Cerebellar Alterations in Glutathione (GSH) and Motor Variations in Welders Exposed to Manganese

Details

• Personal Author:
  George, J. ; Bozymski, B. ; Nossa, G. ; Lee, C. ; Mizimakoski, C. ; Park, J. ; Harold, R. ; Foti, D. ; Dydak, U.
• Description:
  Background and Purpose: Manganese (Mn) is an essential trace mineral vital for human metabolism, particularly within the central nervous system (CNS), where it functions as a cofactor for various enzymes. However, excessive occupational Mn exposure can lead to neurotoxic effects, resulting in cognitive, psychiatric, and motor impairments resembling Parkinsonian symptoms and, in severe cases, progressing to Manganism. While the cerebellum's role in motor control is well-known, its involvement in Mn toxicity in humans remains underexplored. Previous animal and cell studies, as well as our prior research in welders, indicate that Mn overexposure disrupts GABAergic and glutamatergic transmissions within basal ganglia pathways. Decreased GSH concentrations, an indicator of oxidative stress, are critical for mitigating damage from reactive oxygen species. This study investigates the impact of Mn accumulation on motor and metabolic disruptions in the cerebellum, employing Magnetic Resonance Spectroscopy (MRS) to measure neurotransmitter levels and markers of oxidative stress. Methods: We studied 37 steel welders exposed to manganese (Mn) through inhalation of welding fumes (mean air Mn = 200.51 +/- 227.1 mg/ m³), alongside two control groups: non-welding factory workers (N = 29, mean air Mn = 7.43 +/- 9.49 mg/m³) and university controls (N = 12, mean air Mn = 0.075 +/- 0.06 mg/ m³). Each participant underwent magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) on a 3T Siemens MAGNETOM Prisma to non-invasively quantify brain metabolites and neurotransmitters. Cerebellar glutathione (GSH) and gamma-aminobutyric acid (GABA) levels were measured using HERMES editing (TE/TR = 80 ms/2000 ms; 256 averages). The volume of interest (VOI: 35x25x25 mm³) was positioned in the right cerebellar lobe, and non-water-suppressed reference spectra were acquired for each sequence. Spectra were aligned, pre-processed with Osprey, and quantified with LCModel using simulated basis sets for sLASER and HERMES, respectively. Metabolite concentrations were water-referenced and CSF corrected. Outliers were excluded based on LCModel SD% > 50 or poor spectral quality upon visual inspection. Participants completed a battery of motor and cognitive tests, with this abstract focusing specifically on the Unified Parkinson Disease Rating Scale (UPDRS) Part III to assess motor function. UPDRS-III subscores were calculated for rigidity and tremor. Each participant's Cumulative Exposure Index (CEI) was calculated based on recent Mn exposure over the last 3 months, using personal air sampling from a work shift and work history data. Participants were categorized into high (HEX) and low (LEX) exposure groups, with HEX (N = 12) defined as greater than 0.04 mg/m³/yr and LEX (N = 25) below this level. Differences in metabolite and motor outcomes across groups were assessed using a two-tailed, unequal variance t-test, and associations between cerebellar metabolites and motor scores were examined with the Spearman correlation coefficient (R). Results: Cerebellar glutathione (GSH) levels were significantly reduced (p < 0.001) in high exposure welders (HEX, mean = 0.81 +/- 0.6 mM) compared to low-exposure welders (LEX, mean = 1.49 +/- 0.4 mM), with no significant group differences found between LEX, factory controls (FC, mean = 1.49 +/- 0.7 mM) and university controls (UC, mean = 1.59 +/- 0.6 mM). , Additionally, there was a negative correlation between CEI Mn levels and GSH levels (R = -0.32, p = 0.017) amongst welders. Cerebellar GABA levels were lowest in UC, slightly higher in FC, peaked in LEX welders (mean = 1.71 +/- 0.4 mM), but then decreased again in HEX welders (mean = 1.51 +/- 0.5 mM), with a significant difference between HEX and LEX welders (p<0.01), while differences to FC and UC groups were not statistically significant after multiple comparison corrections. Motor impairment, as assessed by UPDRS-III scores, displayed an exposure-response trend, with the highest scores (indicating worse performance) observed in HEX (11 +/- 4.6), followed by LEX (5.18 +/- 3.05), FC (4.93 +/- 3.6), and the lowest in UC (1.92 +/- 1.6). Significant differences were found between LEX and UC (p < 0.001), HEX and UC (p < 0.001), and even factory controls (FC) performed significantly worse than university controls (UC) (p < 0.01). The rigidity and tremor subscores of UPDRS-III showed a similar exposure-related pattern, with the HEX group scoring the worst among all groups (p . 0.001). Both LEX and FC groups performed similarly but still showed significantly worse results compared to UC (p < 0.01 for rigidity and p = 0.1 for tremor severity). For welders, all three motor test scores correlated positively with UPDRS, with correlations as follows: UPDRS (R = 0.39, p = 0.00045), Rigidity (R = 0.35, p = 0.0018), and Tremor (R = 0.23, p = 0.042). Conclusions: Cerebellar GSH levels, an indicator of antioxidant capacity, were significantly reduced in high-exposure welders (HEX) compared to other groups, suggesting increased oxidative stress in the cerebellum associated with Mn exposure. The observed negative correlation between Mn levels and GSH further supports this association. This study highlights the neurotoxic impact of occupational Mn exposure on motor function and cerebellar metabolism. The observed correlations between Mn levels and both motor symptoms and metabolic disruptions provide insights into the underlying mechanisms of Mn neurotoxicity. These findings support the need for enhanced protective measures in occupational settings. Interestingly, GABA levels exhibited a non-linear pattern, with the highest levels observed in low-exposure welders (LEX). This increase in GABA among LEX welders may reflect an adaptive, protective response to moderate Mn exposure, potentially helping to regulate calcium levels and prevent oxidative damage. However, at the higher exposure levels seen in HEX welders, this protective system may become overwhelmed, leading to mitochondrial dysfunction, impaired calcium regulation, and ultimately lower GABA levels as the system fails to compensate for the increased oxidative stress. The exposure-response trend in motor impairment, as measured by UPDRS-III scores and its subscores for rigidity and tremor, aligns with previous literature on the dose-response relationship between Mn exposure and motor function. A limitation of this study is the small sample size of the UC group. Future studies will follow welders longitudinally, especially at the beginning of exposure or after cessation, to gain insight into the temporal changes in cerebellar GABA and GSH, their reversibility, and their relation to motor function. Description provided by NIOSH
• Subjects:
  • Manganese
  • Nervous System
  • Nervous System Diseases
  • Occupational Health
  • Safety
  • Welders
• Keywords:
  • Manganese; Welders; Welding fumes; Neurotoxic effects; Neurotoxicology; Neuromotor disorders
• Source:
  Toxicologist 2025 Mar; 204(S1):362
• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  Chicago Region OSHA ; Indiana
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  2 pdf pages
• Volume:
  204
• NIOSHTIC Number:
  nn:20071594
• CAS Registry Number:
  • Manganese (CAS RN 7439-96-5)
• Federal Fiscal Year:
  2025
• Performing Organization:
  Purdue University, West Lafayette, Indiana
• Peer Reviewed:
  False
• Start Date:
  20010701
• End Date:
  20270630
• Download URL:
  https://stacks.cdc.gov/view/cdc/259369/cdc_259369_DS1.pdf
• File Type:
  [PDF - 260.28 KB]
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7859f3479d1f35e13ff1566480360d46a509d9fe909706a43062665abcf223315f805f592a48b04cdcf26beed6cfe19e4baa3bd04c7a4e3514f5bcafdd1fd583