
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.09.04.24313002
preprint
1
Article
Metabolomic and Lipidomic Analysis of Manganese-Associated Parkinsonism: a Case-Control Study in Brescia, Italy
Lewis Freeman http://orcid.org/0009-0000-5606-8926

Shoieb Daniel
Azmoun Somaiyeh http://orcid.org/0000-0003-4951-614X

Colicino Elena http://orcid.org/0000-0002-1875-8448

Jin Yan
Chi Jinhua
Gu Haiwei http://orcid.org/0000-0002-7598-5022

Placidi Donatella http://orcid.org/0000-0003-1606-5397

Padovani Alessandro http://orcid.org/0000-0002-0119-3639

Pilotto Andrea http://orcid.org/0000-0003-2029-6606

Pepe Fulvio
Turla Marinella
Crippa Patrizia
Wang Xuexia http://orcid.org/0000-0002-0613-2608

Lucchini Roberto G http://orcid.org/0000-0002-9723-0237

06 9 2024
2024.09.04.24313002https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.09.04.24313002
nihpp-2024.09.04.24313002.pdf
Abstract

Background and Objectives

Excessive Manganese (Mn) exposure is neurotoxic and can cause Mn-Induced Parkinsonism (MnIP), marked by cognitive and motor dysfunction. Although metabolomic and lipidomic research in Parkinsonism (PD) patients exists, it remains limited. This study hypothesizes distinct metabolomic and lipidomic profiles based on exposure status, disease diagnosis, and their interaction.

Methods

We used a case-control design with a 2×2 factorial framework to investigate the metabolomic and lipidomic alterations associated with Mn exposure and their link to PD. The study population of 97 individuals was divided into four groups: non-exposed controls (n=23), exposed controls (n=25), non-exposed with PD (n=26) and exposed with PD (n=23). Cases, defined by at least two cardinal PD features (excluding vascular, iatrogenic, and traumatic origins), were recruited from movement disorder clinics in four hospitals in Brescia, Northern Italy. Controls, free from neurological or psychiatric conditions, were selected from the same hospitals. Exposed subjects resided in metallurgic regions (Val Camonica and Bagnolo Mella) for at least 8 continuous years, while non-exposed subjects lived in low-exposure areas around Lake Garda and Brescia city. We conducted untargeted analyses of metabolites and lipids in whole blood samples using ultra-high-performance liquid chromatography (UHPLC) and mass spectrometry (MS), followed by statistical analyses including Principal Component Analysis (PCA), Partial Least Squares–Discriminant Analysis (PLS-DA), and Two-Way Analysis of Covariance (ANCOVA).

Results

Metabolomic analysis revealed modulation of alanine, aspartate, and glutamate metabolism (Impact=0.05, p=0.001) associated with disease effect; butanoate metabolism (Impact=0.03, p=0.004) with the exposure effect; and vitamin B6 metabolism (Impact=0.08, p=0.03) with the interaction effect. Differential relative abundances in 3- sulfoxy-L-Tyrosine (β=1.12, FDR p<0.001), glycocholic acid (β=0.48, FDR p=0.03), and palmitelaidic acid (β=0.30, FDR p<0.001) were linked to disease, exposure, and interaction effects, respectively. In the lipidome, ferroptosis (Pathway Lipids=11, FDR p=0.03) associated with the disease effect and sphingolipid signaling (Pathway Lipids=9, FDR p=0.04) associated with the interaction effect were significantly altered. Lipid classes triacylglycerols, ceramides, and phosphatidylethanolamines showed differential relative abundances associated with disease, exposure, and interaction effects, respectively.

Discussion

These findings suggest that PD and Mn exposure induce unique metabolomic and lipidomic changes, potentially serving as biomarkers for MnIP and warranting further study.
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