Manganese Overexposure Alters Neurogranin Expression and Causes Behavioral Deficits in Larval Zebrafish.

Manganese (Mn), a cofactor for various enzyme classes, is an essential trace metal for all organisms. However, overexposure to Mn causes neurotoxicity. Here, we evaluated the effects of exposure to Mn chloride (MnCl2) on viability, morphology, synapse function (based on neurogranin expression) and behavior of zebrafish larvae. MnCl2 exposure from 2.5 h post fertilization led to reduced survival (60%) at 5 days post fertilization. Phenotypical changes affected body length, eye and olfactory organ size, and visual background adaptation. This was accompanied by a decrease in both the fluorescence intensity of neurogranin immunostaining and expression levels of the neurogranin-encoding genes nrgna and nrgnb, suggesting the presence of synaptic alterations. Furthermore, overexposure to MnCl2 resulted in larvae exhibiting postural defects, reduction in motor activity and impaired preference for light environments. Following the removal of MnCl2 from the fish water, zebrafish larvae recovered their pigmentation pattern and normalized their locomotor behavior, indicating that some aspects of Mn neurotoxicity are reversible. In summary, our results demonstrate that Mn overexposure leads to pronounced morphological alterations, changes in neurogranin expression and behavioral impairments in zebrafish larvae.

Hepatic HIF2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency.

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess. The goal of this study was to determine the basis of erythropoietin excess in SLC30A10 deficiency. Here, we demonstrate that transcription factors hypoxia-inducible factor 1a (Hif1a) and 2a (Hif2a), key mediators of the cellular response to hypoxia, are both upregulated in livers of Slc30a10-deficient mice. Hepatic Hif2a deficiency corrected erythropoietin expression and polycythemia and attenuated aberrant hepatic gene expression in Slc30a10-deficient mice, while hepatic Hif1a deficiency had no discernible impact. Hepatic Hif2a deficiency also attenuated manganese excess, though the underlying cause of this is not clear at this time. Overall, our results indicate that hepatic HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency and expand our understanding of the contribution of HIFs to human disease.

Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels.

Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.

Synergistic suppression of BDNF via epigenetic mechanism deteriorating learning and memory impairment caused by Mn and Pb co-exposure.

Microglia, the resident immune cells of the central nervous system (CNS), play a dual role in neurotoxicity by releasing the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome and brain-derived neurotrophic factor (BDNF) in response to environmental stress. Suppression of BDNF is implicated in learning and memory impairment induced by exposure to manganese (Mn) or lead (Pb) individually. Methyl CpG Binding Protein 2 (MeCp2) and its phosphorylation status are related to BDNF suppression. Protein phosphatase2A (PP2A), a member of the serine/threonine phosphatases family, dephosphorylates substrates based on the methylation state of its catalytic C subunit (PP2Ac). However, the specific impairment patterns and molecular mechanisms resulting from co-exposure to Mn and Pb remain unclear. Therefore, the purpose of this study was to explore the effects of Mn and Pb exposure, alone and in combination, on inducing neurotoxicity in the hippocampus of mice and BV2 cells, and to determine whether simultaneous exposure to both metals exacerbate their toxicity. Our findings reveal that co-exposure to Mn and Pb leads to severe learning and memory impairment in mice, which correlates with the accumulation of metals in the hippocampus and synergistic suppression of BDNF. This suppression is accompanied by up-regulation of the epigenetic repressor MeCp2 and its phosphorylation status, as well as demethylation of PP2Ac. Furthermore, inhibition of PP2Ac demethylation using ABL127, an inhibitor for its protein phosphatase methylesterase1 (PME1), or knockdown of MeCp2 via siRNA transfection in vitro effectively increases BDNF expression and mitigates BV2 cell damage induced by Mn and Pb co-exposure. We also observe abnormal activation of microglia characterized by enhanced release of the NLRP3 inflammasome, Casepase-1 and pro-inflammatory cytokines IL-1ß, in the hippocampus of mice and BV2 cells. In summary, our experiments demonstrate that simultaneous exposure to Mn and Pb results in more severe hippocampus-dependent learning and memory impairment, which is attributed to epigenetic suppression of BDNF mediated by PP2A regulation.

CYP1B1 affects the integrity of the blood-brain barrier and oxidative stress in the striatum: An investigation of manganese-induced neurotoxicity.

AIMS: Excessive influx of manganese (Mn) into the brain across the blood-brain barrier induces neurodegeneration. CYP1B1 is involved in the metabolism of arachidonic acid (AA) that affects vascular homeostasis. We aimed to investigate the effect of brain CYP1B1 on Mn-induced neurotoxicity. METHOD: Brain Mn concentrations and α-synuclein accumulation were measured in wild-type and CYP1B1 knockout mice treated with MnCl2 (30 mg/kg) and biotin (0.2 g/kg) for 21 continuous days. Tight junctions and oxidative stress were analyzed in hCMEC/D3 and SH-SY5Y cells after the treatment with MnCl2 (200 µM) and CYP1B1-derived AA metabolites (HETEs and EETs). RESULTS: Mn exposure inhibited brain CYP1B1, and CYP1B1 deficiency increased brain Mn concentrations and accelerated α-synuclein deposition in the striatum. CYP1B1 deficiency disrupted the integrity of the blood-brain barrier (BBB) and increased the ratio of 3, 4-dihydroxyphenylacetic acid (DOPAC) to dopamine in the striatum. HETEs attenuated Mn-induced inhibition of tight junctions by activating PPARγ in endothelial cells. Additionally, EETs attenuated Mn-induced up-regulation of the KLF/MAO-B axis and down-regulation of NRF2 in neuronal cells. Biotin up-regulated brain CYP1B1 and reduced Mn-induced neurotoxicity in mice. CONCLUSIONS: Brain CYP1B1 plays a critical role in both cerebrovascular and dopamine homeostasis, which might serve as a novel therapeutic target for the prevention of Mn-induced neurotoxicity.

The protective role of sesame oil against Parkinson's-like disease induced by manganese in rats.

Chronic exposure to manganese (Mn) results in motor dysfunction, biochemical and pathological alterations in the brain. Oxidative stress, inflammation, and dysfunction of dopaminergic and GABAergic systems stimulate activating transcription factor-6 (ATF-6) and protein kinase RNA-like ER kinase (PERK) leading to apoptosis. This study aimed to investigate the protective effect of sesame oil (SO) against Mn-induced neurotoxicity. Rats received 25 mg/kg MnCl2 and were concomitantly treated with 2.5, 5, or 8 ml/kg of SO for 5 weeks. Mn-induced motor dysfunction was indicated by significant decreases in the time taken by rats to fall during the rotarod test and in the number of movements observed during the open field test. Also, Mn resulted in neuronal degeneration as observed by histological staining. The striatal levels of lipid peroxides and reduced glutathione (oxidative stress markers), interleukin-6 and tumor necrosis factor-α (inflammatory markers) were significantly elevated. Mn significantly reduced the levels of dopamine and Bcl-2, while GABA, PERK, ATF-6, Bax, and caspase-3 were increased. Interestingly, all SO doses, especially at 8 ml/kg, significantly improved locomotor activity, biochemical deviations and reduced neuronal degeneration. In conclusion, SO may provide potential therapeutic benefits in enhancing motor performance and promoting neuronal survival in individuals highly exposed to Mn.

Forced expression of microRNA-221-3p exerts protective effects against manganese-induced cytotoxicity in human lung epithelial cells.

Manganese (Mn)-induced pulmonary toxicity and the underlying molecular mechanisms remain largely enigmatic. Further, in recent years, microRNAs (miRNAs) have emerged as regulators of several pollutants-mediated toxicity. In this context, our study aimed at elucidating whether miRNAs are involved in manganese (II) chloride (MnCl2) (Mn2+)-induced cytotoxicity in lung epithelial cells. Growth inhibition of Mn2+ towards normal human bronchial epithelial (BEAS-2B) and adenocarcinomic human alveolar basal epithelial (A549) cells was analyzed by MTT assay following 24 or 48 h treatment. Reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔΨm), cell cycle arrest, and apoptosis were evaluated by flow cytometry. RT-qPCR and Western blot were performed to analyze the expression of cyclins, anti-oxidant genes, and miRNAs. We used small RNA sequencing to investigate Mn2+-induced changes in miRNA expression patterns. In both cell lines, Mn2+ treatment inhibited growth in a dose-dependent manner. Further, compared with vehicle-treated cells, Mn2+ (250 µM) treatment induced ROS generation, cell cycle arrest, apoptosis, and decreased ΔΨm as well as altered the expression of cyclins and anti-oxidant genes. Sequencing data revealed that totally 296 miRNAs were differentially expressed in Mn2+-treated cells. Among them, miR-221-3p was one of the topmost down-regulated miRNAs in Mn2+-treated cells. We further confirmed this association in A549 cells. In addition, transient transfection was performed to study gain-of-function experiments. Forced expression of miR-221-3p significantly improved cell viability and reduced Mn2+-induced cell cycle arrest and apoptosis in BEAS-2B cells. In conclusion, miR-221-3p may be the most likely target that accounts for the cytotoxicity of Mn2+-exposed lung epithelial cells.

Joint and interactive effects of metal mixtures on liver damage: Epidemiological evidence from repeated-measures study.

BACKGROUND: The impact of heavy metals on liver function has been examined in numerous epidemiological studies. However, these findings lack consistency and longitudinal validation. METHODS: In this study, we conducted three follow-up surveys with 426 participants from Northeast China. Blood and urine samples were collected, along with questionnaire information. Urine samples were analyzed for concentrations of four metals (chromium [Cr], cadmium [Cd], lead [Pb], and manganese [Mn]), while blood samples were used to measure five liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin [ALB], globulin [GLB], and total protein [TP]). We utilized a linear mixed-effects model (LME) to explore the association between individual heavy metal exposure and liver function. Joint effects of metal mixtures were investigated using quantile g-computation and Bayesian kernel machine regression (BKMR). Furthermore, we employed BKMR and Marginal Effect models to examine the interaction effects between metals on liver function. RESULTS: The LME results demonstrated a significant association between urinary heavy metals (Cr, Cd, Pb, and Mn) and liver function markers. BKMR results indicated positive associations between heavy metal mixtures and ALT, AST, and GLB, and negative associations with ALB and TP, which were consistent with the g-comp results. Synergistic effects were observed between Cd-Cr on ALT, Mn-Cr and Cr-Pb on ALB, while an antagonistic effect was found between Mn-Pb and Mn-Cd on ALB. Additionally, synergistic effects were observed between Mn-Cr on GLB and Cd-Cr on TP. Furthermore, a three-way antagonistic effect of Mn-Pb-Cr on ALB was identified. CONCLUSION: Exposure to heavy metals (Cr, Cd, Mn, Pb) is associated with liver function markers, potentially leading to liver damage. Moreover, there are joint and interaction effects among these metals, which warrant further investigation at both the population and mechanistic levels.

Sensorimotor dysfunction due to developmental manganese exposure is less severe in adult female than male rats and partially improved by acute methylphenidate treatment.

Epidemiological studies have reported associations between elevated manganese (Mn) exposure and poorer psychomotor performance in children. Our studies in adult male rats have established that this relationship is causal and that prolonged methylphenidate (MPH) treatment is efficacious in treating this area of dysfunction. However, it is unclear if sensitivity to these Mn deficits differs between females and males, and whether existing pharmacological therapies are efficacious in improving sensorimotor dysfunction in females. To address these questions, we used our rat model of childhood environmental Mn exposure and the Montoya staircase test to determine whether 1) there are sex differences in the lasting sensorimotor dysfunction caused by developmental Mn exposure, and 2) MPH treatment is efficacious in ameliorating the sensorimotor deficits in females. Female and male neonates were treated orally with Mn (50 mg Mn/kg/d) from postnatal day 1 to 21 and evaluated for skilled forelimb sensorimotor performance as adults. Subsequently, the efficacy of acute oral MPH treatment (doses of 0, 0.5, and 3.0 mg MPH/kg/d) was assessed in females using a within-subject MPH treatment design. Developmental postnatal Mn exposure produced lasting sensorimotor reaching and grasping deficits that were milder in females than in males. Acute MPH treatment of Mn-exposed females with the 0.5 mg/kg/d dose attenuated the reaching dysfunction without alleviating grasping dysfunction. These findings show sex-based variations in sensitivity to the sensorimotor impairment caused by developmental Mn exposure, and they are consistent with prior studies showing less vulnerability of females to Mn-induced dysfunction in other functional domains, possibly due to the protective effects of estrogen. Given our previous work showing the efficacy of MPH treatment to alleviate Mn-induced inattention, impulsiveness, and sensorimotor dysfunctions in adult male rats, they also highlight the need for further research into sex-based differences in cognitive and behavioral areas of brain function, and the efficacy of therapeutics in treating behavioral dysfunction in females. Supported by NIEHS R01ES028369.

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD.

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (GD 3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.

[Bibliometric and visual analysis of neurological damage caused by electrical welding operations].

Objective: To analyze and summarize the trends and hot spots in the field of neurological damage caused by electric welding operations, and to provide ideas for new researches by searching the domestic and international literature. Methods: In December 2022, using Web of Science Citation Index (Web of Science), China Journal Full-Text Database (CNKI) and Wanfang Database as search databases, literature search was conducted on the Chinese and English search terms related to eletrical welding operations and neurological damage. The bibliometric analysis software VOSviewer 1.6.18 and CiteSpace 6.1.6 were used to visualize the publication year, publication quantity, country, research institution and key words of the literature. Results: A total of 309 articles (112 in Chinese and 197 in English) were included in this study. The first domestic and international papers were published in 1976 and 1994 respectively, and the number of papers reached the peak in 2006 and 2018, and then showed a downward trend to varying degrees. In China, Shandong First Medical University (including Shandong Institute of Occupational Health and Occupational Disease Prevention and Shandong Academy of Medical Sciences) and Wuhan University of Science and Technology had the largest number of publications. The 309 articles were from 52 Chinese journals and 86 English journals. The co-occurrence analysis of key words showed that the domestic research mainly focused on eletrical welding operation, welding workers, neurobehavioral function and manganese, and the nervous system damage caused by manganese in welding smoke was the field of international attention. Long term exposure, risk, and performance were key buzzwords in the field. Conclusion: The research focus in the field of nervous system damage caused by electric welding operation has an obvious trend of time evolution, gradually transiting from clinical manifestations to its toxic mechanism and early biomarkers.

Assessment of the oxidative stress intensity and the integrity of cell membranes under the manganese nanoparticles toxicity in wheat seedlings.

A response to manganese nanoparticles was studied in seedlings of two wheat cultivars and a model system of plant cell membranes. Nanoparticles at concentrations of 125 and 250 mg/ml were applied foliar. The application of NPs enhanced the content of Mn in plant cells, indicating its penetration through the leaf surface. The stressful effect in the plant cells was estimated based on changes in the activity of antioxidant enzymes, content of chlorophylls and starch. MnNPs evoked no significant changes in the leaf morphology, however, an increase in enzyme activity, starch accumulation, and a decrease in chlorophyll synthesis indicated the stress occurrence. Moreover, a rise in the electrokinetic potential of the chloroplast membrane surface and the reconstruction of their hydrophobic parts toward an increase in fatty acid saturation was found.

Mechanism of KAT2A regulation of H3K36ac in manganese-induced oxidative damage to mitochondria in the nervous system and intervention by curcumin.

Excessive exposure to manganese in the environment or workplace is strongly linked to neurodegeneration and cognitive impairment, but the precise pathogenic mechanism and preventive measures are still not fully understood. The study aimed to investigate manganese -induced oxidative damage in the nervous system from an epigenetic perspective, focusing on the H3K36ac-dependent antioxidant pathway. Additionally, it sought to examine the potential of curcumin in preventing manganese-induced oxidative damage. Histopathology and transmission electron microscopy revealed that apoptosis and necrosis of neurons and mitochondrial ultrastructure damage were observed in the striatum of manganese-exposed rats. manganese suppressed the expression of mitochondrial antioxidant genes, leading to oxidative damage in the rats' striatum and SH-SY5Y cells. With higher doses of manganese, levels of histone acetyltransferase lysine acetyltransferase 2 A (KAT2A) expression and H3K36ac level decreased. ChIP-qPCR confirmed that H3K36ac enrichment in the promoter regions of antioxidant genes SOD2, PRDX3, and TXN2 was reduced in SH-SY5Y cells after manganese exposure, leading to decreased expression of these genes. Overexpression of KAT2A confirms that it attenuates manganese-induced mitochondrial oxidative damage by regulating H3K36ac levels, which in turn controls the expression of antioxidant genes SOD2, PRDX3, and TXN2 in the manganese-exposed cell model. Furthermore, curcumin might control H3K36ac levels by influencing KAT2A expression, boosting antioxidant genes expression, and reducing manganese-induced mitochondrial oxidative damage. In conclusion, the regulation of mitochondrial oxidative stress by histone acetylation may be an important mechanism of manganese-induced neurotoxicity. This regulation could be achieved by reducing the level of H3K36ac near the promoter region of mitochondrial-associated antioxidant genes via KAT2A. Curcumin mitigates manganese-induced oxidative damage in mitochondria and plays a crucial protective role in manganese-induced oxidative injury in the nervous system.

NRAMPs and manganese: Magic keys to reduce cadmium toxicity and accumulation in plants.

Cadmium (Cd), a toxic heavy metal, poses significant threats to both crop production and human health worldwide. Manganese (Mn), an essential micronutrient, plays a crucial role in plant growth and development. NRAMPs (Natural Resistance-Associated Macrophage Proteins) function as common transporters for both Cd and Mn. Deep understanding of the regulatory mechanisms governing NRAMP-mediated Cd and Mn transport is imperative for developing the crop varieties with high tolerance and low accumulation of Cd. This review reported the advance in studies on the fundamental properties and classification of NRAMPs in plants, and structural characteristics, expression patterns, and diverse functions of NRAMP genes across different plant species. We highlighted the pivotal role of NRAMPs in Cd/Mn uptake and transport in plants as a common transporter. Finally, we also comprehensively discussed over the strategies for reducing Cd uptake and accumulation in plants through using antagonism of Mn over Cd and altering the expression of NRAMP genes.

Nondestructive Evaluation of Metal Bioaccumulation and Biochemical Biomarkers in Blood of Broad-Snouted Caiman (Caiman latirostris) from Northeastern Brasil.

Studies on the bioaccumulation and toxicity of contaminants in Crocodylians are scarce. We evaluated alterations in concentrations of the nondestructive biomarkers butyrylcholinesterase (BChE), glutathione-S-transferase (GST), superoxide dismutase (SOD), and reduced glutathione (GSH), together with bioaccumulation of the metals iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), chronium (Cr), aluminium (Al), and lead (Pb) in Caiman latirostris captured in Tapacurá Reservoir (TR; São Lourenço da Mata, Pernambuco, Brasil), in urbanized areas of Pernambuco State (UA; Brasil) and from the AME Brasil caiman farm (AF; Marechal Deodoro, Alagoas, Brasil); the latter was used as a potential reference with low levels of contamination. For metal analysis, 500 µL of blood was digested in 65% HNO3 and 30% H2O2. The samples were analyzed by inductively coupled plasma-optical emission spectrometry. For analysis of biomarkers, an aliquot of blood was centrifuged to obtain plasma in which biochemical assays were performed. Blood concentrations of metals analyzed in animals from AF were lower compared with TR and UA, confirming that animals from the caiman farm could be used as references with low levels of contamination. Iron, Cu, Mn, Al, and Pb exceeded toxic levels for other vertebrates in animals from TR and UA. Butyrylcholinesterase activity showed significant reduction in adults from UA and TR compared with AF. An increase in the activity of GST and GSH, in adults of TR and UA in relation to AF, was verified. Superoxide dismutase activity showed a significant reduction in adults of TR in relation to AF, and the concentrations of Cu and Mn were negatively correlated with SOD activity. Animals from UA and TR showed greater concentrations of the analyzed metals compared with reference animals, and changes in biomarkers were seen, confirming the potential of these nondestructive chemical and biological parameters in blood of C. latirostris for biomonitoring of pollution. Environ Toxicol Chem 2024;43:878-895. © 2024 SETAC.

Metformin Attenuates Manganese-Induced Oxidative Stress in N27-A Dopaminergic Neuronal Cells.

Metformin is an anti-diabetic drug that exerts protective effects against neurodegenerative diseases. In this study, we investigated the protective effects of metformin against manganese (Mn)-induced cytotoxicity associated with Parkinson's disease-like symptoms in N27-A dopaminergic (DA) cells. Metformin (0.1-1 mM) suppressed Mn (0.4 mM)-induced cell death in a concentration-dependent manner. Metformin pretreatment effectively suppressed the Mn-mediated increase in the levels of oxidative stress markers, such as reactive oxygen species (ROS) and thiobarbituric acid reactive substances. Moreover, metformin restored the levels of the antioxidants, superoxide dismutase, intracellular glutathione, and glutathione peroxidase, which were reduced by Mn. Metformin (0.5 mM) significantly attenuated the decrease in sirtuin-1 (SIRT1) and peroxisome proliferator activated receptor gamma coactivator-1 alpha levels, which were increased by Mn (0.4 mM). In addition, metformin inhibited the expression of microRNA-34a, which directly targeted SIRT1. Metformin also inhibited the loss of Mn-induced mitochondrial membrane potential (ΔΨm) and activation of the apoptosis marker, caspase-3. Furthermore, metformin-mediated inhibition of ROS generation and caspase-3 activation, recovery of ΔΨm, and restoration of cell viability were partially reversed by the SIRT1 inhibitor, Ex527. These results suggest that metformin may protects against Mn-induced DA neuronal cell death mediated by oxidative stress and mitochondrial dysfunction possibly via the regulation of SIRT1 pathway.

Neuroprotective Effect of Resveratrol against Manganese-Induced Oxidative Stress and Matrix Metalloproteinase-9 in an "In Vivo" Model of Neurotoxicity.

Chronic exposure to manganese (Mn) leads to its accumulation in the central nervous system (CNS) and neurotoxicity with not well-known mechanisms. We investigated the involvement of matrix metalloproteinase (MMP)-2 and -9 in Mn neurotoxicity in an in vivo model of rats treated through an intraperitoneal injection, for 4 weeks, with 50 mg/kg of MnCl2 in the presence or in the absence of 30 mg/kg of resveratrol (RSV). A loss of weight was observed in Mn-treated rats compared with untreated and RSV-treated rats. A progressive recovery of body weight was detected in rats co-treated with Mn and RSV. The analysis of brain homogenates indicated that RSV counteracted the Mn-induced increase in MMP-9 levels and reactive oxygen species production as well as the Mn-induced decrease in superoxide dismutase activity and glutathione content. In conclusion, Mn exposure, resulting in MMP-9 induction with mechanisms related to oxidative stress, represents a risk factor for the development of CNS diseases.

Identification of histone acetylation modification sites in the striatum of subchronically manganese-exposed rats.

Aim: To explore the specific histone acetylation sites and oxidative stress-related genes that are associated with the pathogenesis of manganese toxicity. Methods: We employed liquid chromatography-tandem mass spectrometry and bioinformatics analysis to identify acetylated proteins in the striatum of subchronic manganese-intoxicated rats. Results: We identified a total of 12 differentially modified histone acetylation sites: H3K9ac, H3K14ac, H3K18ac, H3K56ac and H3K79ac were upregulated and H3K27ac, H3K36ac, H4K91ac, H4K79ac, H4K31ac, H2BK16ac and H2BK20ac were downregulated. Additionally, we found that CAT, SOD1 and SOD2 might be epigenetically regulated and involved in the pathogenesis of manganism. Conclusion: This study identified histone acetylation sites and oxidative stress-related genes associated with the pathogenesis of manganese toxicity, and these findings are useful in the search for potential epigenetic targets for manganese toxicity.

Manganese nutrient mitigates ammonia, arsenic toxicity and high temperature stress using gene regulation via NFkB mechanism in fish.

The ongoing challenges of climate change and pollution are major factors disturbing ecosystems, including aquatic systems. They also have an impact on gene regulation and biochemical changes in aquatic animals, including fish. Understanding the mechanisms of gene regulation and biochemical changes due to climate change and pollution in aquatic animals is a challenging task. However, with this backdrop, the present investigation was conducted to explore the effects of arsenic (As) and ammonia (NH3) toxicity and high-temperature (T) stress on gene regulation and biochemical profiles, mitigated by dietary manganese (Mn) in Pangasianodon hypophthalmus. The fish were exposed to different combinations of As, NH3, and T, and fed with dietary Mn at 4, 8, and 12 mg kg-1 to evaluate the gene expression of immunity, antioxidative status, cytokine, and NfKB signaling pathway genes. HSP 70, cytochrome P450 (CYP 450), metallothionein (MT), DNA damage-inducible protein (DDIP), caspase (CAS), tumor necrosis factor (TNFα), toll-like receptor (TLR), interleukin (IL), inducible nitric oxide synthase (iNOS), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were noticeably highly upregulated by As + NH3 + T stress, whereas Mn diet at 8 mg kg-1 downregulated these genes. Further, total immunoglobulin (Ig), myostatin (MYST), somatostatin (SMT), growth hormone (GH), growth hormone regulator 1 and ß, insulin-like growth factors (IGF1X1 and IGF1X2) were significantly upregulated by Mn diets. The biochemical profiles were highly affected by stressors (As + NH3 + T). The bioaccumulation of arsenic in different tissues was also notably reduced by Mn diets. Furthermore, the infectivity of the fish was reduced, and survival against pathogenic bacteria was enhanced by Mn diet at 8 mg kg-1. The results of the present investigation revealed that dietary Mn at 8 mg kg-1 controls gene regulation against multiple stressors (As, NH3, As + NH3, NH3 + T, As + NH3 + T) in fish.

Ferroptosis at the crossroads of manganese-induced neurotoxicity: A retrospective study.

Manganese is an essential trace element, but overexposure can cause neurotoxicity and subsequent neurodegenerative diseases. Ferroptosis is a form of cell death characterized by lipid peroxidation and iron overload inside cells, which is closely related to manganese neurotoxicity. Manganese can induce ferroptosis through multiple pathways: causing oxidative stress and increased cellular reactive oxygen species (ROS), resulting in lipid peroxidation; depleting glutathione (GSH) and weakening the antioxidant capacity of cells; disrupting iron metabolism and increasing iron-dependent lipid peroxidation; damaging mitochondrial function and disrupting the electron transport chain, leading to increased ROS production. Oxidative stress, iron metabolism disorders, lipid peroxidation, GSH depletion, and mitochondrial dysfunction, typical features of ferroptosis, have been observed in animal and cell models after manganese exposure. In summary, manganese can participate in the pathogenesis of neurodegenerative diseases by inducing events related to ferroptosis. This provides new insights into studying the mechanism of manganese neurotoxicity and developing therapeutic drugs.