title: Elevated adult neurogenesis in brain subventricular zone following in vivo manganese exposure: roles of copper and DMT1.
abstract: The brain subventricular zone (SVZ) is a source of neural precursor cells; these cells travel along the rostral migratory stream (RMS) to destination areas in the process of adult neurogenesis. Recent x-ray fluorescence (XRF) studies reveal an extensive accumulation of copper (Cu) in the SVZ. Earlier human and animal studies also suggest an altered Cu homeostasis after manganese (Mn) exposure. This study was designed to test the hypothesis that Mn exposure by acting on the divalent metal transporter-1 (DMT1) altered Cu levels in SVZ and RMS, thereby affecting adult neurogenesis. Adult rats received intraperitoneal (i.p.) injections of 6 mg Mn/kg as MnCl2 once daily for 4 weeks with concomitant injections of bromodeoxyuridine (BrdU) for 5 days in the last week. In control rats, Cu levels were significantly higher in the SVZ than other brain regions examined. Mn exposure significantly reduced Cu concentrations in the SVZ (P < 0.01). Immunohistochemical data showed that in vivo Mn exposure significantly increased numbers of BrdU(+) cells, which were accompanied with increased GFAP(+) astrocytic stem cells and DCX(+) neuroblasts in SVZ and RMS. Quantitative RT-PCR and Western blot confirmed the increased expression of DMT1 in SVZ following in vivo Mn exposure, which contributed to Mn accumulation in the neurogenesis pathway. Taken together, these results indicate a clear disruptive effect of Mn on adult neurogenesis; the effect appears due partly to Mn induction of DMT1 and its interference with cellular Cu regulation in SVZ and RMS. The future research directions based on these observations are also discussed.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Sherleen
authors.initials: S
authors.lastname: Fu
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Stefanie
authors.initials: S
authors.lastname: O'Neal
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Lan
authors.initials: L
authors.lastname: Hong
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Wendy
authors.initials: W
authors.lastname: Jiang
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907 wzheng@purdue.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002712:Chlorides / Q000493:pharmacokinetics / Q000633:toxicity*; D003300:Copper / Q000378:metabolism*; D000089662:Doublecortin Protein; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D020547:Lateral Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017895:Manganese Compounds / Q000493:pharmacokinetics; D055495:Neurogenesis / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013054:Spectrophotometry, Atomic; D014018:Tissue Distribution; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D002712:Chlorides; D003300:Copper; D000089662:Doublecortin Protein; D017895:Manganese Compounds; D000099236:Solute Carrier Family 11, Member 2; C000714848:Dcx protein, rat; C025340:manganese chloride
keywords: adult neurogenesis; copper; divalent metal transporter-1; manganese; rostral migratory stream; subventricular zone