title: Subchronic inhalation of soluble manganese induces expression of hypoxia-associated angiogenic genes in adult mouse lungs.
abstract: Although the lung constitutes the major exposure route for airborne manganese (Mn), little is known about the potential pulmonary effects and the underlying molecular mechanisms. Transition metals can mimic a hypoxia-like response, activating the hypoxia inducible factor-1 (HIF-1) transcription factor family. Through binding to the hypoxia-response element (HRE), these factors regulate expression of many genes, including vascular endothelial growth factor (VEGF). Increases in VEGF, an important biomarker of angiogenesis, have been linked to respiratory diseases, including pulmonary hypertension. The objective of this study was to evaluate pulmonary hypoxia-associated angiogenic gene expression in response to exposure of soluble Mn(II) and to assess the genes' role as intermediaries of potential pulmonary Mn toxicity. In vitro, 0.25 mM Mn(II) altered morphology and slowed the growth of human pulmonary epithelial cell lines. Acute doses between 0.05 and 1 mM stimulated VEGF promoter activity up to 3.7-fold in transient transfection assays. Deletion of the HRE within the promoter had no effect on Mn(II)-induced VEGF expression but decreased cobalt [Co(II)]-induced activity 2-fold, suggesting that HIF-1 may not be involved in Mn(II)-induced VEGF gene transcription. Nose-only inhalation to 2 mg Mn(II)/m(3) for 5 days at 6 h/day produced no significant pulmonary inflammation but induced a 2-fold increase in pulmonary VEGF mRNA levels in adult mice and significantly altered expression of genes associated with murine angiogenesis. These findings suggest that even short-term exposures to soluble, occupationally relevant Mn(II) concentrations may alter pulmonary gene expression in pathways that ultimately could affect the lungs' susceptibility to respiratory disease.
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA. sbredow@lrri.org
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bredow
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Falgout
authors.forename: Thomas H
authors.initials: TH
authors.lastname: March
authors.forename: Christin M
authors.initials: CM
authors.lastname: Yingling
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Malkoski
authors.forename: James
authors.initials: J
authors.lastname: Aden
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bedrick
authors.forename: Johnnye L
authors.initials: JL
authors.lastname: Lewis
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Divine
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008345:Manganese / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A; D008345:Manganese