title: Molecular mechanisms of Mn induced neurotoxicity: RONS generation, genotoxicity, and DNA-damage response.
abstract: METHODS
  In industrial countries dietary manganese (Mn) intake is well above the estimated average requirement. Moreover, exposure to high Mn levels is known to cause adverse neurological effects in humans, which are yet mechanistically not well understood.
  
  
  RESULTS
  This study aimed to identify early modes of action of Mn induced toxicity in mammalian brain cells. In primary porcine brain capillary endothelial cells induction of reactive oxygen and nitrogen species was identified as the most sensitive endpoint (≥0.5 μM MnCl2 ). In cultured human astrocytes MnCl2 was rapidly bioavailable, induced a slight increase of cellular reactive oxygen and nitrogen species levels and a slight decrease of ATP levels (1-100 μM MnCl2 ), while no genotoxic effects were observed. However, MnCl2 (≥1 μM) efficiently disturbed DNA-damage-induced poly(ADP-ribosyl)ation in human astrocytes, which indicates sensitization of cells to genotoxic treatment. Additionally, we determined Mn levels in infant formula, which are generally massively supplemented with Mn and thus might pose an important source for Mn overexposure.
  
  
  CONCLUSIONS
  The observed inhibition of DNA-damage-induced poly(ADP-ribosyl)ation in human astrocytes by exposure-relevant Mn concentrations indicate that in terms of Mn the existing guidelines for infant formula but also drinking water should be critically reconsidered.
authors.affiliation: Graduate School of Chemistry, University of Münster, Münster, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bornhorst
authors.forename: Sören
authors.initials: S
authors.lastname: Meyer
authors.forename: Till
authors.initials: T
authors.lastname: Weber
authors.forename: Carolina
authors.initials: C
authors.lastname: Böker
authors.forename: Talke
authors.initials: T
authors.lastname: Marschall
authors.forename: Aswin
authors.initials: A
authors.lastname: Mangerich
authors.forename: Sascha
authors.initials: S
authors.lastname: Beneke
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.forename: Tanja
authors.initials: T
authors.lastname: Schwerdtle
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001682:Biological Availability; D001921:Brain / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D002712:Chlorides / Q000008:administration & dosage / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D005506:Food Contamination / Q000032:analysis; D006801:Humans; D041943:Infant Formula / Q000737:chemistry; D017895:Manganese Compounds / Q000008:administration & dosage; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000503:physiopathology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013552:Swine
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C025340:manganese chloride
keywords: Infant formula; Manganese; Neurotoxicity; Oxidative stress; Poly(ADP-ribosyl)ation