-RET. After incubation in the medium containing 1% FBS for 6 h, TGW cells were treated with 30 μM manganese (Mn) for 24 h. Then, the cells were cultured in the presence or absence of GDNF (25 ng/ml) for 18 h and were analyzed by immunoblotting (a, f) and real-time PCR (e). Expression levels of c-RET (a, b) and TH (a, d) proteins and phosphorylated c-RET (p-c-RET; a, c) in 30 μM manganese-treated (lanes 3 and 4 in a–d) and untreated (lanes 1 and 2 in a–d) TGW cells in the presence (lanes 2 and 4 in a–d) or absence (lanes 1 and 3 in a–d) of GDNF are presented. After calculating levels of c-RET protein expression (b), phosphorylated c-RET (c), and TH protein expression (d) for α-TUBULIN (α-TUB) protein expression levels by densitometric analysis, those in the cells treated with manganese and/or GDNF (lanes 2–4 in b, lanes 1, 3, and 4 in c and d) are presented as relative ratios (means ± SD; n = 3) to that in untreated control cells (lane 1 in b) or in cells treated with GDNF (lane 2 in c and d). Expression levels of TH transcript in the cells treated with 30 μM manganese and/or GDNF (lanes 1, 3, and 4 in e) are presented as relative ratios (means ± SD; n = 3) to that in cells treated with GDNF (lane 2 in e). Phosphorylation and expression levels of TH (f) in 30 μM manganese-treated (lanes 3 and 4 in f and g) and untreated (lanes 1 and 2 in f and g) TGW cells in the presence (lanes 2 and 4 in f and g) or absence (lanes 1 and 3 in f and g) of GDNF are presented. After calculating levels of phosphorylated TH (g) for α-TUBULIN (α-TUB) protein expression levels by densitometric analysis, those in the cells treated with manganese and/or GDNF (lanes 1, 3, and 4 in g) are presented as relative ratios (means ± SD; n = 3) to that in untreated control cells (lane 1 in g). **Significantly different (p < 0.01) by Tukey-Kramer’s test
Source publication
Previous studies showed that overexposure to manganese causes parkinsonism, a disorder of dopaminergic neurons. Previous studies also showed that activity of c-RET kinase controls dopamine production through regulation of tyrosine hydroxylase (TH) expression, suggesting the involvement of c-RET in the development of parkinsonism. To our knowledge,...
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[This corrects the article DOI: 10.1371/journal.pone.0149379.].
Citations
... It has been demonstrated that a significant decrease in dopamine levels and TH and D1 dopamine receptor expression in SNpc following Mn exposure in rats occurred through inhibition of autophagy (Zhang et al., 2013). Inhibition of TH activity following Mn exposure may be at least partially mediated by down-regulation of c-RET transcription and protein ubiquitination (Kumasaka et al., 2017). Chronic Mn exposure was also shown to inhibit TH through up-regulation of PKCδ and PP2A activity (Zhang et al., 2011). ...
The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.
... Transcription factor RE1-silencing transcription factor (REST) was shown to overwhelm Mn-induced alterations in TH activity through up-regulation of mRNA and protein transcription in dopaminergic neuronal cells, as well as ameliorated other toxic effects of Mn exposure (250 µM for 12 h) including apoptosis, inflammation, and oxidative stress [120]. Kumasaka et al. (2017) demonstrated that a decline TH expression in TGW cells may be mediated by Mn (30-100 µM for 24 h) exposure-induced down-regulation of mRNA and protein transcription, as well as increased degradation of c-RET kinase [200,201]. ...
... Transcription factor RE1-silencing transcription factor (REST) was shown to overwhelm Mn-induced alterations in TH activity through up-regulation of mRNA and protein transcription in dopaminergic neuronal cells, as well as ameliorated other toxic effects of Mn exposure (250 µM for 12 h) including apoptosis, inflammation, and oxidative stress [120]. Kumasaka et al. (2017) demonstrated that a decline TH expression in TGW cells may be mediated by Mn (30-100 µM for 24 h) exposure-induced down-regulation of mRNA and protein transcription, as well as increased degradation of c-RET kinase [200,201]. ...
Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.
... Cell physiological and biochemical examinations are also useful for health risk assessment in vitro [27][28][29][30][34][35][36][37][38][39][40][41]. Expression and activity levels of proto-oncogene and oncogene products (protein tyrosine kinases) such as c-SRC, c-RET, and oncogenic RET have been shown to be correlated with malignant transformation from nontumorigenic cells to tumorigenic cells and with progression to further acquirement of malignant characteristics in transformed cells (carcinoma cells) [6,[37][38][39][40][41][42][43][44][45][46][47]. Therefore, expression and activity levels of molecules could be important clues to evaluate malignant transformation and progression in in vitro oncogenic risk analysis. ...
Well water could be a stable source of drinking water. Recently, the use of well water as drinking water has been encouraged in developing countries. However, many kinds of disorders caused by toxic elements in well drinking water have been reported. It is our urgent task to resolve the global issue of element-originating diseases. In this review article, our multidisciplinary approaches focusing on oncogenic toxicities and disturbances of sensory organs (skin and ear) induced by arsenic and barium are introduced. First, our environmental monitoring in developing countries in Asia showed elevated concentrations of arsenic and barium in well drinking water. Then our experimental studies in mice and our epidemiological studies in humans showed arsenic-mediated increased risks of hyperpigmented skin and hearing loss with partial elucidation of their mechanisms. Our experimental studies using cultured cells with focus on the expression and activity levels of intracellular signal transduction molecules such as c-SRC, c-RET, and oncogenic RET showed risks for malignant transformation and/or progression arose from arsenic and barium. Finally, our original hydrotalcite-like compound was proposed as a novel remediation system to effectively remove arsenic and barium from well drinking water. Hopefully, comprehensive studies consisting of (1) environmental monitoring, (2) health risk assessments, and (3) remediation will be expanded in the field of environmental health to prevent various disorders caused by environmental factors including toxic elements in drinking water.
... Manganese exposure also results in increased dopamine oxidation involving Fenton chemistry, also resulting in reduced dopamine availability [125]. Recent findings also demonstrate that Mn2+ may reduce activity of tyrosine hydroxylase, a rate-limiting enzyme of dopamine synthesis [126], although the effect is shown to be dose-, time- [127], and age-dependent [6]. ...
Background
Manganese (Mn) is a metal ubiquitously present in nature and essential for many living organisms. As a trace element, it is required in small amounts for the proper functioning of several important enzymes, and reports of Mn deficiency are indeed rare.
Methods
This mini-review will cover aspects of Mn toxicokinetics and its impact on brain neurotransmission, as well as its Janus-faced effects on humans and other animal’s health.
Results
The estimated safe upper limit of intracellular Mn for physiological function is in anarrow range of 20 to 53 μM.Therefore, intake of higher levels of Mn and the outcomes have been well documented.
Conclusion
The metal affects mostly the brain by accumulating in specific brain areas, altering cognitive functions and locomotion, thus severely impacting the health of the exposed organisms.
... Molecular mechanisms of Mn-induced neuronal cell death have been extensively studied. Mn impaired TH activity and function by decreasing TH mRNA and protein levels both in vitro and in vivo (8,9,(23)(24)(25). Mn disrupted TH activity via protein kinase C (PKC)- and protein phosphatase 2A (PP2A) in dopaminergic neural cell lines (26). ...
... As Mn decreases TH mRNA and protein levels in dopaminergic neurons of the SNpc of the mouse brain (9) as well as in TH-expressing cells (24), and REST increases TH expression in in vitro THexpressing neuronal cultures, we next examined if REST attenuates Mn-decreased TH expression in CAD neurons. Mn reduced promoter activities of both REST and TH in CAD neurons in a concentration-dependent manner (Fig. 4A). ...
Dopaminergic functions are important for various biological activities, and their impairment leads to neurodegeneration, a hallmark of Parkinson’s disease (PD). Chronic manganese (Mn) exposure causes the neurological disorder manganism, presenting symptoms similar to those of PD. Emerging evidence has linked the transcription factor RE1-silencing transcription factor (REST) to PD and also Alzheimer’s disease. But REST’s role in dopaminergic neurons is unclear. Here, we investigated whether REST protects dopaminergic neurons against Mn-induced toxicity and enhances expression of the dopamine-synthesizing enzyme tyrosine hydroxylase (TH). We report that REST binds to RE1 consensus sites in the TH gene promoter, stimulates TH transcription, and increases TH mRNA and protein levels in dopaminergic cells. REST binding to the TH promoter recruited the epigenetic modifier cAMP response element–binding protein (CREB)-binding protein (CBP)/p300 and thereby up-regulated TH expression. REST relieved Mn-induced repression of TH promoter activity, mRNA, and protein levels and also reduced Mn-induced oxidative stress, inflammation, and apoptosis in dopaminergic neurons. REST reduced Mn-induced proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, and Interferon gamma (IFN-γ). Moreover, REST inhibited the Mn-induced proapoptotic proteins Bcl-2-associated X protein (Bax) and death–associated protein 6 (Daxx) and attenuated an Mn-induced decrease in the antiapoptotic proteins Bcl-2 and Bcl-xL. REST also enhanced the expression of antioxidant proteins, including catalase, NF-E2–related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). Our findings indicate that REST activates TH expression and thereby protects neurons against Mn-induced toxicity and neurological disorders associated with dopaminergic neurodegeneration.
... Symbol shape indicates the protein, and open symbols indicate significantly different from respective control (p < .05), based on statistical models that included all five treatment groups 30 µM Mn experienced a c-RET mediated reduction in TH (Kumasaka et al., 2017). Finally, we believe that the reductions in TH, DAT, NET, and D1 immunofluorescence reflect reduced protein levels within Imaris-rendered objects, rather than fewer DAT and/or NET-positive cells/nerve terminals, since there was no Mn effect on total cell number or on the number of Imaris-rendered DAT or NET objects, relative to controls; DAT and NET are widely used as a markers for catecholaminergic nerve terminals (Miller et al., 1997;Moron, Brockington, Wise, Rocha, & Hope, 2002;Stephenson et al., 2007). ...
Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg–1 day–1 during early postnatal life (PND 1–21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti‐inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5–10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control, and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn‐exposed children.
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Serious health hazards including renal, skin and hearing disorders have been reported in Bangladeshi tannery workers (TWs) who were chronically exposed to a large amount of trivalent chromium [Cr(III)]. However, the effects of Cr(III) exposure on the prevalence of hypertension and the prevalence of glycosuria in TWs remain unknown. Since the Cr level in toenails is an established marker reflecting long-term exposure to Cr(III) in humans, the associations of Cr levels in toenails with the prevalence of hypertension and the prevalence of glycosuria in male tannery and non-tannery office workers (non-TWs) in Bangladesh were investigated in this study. The mean toenail Cr level in non-TWs (0.5 μg/g, n = 49) was comparable to that in the general population reported previously. Mean Cr levels in TWs with a low toenail Cr level (5.7 μg/g, n = 39) and those with a high toenail Cr level (298.8 μg/g, n = 61) were >10-fold and >500-fold higher, respectively, than that in non-TWs. Our univariate and multivariate analyses indicated that the prevalence of hypertension and the prevalence of glycosuria in TWs with a high toenail Cr level, but not in TWs with a low toenail Cr level, were significantly lower than those in non-TWs. This study showed for the first time that long-term and excessive exposure to Cr(III) that is more than >500-fold but not >10-fold higher than the usual exposure level could decrease the prevalence of hypertension and the prevalence of glycosuria in TWs. Thus, this study revealed unexpected effects of exposure to Cr(III) on health.
Simultaneous relocation of a group of pollutant sources in a heavily polluted area is a rare event. Such a relocation has been implemented in Hazaribagh, a tannery built-up area with heavy pollution, in Bangladesh. This provides a valuable opportunity to compare the changes in environmental conditions associated with the relocation of multiple putative sources. Our environmental monitoring for a period of 6 years at the stationary areas centered on Hazaribagh geographically revealed trivalent [Cr(III)], hexavalent [Cr(VI)] chromium, lead, iron, and manganese as tannery-related elements after the legal deadline for tannery relocation. The median Cr(III) level in canal water, into which wastewater from tanneries was directly discharged, after the relocation was 97% lower of that before the relocation, indicating a beneficial effect of the relocation. In contrast, the median Cr(VI) level in water samples just after the relocation and 2 years after the relocation were approximately 5-fold and 30-fold higher, respectively, than those before the relocation. These results indicate not only a harmful effect of the relocation but also the possibility of conversion from Cr(III) to Cr(VI) in nature. Although the health hazard indexes considering all of the tannery-related elements in all of the canal water samples before the relocation exceeded the safety thresholds, the percentages of samples in which the indexes exceeded their safety thresholds after the relocation decreased by 32.5%–45.0%. Treatment with our patented hydrotalcite-like compound consisting of magnesium and iron (MF-HT) resulted in decreases in the health hazard indexes in all of the water samples in which the indexes exceeded their safety thresholds to levels lower than their thresholds. Thus, this study shows the double-edged effects associated with the relocation and a potential solution.
