Impact of Manganese on Neuronal Function: An Exploratory MultiOmic Study on Ferroalloy Workers in Brescia, Italy.

Interest is growing in the potential role of manganese (Mn) in Alzheimer's Disease (ADRD). This nested pilot study of a ferroalloy workers cohort was aimed to investigate the effects of long-term occupational Mn exposure on cognitive function through β-amyloid (Aβ) modification and brain deposition, as well as metabolomic, lipidomic and proteomic profiling. We examined 6 male exposed workers (median age 63, exposure duration 31 yrs), and 5 historical controls (median age 60) who had undergone brain PET scan imaging showing higher Aβ deposition among the exposed compared to the controls (p < 0.05). The average annual cumulative respirable Mn of the ferroalloy workers was 329.23 ± 516.39 μg/m3 (geometric mean 118.59). Average Mn level in plasma of the exposed subjects (0.704 ± 0.2 ng/mL) was significantly higher than the controls (0.397 ± 0.18). Pathway analyses using LC-MS/MS results revealed impacted metabolomic pathways such as olfactory signaling, mitochondrial fatty acid beta-oxidation, biogenic amine synthesis, SLC-mediated transmembrane transport, and glycerophospholipid and choline metabolism in the Mn exposed group. Single molecule arrays (Simoa) analysis revealed notable modifications of AD-related plasma biomarkers; protein microarray (chip) showed significant changes (p < 0.05) in the levels of some plasma antibodies targeting autoimmune and neuronal associated proteins such as Aβ (25-35), GFAP, Serotonin, Human NOVA1, and Human Siglec-1/CD169 among the Mn exposed individuals. This data provides evidence on Mn-induced alterations of pathways and biomarkers associated with cognitive neurodegenerative diseases.