Changes in Brain Metallome/Metabolome Pattern due to a Single i.v. Injection of Manganese in Rats

Abstract

Exposure to high concentrations of Manganese (Mn) is known to potentially induce an accumulation in the brain, leading to a Parkinson related disease, called manganism. Versatile mechanisms of Mn-induced brain injury are discussed, with inactivation of mitochondrial defense against oxidative stress being a major one. So far, studies indicate that the main Mn-species entering the brain are low molecular mass (LMM) compounds such as Mn-citrate. Applying a single low dose MnCl2 injection in rats, we observed alterations in Mn-species pattern within the brain by analysis of aqueous brain extracts by size-exclusion chromatography—inductively coupled plasma mass spectrometry (SEC-ICP-MS). Additionally, electrospray ionization—ion cyclotron resonance-Fourier transform-mass spectrometry (ESI-ICR/FT-MS) measurement of methanolic brain extracts revealed a comprehensive analysis of changes in brain metabolisms after the single MnCl2 injection. Major alterations were observed for amino acid, fatty acid, glutathione, glucose and purine/pyrimidine metabolism. The power of this metabolomic approach is the broad and detailed overview of affected brain metabolisms. We also correlated results from the metallomic investigations (Mn concentrations and Mn-species in brain) with the findings from metabolomics. This strategy might help to unravel the role of different Mn-species during Mn-induced alterations in brain metabolism.

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

“…Our results supported previous observations by demonstrating that Mn exposure alters the Fe 3+ /Fe 2+ towards redox- active Fe 2+ , leading to cytoplasmic and lipid ROS generation (Kwik-Uribe et al 2003;Fernsebner et al 2014;Neth et al 2015).…”

“…In summary, Mn-altered IRP1/IRE-binding affinity coordinates the translational suppression of neuroprotective APP and H-Ferritin that in turn leads to a profound increase of redox-active iron, providing a more complete explanation of the Mn-induced shift in the Fe 2+ /Fe 3+ ratio and neurotoxic oxidative stress accumulation that we and others previously observed in vitro and in vivo (Kwik-Uribe et al 2003;Fernsebner et al 2014;Neth et al 2015). General Hospital and Harvard Medical School) for excellent technical assistance, Susann Diegmann (Department of Neuropediatrics, University Medical Center G€ ottingen) for ALK Sanger sequencing of SH-SY5Y cells, Ulrike M€ uller (University Heidelberg) for providing APP +/+ and APP À/À MEFs and Christopher J. Chang (University of California, Berkeley) for critical discussion and data analysis of IP-1 and Rho-Nox1 experiments, and Jens C. Hamann (Weil Cornell Medicine) for critical reading and editing of the manuscript.…”

“…However, Mn-catalyzed auto-oxidation of dopamine involves redox cycling of Mn 3+ and Mn 2+ in a reaction that can result in ROS and dopamine-o-quinone generation, both fueling oxidative stress (Segura-Aguilar and Lind 1989). We and others previously demonstrated that Mn exposure results in a shift of Fe 2+ /Fe 3+ ratio toward redox active Fe 2+ accompanied by depleted levels of the antioxidant glutathione and increased oxidative stress markers in vitro and in vivo (Kwik-Uribe et al 2003;Fernsebner et al 2014;Neth et al 2015). However, the molecular basis of the Mninduced iron shift and redox alteration remains to be elucidated.…”

“…; Neth et al . ). However, the molecular basis of the Mn‐induced iron shift and redox alteration remains to be elucidated.…”

The Use of Metabolomics to Identify Biological Signatures of Manganese Exposure

“…However, the other few human metabolomics studies investigating biomarkers of exposure have looked only at dietary exposure to vitamins or minerals, not chemical exposures in an environmental or occupational setting (Astle et al 2007;Johansson-Persson et al 2013). Few studies have investigated metabolomics related to Mn exposure, and those that have analyzed biofluids or tissues collected from model organisms, not biofluids collected from humans exposed in an occupational setting (Dorman et al 2008;Fordahl et al 2012;Kumar et al 2015;Neth et al 2015). Our study of occupational exposed workers is particularly important given the substantial limitations in available biomarkers of acute and chronic exposure to Mn.…”