Lewis Freeman, Shoieb Daniel, Azmoun Somaiyeh, Colicino Elena, Jin Yan, Chi Jinhua, Krishnamurthy Hari, Placidi Donatella, Padovani Alessandro, Pilotto Andrea, Pepe Fulvio, Tula Marinella, Crippa Patrizia, Wang Xuexia, Gu Haiwei, Lucchini Roberto
Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA.
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy.
Metabolites. 2025 Jul 20;15(7):487. doi: 10.3390/metabo15070487.
BACKGROUND/OBJECTIVES: Chronic manganese (Mn) exposure is a recognized environmental contributor to Parkinsonian syndromes, including Mn-induced Parkinsonism (MnIP). This study aimed to evaluate whole-blood Mn levels and investigate disease/exposure-status-related alterations in metabolomic and lipidomic profiles.
A case-control study (N = 97) was conducted in Brescia, Italy, stratifying participants by Parkinsonism diagnosis and residential Mn exposure. Whole-blood Mn was quantified using ICP-MS. Untargeted metabolomic and lipidomic profiling was conducted using LC-MS. Statistical analyses included Mann-Whitney U tests, conditional logistic regression, ANCOVA, and pathway analysis.
Whole-blood Mn levels were significantly elevated in Parkinsonism cases vs. controls (median: 1.55 µg/dL [IQR: 0.75] vs. 1.02 µg/dL [IQR: 0.37]; = 0.001), with Mn associated with increased odds of Parkinsonism (OR = 2.42, 95% CI: 1.13-5.17; = 0.022). The disease effect metabolites included 3-sulfoxy-L-tyrosine (β = 1.12), formiminoglutamic acid (β = 0.99), and glyoxylic acid (β = 0.83); all FDR < 0.001. The exposure effect was associated with elevated glycocholic acid (β = 0.51; FDR = 0.006) and disrupted butanoate (Impact = 0.03; = 0.004) and glutamate metabolism ( = 0.03). Additionally, SLC-mediated transmembrane transport was enriched ( = 0.003). The interaction effect identified palmitelaidic acid (β = 0.30; FDR < 0.001), vitamin B6 metabolism (Impact = 0.08; = 0.03), and glucose homeostasis pathways. In lipidomics, triacylglycerols and phosphatidylethanolamines were associated with the disease effect (e.g., TG(16:0_10:0_18:1), β = 0.79; FDR < 0.01). Ferroptosis and endocannabinoid signaling were enriched in both disease and interaction effects, while sphingolipid metabolism was specific to the interaction effect.
Mn exposure and Parkinsonism are associated with distinct metabolic and lipidomic perturbations. These findings support the utility of omics in identifying environmentally linked Parkinsonism biomarkers and mechanisms.
背景/目的：长期接触锰（Mn）是帕金森综合征的一个公认的环境致病因素，包括锰诱导的帕金森病（MnIP）。本研究旨在评估全血锰水平，并调查代谢组学和脂质组学谱中与疾病/暴露状态相关的变化。
在意大利布雷西亚进行了一项病例对照研究（N = 97），根据帕金森病诊断和居住环境锰暴露对参与者进行分层。使用电感耦合等离子体质谱法（ICP-MS）对全血锰进行定量。使用液相色谱-质谱法（LC-MS）进行非靶向代谢组学和脂质组学分析。统计分析包括曼-惠特尼U检验、条件逻辑回归、协方差分析（ANCOVA）和通路分析。
与对照组相比，帕金森病病例的全血锰水平显著升高（中位数：1.55μg/dL[四分位间距：0.75]对1.02μg/dL[四分位间距：0.37]；P = 0.001），锰与帕金森病发病几率增加相关（比值比[OR]=2.42，95%置信区间[CI]：1.13 - 5.17；P = 0.022）。疾病效应代谢物包括3-磺氧基-L-酪氨酸（β = 1.12）、亚胺基谷氨酸（β = 0.99）和乙醛酸（β = 0.83）；所有错误发现率（FDR）<0.001。暴露效应与甘氨胆酸升高（β = 0.51；FDR = 0.006）以及丁酸和谷氨酸代谢紊乱（影响值=0.03；P = 0.004）相关。此外，溶质载体（SLC）介导的跨膜转运富集（P = 0.003）。相互作用效应确定了棕榈油酸（β = 0.30；FDR < 0.001）以及维生素B6代谢（影响值=0.08；P = 0.03）和葡萄糖稳态途径。在脂质组学中，三酰甘油和磷脂酰乙醇胺与疾病效应相关（例如，TG(16:0_10:0_18:1)，β = 0.79；FDR < 0.01）。铁死亡和内源性大麻素信号通路在疾病和相互作用效应中均富集，而鞘脂代谢则特定于相互作用效应。
锰暴露和帕金森病与不同的代谢和脂质组学扰动相关。这些发现支持了组学在识别与环境相关的帕金森病生物标志物和机制方面的实用性。
