Environmental Manganese Research Articles

P02-09: Manganese biomarkers and neurofunctional outcomes following environmental manganese exposure

P02-09: Manganese biomarkers and neurofunctional outcomes following environmental manganese exposure

Environmental manganese exposure and cognitive control in a South African population

ObjectiveTo characterize the association between environmental (residential air) manganese (Mn) exposure and cognitive performance, focusing on cognitive control, in a Black African population. MethodsWe administered the Go-No-Go, Digit Span, and Matrix Reasoning tests to population-based samples age ≥40 from a high Mn (smelter) exposed community, Meyerton (N = 629), and a demographically comparable low (background levels) non-exposed community, Ethembalethu, (N = 96) in Gauteng province, South Africa. We investigated the associations between community and performance on the cognitive tests, using linear regression. We adjusted a priori for age and sex, and examined the effect of adjustment for education, nonverbal IQ, smoking, and alcohol consumption. We measured airborne PM2.5-Mn to confirm community exposure differences. ResultsCompared to Ethembalethu residents, Meyerton residents’ test scores were lower (poorer) for all tests: 0.55 (95 % confidence interval [CI] 0.08, 1.03) lower scores for Matrix Reasoning, 0.34 (95 % CI -0.07, 0.75) lower for Digit Span, and 0.15 (95 % CI 0.09, 0.21) lower for Go-No-Go (high frequency discriminability index [probability]). The latter represented the most marked difference in terms of z-scores (0.50, 95 % CI 0.30, 0.71 standard deviations lower). The mean of the z-score of each of the three tests was also lower (0.34, 95 % CI 0.18, 0.50 standard deviations lower). These associations were similar in men and women, but attenuated with adjustment for education. Differences for Matrix Reasoning and Digit Span between the two communities were observed only among those who had lived in Meyerton ≥10 years, whereas for Go-No-Go, differences were also apparent among those who had lived in Meyerton <10 years. Mean PM2.5-Mn at a long-term fixed site in Meyerton was 203 ng/m3 and 10 ng/m3 in Ethembalethu. ConclusionResidence in a community near a high Mn emission source is associated with cognitive dysfunction, including aspects of cognitive control as assessed by the Go-No-Go test.

Pathways of Environmental Manganese Exposures to Biomarkers of Manganese in 7-9 Year Old Children Living Near a Ferromanganese Refinery

Pathways of Environmental Manganese Exposures to Biomarkers of Manganese in 7-9 Year Old Children Living Near a Ferromanganese Refinery

Clinical relevance of environmental manganese exposure with liver stiffness and steatosis detected by transient elastography in adults.

Global manganese pollution to air and water is a significant threat to human health. The associations between manganese and liver stiffness and steatosis have not been reported in epidemiological studies. This study aimed to explore the clinical relevance of blood manganese with liver stiffness and steatosis in adults from the 2017-2018 National Health and Nutrition Examination Survey (N = 4,192). Subjects with excessive alcohol consumption and hepatitis B or C infection were excluded. Liver stiffness and steatosis were detected by transient elastography. Logistic regression and restricted cubic splines were adopted to explore the non-linear dose-response relationships. In multivariate analysis, while higher blood manganese concentrations were not associated with liver stiffness in the total sample and in males, an increased odds of significant liver fibrosis was found with higher blood manganese concentrations (tertile 3 vs. tertile 1) in females [odds ratios (95% confidence intervals): 2.34 (1.32-4.14), P trend < 0.01] and in other races [1.47 (1.05-2.05), P trend = 0.03]. Higher blood manganese concentrations were associated with liver steatosis in the total sample [1.33 (1.04-1.70), P trend = 0.03], in females [1.58 (1.02-2.44), P trend = 0.04], in other races [1.91 (1.50-2.43), P trend < 0.01], and in obese subjects [2.29 (1.13-4.65), P trend = 0.02]. Dose-response analysis showed that the departures from non-linear relationships between blood manganese concentrations and significant liver fibrosis (Pnon-linearity = 0.30) and steatosis (Pnon-linearity = 0.47) were not significant, suggesting that the observed associations were linear. In conclusion, higher blood manganese concentrations were positively associated with liver stiffness and steatosis, and the associations were mainly observed in females, in races other than Non-Hispanic White, and in obese subjects.

Depression and anxiety in a manganese-exposed community

ObjectiveTo characterize the association between residential environmental manganese (Mn) exposure and depression and anxiety, given prior associations among occupationally-exposed workers. MethodsWe administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) to 697 study participants in their preferred languages. These participants represented a population-based sample of residents aged ≥40 from two predominantly Black African communities in Gauteng province, South Africa: 605 in Meyerton, adjacent to a large Mn smelter, and 92 in Ethembalethu, a comparable non-exposed community. We investigated the associations between community (Meyerton vs. Ethembalethu) and severity of depression and anxiety, using linear regression, adjusting for age and sex. To document community-level differences in Mn exposure, we measured airborne PM2.5-Mn. ResultsMeyerton residents had BDI scores 5.63 points (95 % CI 3.07, 8.20) higher than Ethembalethu residents, with all questions contributing to this significant difference. STAI-state scores were marginally higher in Meyerton than Ethembalethu residents [2.12 (95 % CI -0.17, 4.41)], whereas STAI-trait scores were more similar between the communities [1.26 (95 % CI -0.82, 3.35)]. Mean PM2.5-Mn concentration was 203 ng/m3 at a long-term fixed site in Meyerton and 10 ng/m3 in Ethembalethu. ConclusionResidence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety.

Severity of parkinsonism associated with environmental manganese exposure

BackgroundExposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016–2020.MethodsA movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an accelerometry-based kinematic test and a grooved pegboard test. We compared performance on the UPDRS3, grooved pegboard, and the accelerometry-based kinematic test between the settlements using linear regression, adjusting for covariates. We also measured airborne PM2.5-Mn in the study settlements.ResultsMean PM2.5-Mn concentration at a long-term fixed site in Meyerton was 203 ng/m3 in 2016–2017 – approximately double that measured at two other neighborhoods in Meyerton. The mean Mn concentration in Ethembalethu was ~ 20 times lower than that of the long-term Meyerton site. UPDRS3 scores were 6.6 (CI 5.2, 7.9) points higher in Meyerton than Ethembalethu residents. Mean angular velocity for finger-tapping on the accelerometry-based kinematic test was slower in Meyerton than Ethembalethu residents [dominant hand 74.9 (CI 48.7, 101.2) and non-dominant hand 82.6 (CI 55.2, 110.1) degrees/second slower]. Similarly, Meyerton residents took longer to complete the grooved pegboard, especially for the non-dominant hand (6.9, CI -2.6, 16.3 s longer).ConclusionsEnvironmental airborne Mn exposures at levels substantially lower than current occupational exposure thresholds in the United States may be associated with clinical parkinsonism.

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems.

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 50mg Mnkg-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 5-10min 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.

Manganese transporter genetics and sex modify the association between environmental manganese exposure and neurobehavioral outcomes in children

Manganese transporter genetics and sex modify the association between environmental manganese exposure and neurobehavioral outcomes in children

Manganese transporter genetics and sex modify the association between environmental manganese exposure and neurobehavioral outcomes in children

There is increasing evidence that environmental manganese (Mn) exposure early in life can have negative effects on children's neurodevelopment and increase the risk of behavioral problems, including attention deficit hyperactivity disorder (ADHD). Factors that may contribute to differences in sensitivity to Mn exposure are sex and genetic variation of proteins involved in the regulation of Mn concentrations. Here we investigate if sex and polymorphisms in Mn transporter genes SLC30A10 and SLC39A8 influence the association between Mn exposure and ADHD-related behavioral problems in children.The SNPs rs1776029 and rs12064812 in SLC30A10, and rs13107325 in SLC39A8 were genotyped by TaqMan PCR or pyrosequencing in a population of Italian children (aged 11–14 years; n = 645) with a wide range of environmental Mn exposure. Mn in surface soil was measured in situ using XRF technology or modeled by geospatial analysis. Linear regression models or generalized additive models (GAM) were used for analyzing associations between soil Mn and neurobehavioral problems assessed by the Conners' behavior rating scales (self-, and parent-reported). Gene-environment interactions (Mn transporter genotype x soil Mn) were evaluated using a genetic score in which genotypes for the three SNPs were combined based on their association with blood Mn, as an indication of their influence on Mn regulation.We observed differences in associations between soil Mn and neurobehavior between sexes. For several self-reported Conners' scales, girls showed U-shaped relationships with higher (worse) Conners' scoring at higher soil Mn levels, and several parent-reported scales showed positive linear relationships between increasing soil Mn and higher Conner's scores. For boys, we observed a positive linear relationship with soil Mn for one Conner's outcome only (hyperactivity, parent-reported). We also observed some interactions between soil Mn and the genetic score on Conner's scales in girls and girls with genotypes linked to high blood Mn showed particularly strong positive associations between soil Mn and parent-reported Conners' scales.Our results indicate that sex and polymorphisms in Mn transporter genes contribute to differences in sensitivity to Mn exposure from the environment and that girls that are genetically less efficient at regulating Mn, may be a particularly vulnerable group.

Physiological and Biochemical Effects of Echium Amoenum Extract on Mn2+-Imposed Parkinson Like Disorder in Rats.

Purpose: Manganism is a cognitive disorder take places in peoples are exposed to environmental manganese pollution. Overexposure to manganese ion (Mn2+) mainly influences central nervous system and causes symptoms that increase possibility of hippocampal damages.Methods: In this study rats were administrated by two different doses of MnCl2 and behavioral and physiological consequences were evaluated. We also investigated effects of E. Amoenum on Mn2+-imposed toxicity by behavioral, biochemical, immunoblotting and histological studies on hippocampus tissue.Results: Results showed metal overexposure increases oxidative stress mainly by lipid peroxidation and reactive oxygen species overproduction. Histological studies and caspase 3 analyses by immunoblotting revealed Mn2+ induced apoptosis from mitochondrial-dependent pathway in the presence of low metal dose. This study provides evidence that oral administration of E. amoenum extract inhibited manganese neurotoxicity by oxidative stress attenuation and apoptosis reduction that lead to improved depression like behavior. Plant extract also increased catecholamine content in Mn2+ treated hippocampus.Conclusion: As molecular and pathophysiological effects of E. amoenum, it could be considered as a pre-treatment for Parkinson and Parkinson like disorders in high-risk people.

Follow-up of the manganese-exposed workers healthy cohort (MEWHC) and biobank management from 2011 to 2017 in China

BackgroundLong-term excess exposure to environmental manganese (Mn) can lead to multi-system damage, especially in occupational populations. Therefore, we established a manganese-exposed workers healthy cohort (MEWHC), focusing on the systemic health effects related to Mn exposure. Here, we aimed to describe the follow-up activity for the MEWHC study and establish a standardized biological sample bank for the scientific management of high-quality biospecimens and the attached data from 2011 to 2017.MethodsBaseline examinations for onsite workers were conducted, and the biobank for the MEWHC was first established in 2011; follow-up examinations occurred four times between July 2012 and November 2017. All questionnaires, clinical data and biological samples were routinely collected during each follow-up activity. Additional workers were recruited in 2016, which further enriched the resources of the biobank.ResultsA total of 2359 onsite workers and 612 retired workers at a ferromanganese refinery were enrolled in the prospective cohort, and their biological samples were obtained in the preliminary baseline survey and the follow-up investigation, including 2971 blood and urine samples from the cohort. In addition, 1524 hair samples, 1404 nail (toe and finger nails) and 1226 fecal samples were also collected. All specimens were preserved in the biobank, and the data were scientifically managed using a computer system.ConclusionsThe MEWHC study in China provides an effective way to obtain biological samples such as plasma, DNA, hair and urine for storage in a biobank for further study. The standardized management of various samples is crucial for accessing high-quality biospecimens.

Growth parameters at birth mediate the relationship between prenatal manganese exposure and cognitive test scores among a cohort of 2- to 3-year-old Bangladeshi children.

Our previous study demonstrated that prenatal manganese exposure is associated with cognitive test scores among a cohort of 2- to 3-year-old Bangladeshi children. This study tested the hypothesis that the adverse effects of manganese are mediated through poor prenatal growth. Pregnant mothers were enrolled in a birth cohort in Bangladesh between 2008 and 2011, and children were followed at birth and age 20-40 months. Manganese concentration was measured in umbilical cord blood. Anthropometric measurements (weight, length, head circumference) were assessed at delivery. Children's cognitive development was assessed at age 20-40 months using the Bayley Scales of Infant and Toddler Development-Third Edition. Using recently developed statistical approaches that estimate mediation and interaction effects simultaneously, we evaluated whether the association between cord blood manganese and cognitive score was mediated through anthropometric measures at birth. This analysis included 764 mother-child pairs. Higher manganese concentration was associated with lower cognitive score [β=-0.61, standard error (SE)=0.23, p = 0.009]. Among the birth measures, we found a significant indirect effect only through birth length (β=-0.10, SE = 0.03, p = 0.001). We also found evidence of mediated interaction (both mediation and interaction, β=-0.03, SE = 0.01, p = 0.01) with birth length in the association between cord blood manganese and cognitive score. The overall proportion mediated by birth length was 33% (p = 0.02) and the proportion attributed to interaction was 11% (p = 0.04). We did not find evidence of a mediating effect through birth weight or head circumference. Our findings confirm that prenatal growth, particularly birth length, contributes to the overall effect of environmental manganese exposure on a child's cognitive development.

Environmental manganese exposure and associations with memory, executive functions, and hyperactivity in Brazilian children

Manganese (Mn) is an essential element, however high levels of Mn have been associated with lower neuropsychological performance and behavioral problems in children. We investigated the associations between hair Mn concentrations and neuropsychological and behavioral performances among children with long-term exposure to airborne Mn aged between 7 and 12 years. Neuropsychological performance included tests of: verbal memory, inhibitory control, cognitive flexibility, verbal fluency, and motor function. We used the Conners Abbreviated Rating Scale for teachers to assess students’ behaviors of hyperactivity. Hair manganese (MnH) concentrations in children and exposure to airborne manganese from a ferro-manganese alloy plant were analyzed and correlated with tests scores. Multivariable linear models adjusting for potential confounders showed that elevated levels of MnH were associated with lower performance in verbal memory, as measured by the free recall after interference (β = – 1.8; 95% CI: – 3.4, – 0.2), which indicates susceptibility to interference, and Delayed Effect (β = –2.0; 95% CI: –3.7, – 0.2), representing a loss of information over time. Additionally, we found patterns of effect modification by sex in three subtests measuring verbal memory: the free recall after interference score, Interference Effect, and Delayed Effect (all at p < 0.10). Overall, the results suggest that long-term airborne Mn exposure may be associated with lower performance in verbal memory, and hyperactivity behaviors.

Maternal and Cord Blood Manganese Concentrations and Early Childhood Neurodevelopment among Residents near a Mining-Impacted Superfund Site.

Background:Environmental manganese exposure has been associated with adverse neurodevelopmental outcomes among school-aged children; yet, few studies have evaluated prenatal exposure.Objectives:Our study examines associations between prenatal manganese concentrations and placental transfer of manganese with neurodevelopment in 224 2-y-old children residing near the Tar Creek Superfund Site.Methods:We collected maternal and cord blood at delivery, measured manganese using inductively coupled plasma mass spectrometry, and assessed neurodevelopment using the Bayley Scales of Infant Development-II. Associations between manganese and mental (MDI) and psychomotor (PDI) development indices were estimated in multivariable models. Placental transfer, approximated by cord/maternal manganese ratio, cord/total manganese ratio (), and by joint classification according to high or low (above or below median) maternal and cord manganese, was evaluated as a predictor of neurodevelopment.Results:Median levels [interquartile ranges (IQR)] of manganese in maternal and cord blood, respectively, were 24.0 (19.5–29.7) and . Adjusting for lead, arsenic, and other potential confounders, an IQR increase in maternal manganese was associated with (95% CI: , ) points on MDI and (95% CI: , ) points on PDI. Cord manganese concentrations were not associated with neurodevelopment scores. Cord/maternal and cord/total manganese ratios were positively associated with MDI [cord/maternal: ; cord/total: ] and PDI (cord/maternal: ; cord/total: ). Compared to mother–child pairs with low maternal and cord manganese, associations with neurodevelopment scores were negative for pairs with either high maternal, high cord, or high maternal and cord manganese.Conclusions:Maternal blood manganese concentrations were negatively associated with early childhood neurodevelopment scores in our study. Findings highlight the importance of understanding maternal exposures during pregnancy and factors influencing placental transfer. https://doi.org/10.1289/EHP925

Environmental neurotoxicant manganese regulates exosome-mediated extracellular miRNAs in cell culture model of Parkinson's disease: Relevance to α-synuclein misfolding in metal neurotoxicity

Many chronic neurodegenerative disorders share a common pathogenic mechanism involving the aggregation and deposition of misfolded proteins. Recently, it was shown that these aggregated proteins could be transferred from one cell to another via extracellular nanovesicles called exosomes. Initially thought to be a means of cellular waste removal, exosomes have since been discovered to actively participate in cell-to-cell communication. Importantly, various inflammatory and signaling molecules, as well as small RNAs are selectively packaged in these vesicles. Considering the important role of environmental manganese (Mn) in Parkinson's disease (PD)-like neurological disorders, we characterized the effect of Mn on exosome content and release using an MN9D dopaminergic cell model of PD, which was generated to stably express wild-type human α-synuclein (αSyn). Mn exposure (300μM MnCl2) for 24h induced the release of exosomes into the extracellular media prior to cytotoxicity, as determined by NanoSight particle analysis and electron microscopy. Strikingly, Western blot analysis revealed that Mn treatment in αSyn-expressing cells increases the protein Rab27a, which regulates the release of exosomes from cells. Moreover, next-generation sequencing showed more small RNAs in exosomes isolated from Mn-exposed cells than from control exosomes. Our miRNA profiling analysis led to the discovery of increased expression of certain miRNAs previously shown to regulate key biological pathways, including protein aggregation, autophagy, inflammation and hypoxia. Collectively, our results provide a glimpse of Mn's role in modulating extracellular miRNA content through exosomal release from dopaminergic neuronal cells and thus potentially contributing to progressive neurodegeneration. Further characterization of extracellular miRNAs and their targets will have major impacts on biomarker discovery and translational strategies for environmentally linked neurodegenerative diseases including PD.

Changes in Olfactory discrimination associated to environmental Manganese in Adolescents

Introduction: Olfactory changes are frequently shown in Parkinsonian patients and may be related to dysregulation of Dopaminergic control. While studies have suggested that exposure to manganese (Mn) may be associated with Parkinsonism, there is limited information on Mn exposures and the olfactory function in children. Methods: We measured soil and house dust Mn levels in the household of 389 children in Brescia, Italy. Surface soil was assessed with a Niton pXRF instrument and dust samples were collected by sweeping a measured area with a plastic brush, or using a cyclone vacuum. Mn was determined with ICP-OES. To assess odor identification we used Sniffin’ Sticks-Olfactory Screening 12 test (Burghart Medical Technology). We examined the relationships of soil and indoor-outdoor dust Mn (log-transformed) with olfactory discrimination (log-odds of correct identification) using generalized linear models and generalized additive models, adjusting for age, sex, socioeconomic status index, mother education, smoking and drinking. We also tested the effect of environmental Mn using a generalized linear mixed effects model, that allowed us to estimate the difficulty associated with recognizing each of the 12 odors, taking into account the olfactory ability of each subject Results: We found that soil Mn (estimate=-0.125, p=0.02) indoor dust (-0.06, p=0.045) and outdoor dust Mn (estimate=-0.07, p=0.03) were associated with decreased odds of correct odor identifications. This effect was particularly evident in boys. Cloves (when compared with peppermint) was the most difficult odor to be recognized by boys and girls. Conclusions: Our findings suggest that higher environmental Mn levels measured in household dust, outdoor dust and soil may be associated with worse odor identification. These data support the potential influence of Mn on dopaminergic control of olfactory functions that may represent an early sign of neurotoxicity.

Effects of Manganese Exposure on Olfactory Functions in Teenagers: A Pilot Study.

Long-term exposure to environmental manganese (Mn) affects not only attention and neuromotor functions but also olfactory functions of a pre-adolescent local population who have spent their whole life span in contaminated areas. In order to investigate the effect of such exposure at the level of the central nervous system we set up a pilot fMRI experiment pointing at differences of brain activities between a non-exposed population (nine subjects) and an exposed one (three subjects). We also measured the volume of the olfactory bulb as well as the identification of standard olfactory stimuli. Our results suggest that young subjects exposed to Mn exhibit a reduction of BOLD signal, subjective odor sensitivity and olfactory bulb volume. Moreover a region of interest SPM analysis showed a specifically reduced response of the limbic system in relation to Mn exposure, suggesting an alteration of the brain network dealing with emotional responses.

Modeling and estimating manganese concentrations in rural households in the mining district of Molango, Mexico.

Airborne manganese (Mn) is considered the most hazardous route of exposure since Mn particles can enter into the body through the lung and may access the brain directly through olfactory uptake, thereby bypassing homeostatic excretory mechanisms. Environmental indoor and outdoor manganese concentrations in PM2.5 were monitored in ten rural households from two communities of Hidalgo, Mexico, from 2006 to 2007. Indoor and outdoor air samples of PM2.5 were collected using MiniVol samplers, and Mn concentrations in the filters were measured using proton-induced X-ray emission (PIXE). An adjusted generalized linear mixed model was applied and then used for estimating indoor concentrations in non-monitored households. Our monitoring results showed a higher daily average concentration of indoor PM2.5 vs. outdoor PM2.5 (46.4 vs. 36.2 μg/m(3), respectively); however, manganese concentration in PM2.5 indoor and outdoor was 0.09 μg/m(3) in both sceneries. Predictor variables of indoor Mn concentration were outdoor Mn concentration (64.5% increase per 0.1 μg/m(3) change in Mn) and keeping the windows open (4.2% increase). Using these predictors, the average estimated indoor Mn concentration in PM2.5 was 0.07 μg/m(3) (SD = 0.05). Our results confirm the direct effect of outdoor Mn levels, opening house windows, and the distance to the mining chimney in indoor Mn levels in houses.

Challenges Posed By Manganese Neurotoxicity In Latin America

In Latin America, several sources of environmental airborne and waterborne manganese have been identified, including manganese mining and transformation, use of manganese-based pesticides and drink...

Lysosomal dysfunction caused by the environmental neurotoxicant manganese increases exosome-mediated cell-to-cell transfer of α-synuclein by a prion-like mechanism

Lysosomal dysfunction caused by the environmental neurotoxicant manganese increases exosome-mediated cell-to-cell transfer of α-synuclein by a prion-like mechanism