Endothelial Cells as Biosensors for Occupational Cardiovascular Risk

Details

• Personal Author:
  Campen M
• Description:
  Engineered nanomaterials (ENMs) have an unknown toxic potential and the relationship between their biological effects and physicochemical properties remains uncertain. ENM inhalation studies have identified several potential systemic outcomes that are relevant to human health, including the development or exacerbation of inflammatory vascular disease / atherosclerosis, vasoconstriction, and neuropathies, possibly related to abnormal signaling in endothelial cells. However, ENMs translocate only minimally beyond the lungs, thus cardiovascular and neurological effects thereof may be caused by generation of secondary biomolecular factors from MWCNT-pulmonary interactions that spill over into the systemic circulation. The present study was implemented to develop a novel, translational in vitro model to assess systemic inflammatory changes caused by inhaled ENMs. Initial efforts focused on the optimization and development of assays based on cultured endothelial cells or isolated vascular tissue responses to whole serum, which represents a cumulative balance of anti- and pro-inflammatory factors. In two principal studies, we elucidated the utility of this general paradigm in terms of establishing a serum-borne inflammatory potential arising from pulmonary exposure to MWCNT and also in terms of establishing an improved mechanistic understanding of systemic outcomes. In the first application of this paradigm, wildtype (WT; C57BL/6) and MMP-9-/- mice were exposed to varying doses (10 or 40 ug) of MWCNTs (MWCNT-7) via oropharyngeal aspiration and serum was collected at 4 and 24 h post-exposure. Primary cerebrovascular endothelial cells treated with serum from MWCNT-7-exposed WT mice exhibited significantly reduced nitric oxide (NO) generation, as measured by electron paramagnetic resonance, an effect that was independent of NO scavenging. Serum from MWCNT-7- exposed WT mice inhibited acetylcholine-mediated relaxation of aortic rings at both time points, an effect dependent on vascular CD36 scavenger receptors. Interestingly, serum from MMP-9-/- mice exposed to MWCNT did not diminish the magnitude of vasorelaxation in naive WT aortic rings. In the second application of this endothelial cell biosensor paradigm, WT and MMP-9-/- mice were again exposed to MWCNT-7 via pharyngeal aspiration, leading to enhanced hippocampal and cerebellar GFAP staining, indicative of astrocyte activation. MWCNT exposure impaired blood brain barrier integrity, as noted by fluorescein uptake, which was associated with increased gene expression of IL-6 and CCL5 in the cortex and hippocampus. Pretreatment with the rho kinase inhibitor, fasudil, was able to prevent brain fluorescein uptake and neuroinflammation. In vitro, serum from MWCNT exposed mice was able to induce expression of adhesion molecules at both the gene and protein level. Treatment of endothelial cells with serum from MWCNT-exposed mice in a wound-healing assay resulted in decreased cell motility and cytokinesis, also consistent with mRNA expression patterns in microarray analysis. Combined, these studies highlight the value of the endothelial cell biosensor paradigm as a valuable tool for dissecting the pathways connecting pulmonary exposures to ENMs and systemic vascular and neural effects. Future studies should further explore the mechanistic pathways and additionally utilize this assay platform for the confirmation of outcomes in occupationally exposed humans. Linkage of this assay platform to an information-rich discovery platform would be valuable for the determination of exposure-linked biomarkers. [Description provided by NIOSH]
• Subjects:
  Animals Chemistry Environmental Exposure Genetics Hazardous Substances Laboratories Lung Nitric Oxide Occupational Health Respiratory System Risk Assessment Risk Factors Safety

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• Keywords:
  Biological Effects Cardiovascular System Chemical Properties Endothelial Cells Exposure Levels Genes Health Effects In Vitro Study Laboratory Animals Models Molecular Biology Nanomaterials Nanotechnology Neurological System Nitric Oxide Physical Properties Proteins Pulmonary Effects Pulmonary System Risk Factors Tissue Culture Toxins

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• Series:
  Grant Final Reports
• Publisher:
  National Institute for Occupational Safety and Health
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Final Grant Report
• Place as Subject:
  New Mexico ; OSHA Region 6
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  OEP - Office of Extramural Programs
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-37
• NIOSHTIC Number:
  nn:20048875
• NTIS Accession Number:
  PB2017-101415
• Citation:
  Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) R21-OH-010495, 2015 Nov; :1-37
• Contact Point Address:
  Matthew Campen, Ph.D., MCS09 5360, 1 University of New Mexico, Albuquerque, NM 87131
• CAS Registry Number:
  Nitric oxide (CAS RN 10102-43-9)
• Federal Fiscal Year:
  2016
• Performing Organization:
  University of New Mexico Health Sciences Center, Albuquerque, New Mexico
• Peer Reviewed:
  False
• Start Date:
  20130901
• Source Full Name:
  National Institute for Occupational Safety and Health
• End Date:
  20150831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:707e4726d023fbee26a3ace70fba93522a9eb9a2f38a12da50ee0d11ca8dbc0b69c83549544060c7c2b78fda9a675b7fd2bf633e11d07e0833fb003bbc6c9f23
• Download URL:
  https://stacks.cdc.gov/view/cdc/218649/cdc_218649_DS1.pdf
• File Type:
  [PDF - 924.03 KB ]