Systemic Health Implications of Occupational Nanomaterial Exposure

Details

• Personal Author:
  Campen MJ ; Ottens A
• Description:
  Introduction: Nanomaterials have become a major engineering and industrial endeavor for a wide variety of applications, however concerns regarding risk to human health have arisen due to the multitude of physicochemical variables associated with compositional variations and the difficulty of rapid screening for possible toxicity. We've previously demonstrated a link between nanomaterial exposure, specifically multiwalled carbon nanotube (MWCNT), and serum compositional changes that promote inflammatory pathways and vascular dysfunction. This project sought to determine the origin and assess the functional inflammatory potential of MWCNT exposure-derived serum byproducts. To this end, a multipronged research approach was designed using functional in vitro assays, advanced peptidomic analysis, controlled rodent exposures and samples from an occupationally-exposed human cohort. Results: To determine the role of matric metalloproteinases (MMPs) in MWCNT-exposure derived serum-bioactivity, a broad-spectrum MMP inhibitor was selectively delivered to the lung of C57BL/6 mice prior to oropharyngeal MWCNT exposure. We observed a significant pulmonary inflammatory response to MWCNT exposure that was independent of MMP blockade. However, cultured mouse cerebrovascular endothelial cells treated with serum from MWCNT-exposed mice pretreated with MMP blockade exhibited approx. 50% recovery in barrier integrity compared to 75% in vehicle only pretreated MWCNT-exposed animals. Analysis of biofluids from these animals revealed that upwards of 85% of the MWCNT-induced peptidomic signal released into the circulation was returned to control levels with MMP blockade. Moreover, a distinct MWCNT-induced peptidomic shift was observed within the CSF. Identified MWCNT-responsive peptides depicted a mechanism involving aberrant fibrinolysis in connection with blood-brain barrier permeation, astrocyte and microglial reactivity with dose-dependent differences and a pro-degradative anti-plastic hyperexcited state. Cultured endothelial cells treated with serum from occupationally-exposed individuals participating in a NIOSH exposure assessment study showed only modest changes in inflammatory response patterns likely due to tight occupational controls with most personal breathing zone measures below 10 ug/m3. Using our in-lab developed software, EndogeSeq, we identified 27 of the 104 most-discriminant peptides in the serum of 24 subjects divided evenly between high and low-exposure groups. Peptide compilation was functionally related to pulmonary injury, vascular dysfunction, altered translation, and autophagy/endocytosis processes consistent with pathogenesis observed in model CNT/F exposures. Conclusion: Animal studies revealed that while lung MMP activity does not play a significant role in mediating MWCNT-induced pulmonary inflammation, pulmonary MMP activity largely drives MWCNT-induced serum bioactivity which disrupts the endothelial barrier. These data substantiate the role of MMP proteolytic fragment generation in the lung, its release into the circulation and the reactive bioactivity of that peptidomic response. Moreover, MWCNT-exposure in mice induces a distinct peptidomic response in the CSF reflecting a compromised blood-brain barrier, neuroinflammation, and hyperexcited neuronal state consistent with early-pathobiology of neurodegenerative disease. Analysis of serum from a subset of occupationally-exposed workers revealed a robust and highly discriminatory shift within the circulating peptidome that is linearly correlated with the log of personal breathing zone metrics of exposure. Taken together, our data support further development of peptide biomarkers for monitoring in vivo responses to CNT/F exposure and the use of such diagnostics in longitudinal observational studies. [Description provided by NIOSH]
• Subjects:
  Animals Biomarkers Nervous System Occupational Exposure Occupational Health Safety
• Keywords:
  Animal Studies Health Effects Multi-walled Carbon Nanotubes MWCNT Nanomaterials Neurological System Neuropathology Occupational Exposure Peptides
• 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:
  1-52
• NIOSHTIC Number:
  nn:20063324
• 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, R01-OH-010828, 2020 Dec; :1-52
• Contact Point Address:
  Matthew J. Campen and Andrew Ottens, University of New Mexico, 2502 Marble Ave, NE, Albuquerque, NM
• Email:
  mcampen@salud.unm.edu
• CAS Registry Number:
  Carbon nanotubes (CAS RN 308068-56-6)
• Federal Fiscal Year:
  2021
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of New Mexico Health Sciences Center, Albuquerque, New Mexico
• Peer Reviewed:
  False
• Start Date:
  20150930
• Source Full Name:
  National Institute for Occupational Safety and Health
• End Date:
  20190929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:eb3a650ead869985b40cd801af5537574a02364779fe0805e03956642c70e77e1218ed9e7a445374bfa9416b7f59ac99ddf2f46e2cabfbe1a8d97a9dcd9e1eec
• Download URL:
  https://stacks.cdc.gov/view/cdc/219072/cdc_219072_DS1.pdf
• File Type:
  [PDF - 10.31 MB ]