Health & Environmental Research Online (HERO)


Print Feedback Export to File
2621163 
Journal Article 
Abstract 
Exposure of mice to concentrated ambient particulate matter air pollution results in hypermethlyation of the p16 promoter in the lung 
Soberanes, S; Gonzalez, A; Urich, D; Chiarella, SE; Radigan, KA; Osornio-Vargas, AR; De Vizcaya-Ruiz, A; Chandel, NS; Mutlu, GM; Budinger, GS 
2010 
Yes 
American Journal of Respiratory and Critical Care Medicine
ISSN: 1073-449X
EISSN: 1535-4970 
181 
A1165 
English 
WOS:000208771000166 
is part of a larger document 3452678 Proceedings of the American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans
Rationale: Chronic exposure to elevated levels of airborne particulate matter (PM) has been associated with an increase in the incidence of lung cancer. It has been estimated that an increase of 10 μg/m^3 in the yearly average level of PM with a dynamic diameter smaller than 2.5 μm (PM2.5) is associated with a 20.8% increase in the risk of cancer mortality. However, the molecular mechanisms linking PM exposure with the development of cancer remain unclear. The p16 gene generates two transcript variants which regulate the cell cycle, either by inhibition of CDK4 kinase or stabilizing p53 by sequestering its repressor MDM2. Exposure to tobacco smoke or heavy metals has been reported to induce hypermethylation of the p16 promoter and suppress its transcription. We hypothesized that PM2.5 exposure might result in methylation of the p16 gene promoter in mice, potentially predisposing to the development of lung cancer.

Methods: Wild-type C57Bl/6 mice were exposed for 8 hr daily (M-F) to concentrated PM2.5 from the ambient air in Chicago using a semi-mobile versatile aerosol concentration and enrichment system (VACES) connected whole body exposure chamber. Control mice were exposed to identical conditions, however a HEPA filter was placed before the inlet of the chamber. Between exposures, the mice were maintained in filtered cages in an environmentally controlled rack. After 3 and 6 weeks of exposure, the mice were harvested for isolation of whole lung DNA. This DNA was treated with sodium bisulfite and methylation of p16 was determined by methylation-specific PCR (MSP).

Results: The mean level of ambient PM2.5 in the chamber was 10^5 particles/cc, whereas no detectable particles were present downstream of the filter in the control chamber (TSI particle counter). Compared with mice exposed to filtered air, mice exposed to concentrated ambient PM2.5 had a significant increase in the methylation of the p16 promoter as determined by MSP.

Conclusions: Exposure of mice to concentrated ambient PM2.5 results in hypermethylation of the p16 promoter. This may contribute to the increased incidence of lung cancer observed in populations exposed to higher levels of PM2.5. 
American Thoracic Society 2010 International Conference 
New Orleans, LA 
May 14-19, 2010