title: Environmental manganese compounds accumulate as Mn(II) within the Golgi apparatus of dopamine cells: relationship between speciation, subcellular distribution, and cytotoxicity.
abstract: Manganese is a neurotoxic element that leads to severe neurological disorders when excessive exposure occurs, mainly in occupational settings, but that can also lead to more subtle neurological deficits, especially to the dopaminergic system, under lower exposure conditions. Mn exists in a variety of chemical species in the environment but the influence of Mn speciation on its neurotoxicity has not been fully evaluated yet. In this study we compared the cytotoxicity towards dopamine producing cells of environmental Mn compounds with a diversity of physico-chemical forms: inorganic compounds having distinct oxidation states and solubility (MnCl2, MnSO4, and Mn2O3) and organic compounds such as MMT, a gasoline additive, and maneb, a Mn-dithiocarbamate fungicide. We observed that maneb exhibited the highest toxicity, followed by MnCl2, MnSO4 and MMT which resulted in a similar intermediate toxicity, the less toxic compound being the insoluble compound Mn2O3. We combined micro-SXRF (Synchrotron X-Ray Fluorescence) for imaging and micro-XANES (X-ray Absorption Near Edge Structure) to determine the Mn oxidation state at the single cell level. Mn2O3 readily entered the cell but remained in its initial state as Mn(III) particles within the cytoplasm. The lack of toxicity of Mn2O3 can be explained by its insolubility. For all the other compounds, Mn(II) was observed and was located mainly in the Golgi apparatus, probably for detoxification purposes via exocytosis. Organic compounds MMT and maneb were degraded releasing Mn and behaved similar to the soluble Mn(II) inorganic compounds. Maneb cytotoxicity was higher probably because of the combined toxicity due to both Mn and dithiocarbamate residues. Overall these results raise the concern about environmental exposure to Mn since either inhalation of Mn combustion products or ingestion of contaminated food and drinking water will end up in neurotoxic soluble and bioavailable Mn species.
authors.affiliation: CNRS, IN2P3, CENBG, UMR 5797, F33170 Gradignan, France. acarmona@cenbg.in2p3.fr ortega@cenbg.in2p3.fr.
authors.forename: Asuncion
authors.initials: A
authors.lastname: Carmona
authors.forename: Stéphane
authors.initials: S
authors.lastname: Roudeau
authors.forename: Laura
authors.initials: L
authors.lastname: Perrin
authors.forename: Giulia
authors.initials: G
authors.lastname: Veronesi
authors.forename: Richard
authors.initials: R
authors.lastname: Ortega
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D004298:Dopamine / Q000378:metabolism; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis; D005659:Fungicides, Industrial / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism*; D008345:Manganese / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D017895:Manganese Compounds / Q000032:analysis / Q000378:metabolism*; D009942:Organometallic Compounds / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D051381:Rats
chemical_list: D003603:Cytotoxins; D005659:Fungicides, Industrial; D017895:Manganese Compounds; D009942:Organometallic Compounds; D008345:Manganese; D004298:Dopamine