Thalamic GABA levels and occupational manganese neurotoxicity: Association with exposure levels and brain MRI

Abstract

Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson's disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N=39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N=26; mean air Mn=0.13±0.1mg/m; High: N=13; mean air Mn=0.23±0.18mg/m), as well as unexposed control workers (N=22, mean air Mn=0.002±0.001mg/m) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p<0.01, F(1,33)=9.55), as well as significantly worse performance in general motor function (p<0.01, F(1,33)=11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect.

SLC30A10 transporter in the digestive system regulates brain manganese under basal conditions while brain SLC30A10 protects against neurotoxicity

“…To enhance the strength of the experiment, instead of measuring brain manganese levels using a part of the midbrain as performed for other assays in this study, we used a brain punching method to collect tissue from the caudate/putamen, globus pallidus, and substantia nigra (all subregions within the basal ganglia) and the thalamus. This was important because manganese is known to induce injury in the basal ganglia and the thalamus (2,3,37). We verified that SLC30A10 was expressed in these brain regions in WT mice (Fig.…”

“…Notably, the globus pallidus is particularly sensitive to manganese accumulation and induced injury (2,3). The thalamus is also a known manganese target (37). The reason why activity of SLC30A10 is critical to regulate manganese levels in these regions remains to be elucidated.…”

Brain manganese and the balance between essential roles and neurotoxicity

“…Using magnetic resonance imaging (MRI), several studies have shown significant brain accumulation of Mn in both humans and other animal models, are associated with increased risk of neurotoxicity. These subjects often show a characteristic accumulation of manganese in the basal ganglia, particularly in the globus pallidus (59)(60)(61). Mn accumulation was also observed in the frontal cortex ( Figure 1) (59).…”

“…These subjects often show a characteristic accumulation of manganese in the basal ganglia, particularly in the globus pallidus (59)(60)(61). Mn accumulation was also observed in the frontal cortex ( Figure 1) (59). While recovery upon cessation is possible (62), this rarely happens in cases of occupational exposures which are prolonged and cumulative.…”

Neurotoxicity of manganese: Indications for future research and public health intervention from the Manganese 2016 conference

“…Criswell et al (Criswell et al, 2018) used 6-[18F] fluoro-L-DOPA PET on Mn-exposed welders and workers and demonstrated lower caudate FDOPA uptake, indicating pre synaptic dopaminergic dysfunction in Mn-exposed subjects that was not associated with clinical parkinsonism. Magnetic Resonance Spectroscopy (MRS) was used to measure γ-amminobutyric acid (GABA), and thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure among welders, suggesting a threshold effect (Ma et al, 2018). Striatal and thalamic GABA did not differ between Mn-exposed workers, Parkinsonian patients or hemochromatosis patients, and controls (Casjens et al, 2018).…”