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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{sup 3} for 5 days at 6 h/day produced no significant pulmonary inflammation but induced a 2-foldmore » 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.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [3];  [4];  [2]
  1. Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute 2425 Ridgecrest Dr. SE Albuquerque, NM 87108 (United States). E-mail: sbredow@LRRI.org
  2. Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute 2425 Ridgecrest Dr. SE Albuquerque, NM 87108 (United States)
  3. Department of Math and Statistics, University of New Mexico, Albuquerque, NM 87131 (United States)
  4. Community Environmental Health Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States)
Publication Date:
OSTI Identifier:
20976943
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 221; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2007.03.010; PII: S0041-008X(07)00105-6; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANOXIA; BIOLOGICAL MARKERS; COBALT; DOSES; GENES; GROWTH FACTORS; HUMAN POPULATIONS; HYPERTENSION; IN VITRO; INFLAMMATION; INHALATION; LUNGS; MANGANESE; MICE; MORPHOLOGY; NOSE; PROMOTERS; TOXICITY; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Bredow, Sebastian, Falgout, Melanie M., March, Thomas H., Yingling, Christin M., Malkoski, Stephen P., Aden, James, Bedrick, Edward J., Lewis, Johnnye L., and Divine, Kevin K. Subchronic inhalation of soluble manganese induces expression of hypoxia-associated angiogenic genes in adult mouse lungs. United States: N. p., 2007. Web. doi:10.1016/j.taap.2007.03.010.
Bredow, Sebastian, Falgout, Melanie M., March, Thomas H., Yingling, Christin M., Malkoski, Stephen P., Aden, James, Bedrick, Edward J., Lewis, Johnnye L., & Divine, Kevin K. Subchronic inhalation of soluble manganese induces expression of hypoxia-associated angiogenic genes in adult mouse lungs. United States. doi:10.1016/j.taap.2007.03.010.
Bredow, Sebastian, Falgout, Melanie M., March, Thomas H., Yingling, Christin M., Malkoski, Stephen P., Aden, James, Bedrick, Edward J., Lewis, Johnnye L., and Divine, Kevin K. Fri . "Subchronic inhalation of soluble manganese induces expression of hypoxia-associated angiogenic genes in adult mouse lungs". United States. doi:10.1016/j.taap.2007.03.010.
@article{osti_20976943,
title = {Subchronic inhalation of soluble manganese induces expression of hypoxia-associated angiogenic genes in adult mouse lungs},
author = {Bredow, Sebastian and Falgout, Melanie M. and March, Thomas H. and Yingling, Christin M. and Malkoski, Stephen P. and Aden, James and Bedrick, Edward J. and Lewis, Johnnye L. and Divine, Kevin K.},
abstractNote = {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{sup 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.},
doi = {10.1016/j.taap.2007.03.010},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 221,
place = {United States},
year = {Fri Jun 01 00:00:00 EDT 2007},
month = {Fri Jun 01 00:00:00 EDT 2007}
}