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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}
}
  • Adult male mice were exposed either to sublethal levels of MnO2 dust or filtered air (control group) 7 hours/day, 5 days/week for 16 to 32 weeks. Following a 16 week initial exposure period, randomly selected samples (8 animals) from both the control and Mn-exposed groups were observed for behavioral performance (ambulations and rearings in the open-field, ''hole-in-board'' explorations, rotarod) and learning (passive avoidance) and tissue Mn levels were determined via atomic absorption spectrometry. Exposure continued for the remaining animals and the sampling procedure was repeated biweekly for an additional 8 time points. At week 32, Mn exposure was terminated. However,more » biweekly testing of the remaining animals continued for an additional 3 time points. Mn-exposed animals had significantly higher blood, liver, kidney, lung, cerebrum, cerebellum plus brainstem, and testis Mn levels than control animals. With the exception of the liver, these levels declined with increasing exposure time. No histopathologic effects attributable to Mn-exposure were observed. However, significant overall effects on growth and behavior were obtained. When the post-exposure data were analyzed separately, no significant effects were obtained. While no general relationship was obtained between tissue Mn levels and behavior, selected behavioral measures did correlate with tissue Mn levels.« less
  • Zinc is a common metal in most ambient particulate matter (PM), and has been proposed to be a causative component in PM-induced adverse cardiovascular health effects. Zinc is also an essential metal and has the potential to induce many physiological and nonphysiological changes. Most toxicological studies employ high levels of zinc. We hypothesized that subchronic inhalation of environmentally relevant levels of zinc would cause cardiac changes in healthy rats. To address this, healthy male WKY rats (12 weeks age) were exposed via nose only inhalation to filtered air or 10, 30 or 100 {mu}g/m{sup 3} of aerosolized zinc sulfate (ZnSO{submore » 4}), 5 h/day, 3 days/week for 16 weeks. Necropsies occurred 48 h after the last exposure to ensure effects were due to chronic exposure rather than the last exposure. No significant changes were observed in neutrophil or macrophage count, total lavageable cells, or enzyme activity levels (lactate dehydrogenase, n-acetyl {beta}-D-glucosaminidase, {gamma}-glutamyl transferase) in bronchoalveolar lavage fluid, indicating minimal pulmonary effect. In the heart, cytosolic glutathione peroxidase activity decreased, while mitochondrial ferritin levels increased and succinate dehydrogenase activity decreased, suggesting a mitochondria-specific effect. Although no cardiac pathology was seen, cardiac gene array analysis indicated small changes in genes involved in cell signaling, a pattern concordant with known zinc effects. These data indicate that inhalation of zinc at environmentally relevant levels induces cardiac effects. While changes are small in healthy rats, these may be especially relevant in individuals with pre-existent cardiovascular disease.« less
  • Manganese (II), a transition metal, causes pulmonary inflammation upon environmental or occupational inhalation in excess. We investigated a potential molecular mechanism underlying manganese-induced pulmonary inflammation. Manganese (II) delayed HIF-1{alpha} protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1{alpha} hydroxylation and subsequent von Hippel-Lindau(VHL)-dependent HIF-1{alpha} degradation. HPH inhibition by manganese (II) was neutralized significantly by elevated dose of iron. Consistent with this, the induction of cellular HIF-1{alpha} protein by manganese (II) was abolished by pretreatment with iron. Manganese (II) induced the HIF-1 target gene involved in pulmonary inflammation, vascular endothelial growth factor (VEGF), in lung carcinomamore » cell lines. The induction of VEGF was dependent on HIF-1. Manganese-induced VEGF promoted tube formation of HUVEC. Taken together, these data suggest that HIF-1 may be a potential mediator of manganese-induced pulmonary inflammation.« less
  • Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic compound that was introduced as an antiknock additive to replace lead in unleaded fuel. The combustion of MMT results in the emission of fine Mn particulates mainly in the form of manganese sulfate and manganese phosphate. The objective of this study is to determine the effects of subchronic exposure to Mn sulfate in different tissues, on locomotor activity, on neuropathology, and on blood serum biochemical parameters. A control group and three groups of 30 male Sprague-Dawley rats were exposed 6-h/day, 5 days/week for 13 consecutive weeks at 30, 300, or 3000 {mu}g/m{sup 3}more » Mn sulfate. Locomotor activity was measured during 36 h using an Auto-Track System. Blood and the following tissues were collected and analyzed for manganese content by neutron activation analysis: olfactory bulb, globus pallidus, caudate/putamen, cerebellum, frontal cortex, liver, lung, testis, and kidney. Neuronal cell counts were obtained for the caudate/putamen and the globus pallidus and clinical biochemistry was assessed. Manganese concentrations were increased in blood, kidney, lung, and testis and in all brain regions in the 3000 {mu}g/m{sup 3} exposure group. Significant differences were also noted in the 300 {mu}g/m{sup 3} exposure group. Neuronal cell counts for the globus pallidus were significantly different between the two highest exposed groups and the controls. Locomotor activity for all exposure concentrations and resting time for the middle and highest concentrations for the two night resting periods were significantly increased. Total ambulatory count was decreased significantly for all exposure concentrations. Biochemical profiles also presented significant differences. No body weight loss was observed between all groups. These results suggest that neurotoxicity could occur at low exposure levels of Mn sulfate, one of the main combustion products of MMT.« less
  • Ozone is an oxidant gas which primarily injures the centroacinar portion of the lung. While the classical lesion of oxidant-mediated lung damage is relatively well described, the effect of this form of injury on the lymphocytic arm of the pulmonary defense system is less clear. In the present experiments Cd-1 female mice were exposed to ozone at a level of 0.7 ppm for 20 hr per day for 1-28 days and the lymphocyte response was observed in the pulmonary lymph nodes and the thymus. In the mediastinal lymph nodes a marked hyperplastic response was observed that was prominent in themore » paracortex and was characterized by the presence of blastic forms. In contrast, the thymus underwent an atrophic response characterized by cellular loss in the cortical region. Prior surgical adrenalectomy of ozone-exposed animals eliminated part, but not all of the thymic atrophy response, indicating that adrenal-mediated stress alone did not account for all the observed effect. Thymectomy of animals prior to ozone exposure produced a 40% reduction in the mediastinal lymph node response, suggesting that a part of the node hyperplasia is thymus dependent. The results of these experiments indicate that lymphoid organs are altered following oxidant-mediated lung damage in the mouse. The changes are observed in the absence of exogenous antigenic stimulation and suggest that lymphoid cells are in integral aspect of the host response to high-level ozone inhalation.« less