Effects of Exposure to Diesel Exhaust Particles (DEP) on Pulmonary Activation of Mutagenic Agents

Details

• Personal Author:
  Barger MW ; Castranova, Vincent ; Ma JK ; Ma JY ; Zhao HW
• Description:
  DEP have been shown to induce a transient increase in CYP1A1 that returns to basal level at 7 days post-exposure, but to cause a sustained decrease in CYP2B1 in rat lung, whereas carbon black (CB) results only in a sustained decrease of CYP2B1. The present study examined the effects of DEP-altered pulmonary cytochrome P450 on the metabolization of mutagenic agents. Sprague Dawley rats were intratracheally instilled with saline or a single dose of DEP or CB at 35 mg/kg body weight. At 1, 3, or 7 days post-exposure, S9, microsomes, and cytosol were isolated from lung tissue. The mutagenicity of 2-aminoanthracene (2-AA) and 2-aminofluorene (2-AF) were monitored using the Ames test with S. typhimurium YG1024. The results show that S9 or microsomes, but not the cytosolic enzymes, activated the mutagenicity of 2-AA and 2-AF in a dose-dependent manner. The CB-exposed S9, with down-regulated CYP2B1, significantly reduced 2-AA mutagenicity compared to the control S9 at all time points. In contrast, the induction of 2-AA mutagenicity by DEP-exposed S9, with down-regulated CYP2B1 but induced CYP1A1 at 1 and 3 days post-exposure, decreased with increasing exposure time. At 1 day post-exposure, the DEP-S9 had a similar effect to that of control S9, but induced higher mutagenicity than the CB-S9. This DEP-derived S9 activated 2-AA mutagenicity decreased at 3 days post-exposure and further declined to the level of CB-S9 at 7 days post-exposure. Heat-inactivated S9 or addition of a CYP1A1 inhibitor, alpha-naphthoflavone, blocked 2-AA activation. These results suggest that both CYP1A1 and CYP2B1 activate 2-AA mutagenicity. At 3 days post exposure, DEP-S9 decreased, while CB-S9 increased 2-AF mutagenicity compared to control S9, suggesting that both CYP1A1 and CYP2B1 decrease 2-AF mutagenicity. These results show that mutagenic activation is substrate-specific, depending on competing metabolic pathways. DEP exposure, which alters the cytochrome P450 system, may have a profound effect on pulmonary handling of mutagenic agents. [Description provided by NIOSH]
• Subjects:
  Animals Laboratories Lung Mutagens Occupational Health Respiratory System Safety Vehicle Emissions
• Keywords:
  Animal-studies Diesel-exhausts Exposure-levels Laboratory-animals Lung-tissue Mutagenicity
• ISSN:
  1096-6080
• Publisher:
  Society of Toxicology
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; 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:
  72
• NIOSHTIC Number:
  nn:20022686
• Citation:
  Toxicologist 2003 Mar; 72(S-1):297
• Federal Fiscal Year:
  2003
• NORA Priority Area:
  Work Environment and Workforce: Mixed Exposures
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah
• Supplement:
  1
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:509fe12af6c33aebcb2f2fcfb7c90a29bef7d89bca5684d7fbf70260ee5c86bac5854f5a22c01191e72b628f7ca96929f34fe6b997ea843cfe2514ba9b2337c4
• Download URL:
  https://stacks.cdc.gov/view/cdc/199375/cdc_199375_DS1.pdf
• File Type:
  [PDF - 51.63 KB ]