Effects of Repeated Nanomaterial Exposure and Recovery on Circulating Mediators and Neurotoxicity

Details

• Personal Author:
  Campen MJ ; Erdely A ; Fraser K ; Mostovenko E ; Ottens AK ; Saunders SA ; Vucetic A
• Description:
  We recently reported that modeled acute exposure to multi-walled carbon nanotubes (MWCNT) increased systemic inflammation, induced vascular dysfunction, disrupted the blood-brain barrier (BBB) and induced neuroinflammation. We further identified a dramatic shift in circulating peptides, found to be mediators of systemic bioactivity and a promising source of health-effect biomarkers. Here we assessed the burden of repeated MWCNT exposure in inciting a peptidomic response, its association with MMP-9 proteolysis, and longer term neuroinflammatory ramifications. Male C57BL/6 wild-type (WT) and MMP-9-/- knockout (KO) mice were exposed to MWCNT-7 by oropharyngeal aspiration (n=7/grp): 0 microg control vehicle (0.6 mg/ml albumin, 0.01 mg/ml DPPC) once per week, 10 microg once per week, and 40 microg at week-1 followed by 0 microg once per week until collecting serum and brains at 28 days after the initial treatment (7 days after the last aspiration). An enriched-peptide fraction was extracted and assessed by untargeted data-independent mass spectrometry while brains were assessed by immunofluorescence microscopy. In WT mice, 1613 (34%) of 4759 reproducibly quantified serum peptide factors were significantly responsive across all exposures (5% FDR) with half (785) directly dependent on MMP-9, speaking to the sizeable, though non-exclusive, role of MMP-9 in production of the MWCNT-responsive peptidome. Repeated 10 microg exposure significantly induced 957 (59%) of the peptidomic response, highlighting the significance of repeated lower dose exposures. Separately, 1119 (69%) peptide factors were significantly shifted a full 4-weeks after the larger 40 microg bolus dose, supporting a prolonged impact to circulating factors. Likewise, albumin leakage across the BBB and pronounced microglial activation proximal to impacted vessels were observed after repeated low dose as well as after 4-week recovery from high dose MWCNT. These effects were strikingly muted in brains of MMP-9 KO animals. Overall findings affirm significant MWCNT effects on the circulating peptidome, a sustained neurotoxicological burden of exposure, and a dependence on MMP-9 proteolytic function, together substantiating a prolonged impact of exposure. [Description provided by NIOSH]
• Subjects:
  Albumins Biomarkers Blood Body Fluids Environmental Exposure Immune System Laboratories Nervous System Occupational Exposure Occupational Health Respiratory System Safety Toxicology

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• Keywords:
  Acute Exposure Albumin Bioactivation Biological Systems Blood Stream Blood Vessels Body Fluids Brain Matter Cell Wall Permeability Central Nervous System Dose Response Exposure Assessment Exposure Levels Immune Reaction Inhalation Laboratory Animals Laboratory Testing Metalloproteins Multi-walled Carbon Nanotubes MWCNT Nanotechnology Neurological Reactions Neurological System Neurotoxic Effects Peptides Serology Vasomotor System

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; New Mexico ; OSHA Region 3 ; OSHA Region 6 ; Virginia ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  168
• Issue:
  1
• NIOSHTIC Number:
  nn:20055064
• Citation:
  Toxicologist 2019 Mar; 168(1):294
• Federal Fiscal Year:
  2019
• 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:
  The Toxicologist. Society of Toxicology 58th Annual Meeting and ToxExpo, March 10-14, 2019, Baltimore, Maryland
• End Date:
  20190929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:bc998f3e047df1cdf1c64bdf4238f769a06e5890ef4955f4077592f4a00b127ee1c94ec83992f6e2c7a821eebb8c89f1f24723dfde9217ea0b66b21e4e4444bc
• Download URL:
  https://stacks.cdc.gov/view/cdc/217442/cdc_217442_DS1.pdf
• File Type:
  [PDF - 858.92 KB ]