Particulate matter air pollution induces hypermethylation of the p16 promoter Via a mitochondrial ROS-JNK-DNMT1 pathway

Saul Soberanes, Angel Gonzalez, Daniela Urich, Sergio E. Chiarella, Kathryn A. Radigan, Alvaro Osornio-Vargas, Joy Joseph, Balaraman Kalyanaraman, Karen M. Ridge, Navdeep S. Chandel, Gökhan M. Mutlu, Andrea De Vizcaya-Ruiz, G. R Scott Budinger*

*Corresponding author for this work

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Abstract

Exposure of human populations to chronically elevated levels of ambient particulate matter air pollution < 2.5 mm in diameter (PM 2.5) has been associated with an increase in lung cancer incidence. Over 70% of lung cancer cell lines exhibit promoter methylation of the tumor suppressor p16, an epigenetic modification that reduces its expression.Weexposed mice to concentrated ambientPM 2.5 via inhalation, 8 hours daily for 3 weeks and exposed primary murine alveolar epithelial cells to daily doses of fine urban PM (5 μg/cm 2). In both mice and alveolar epithelial cells, PM exposure increased ROS production, expression of the DNA methyltransferase 1 (DNMT1), and methylation of the p16 promoter. In alveolar epithelial cells, increased transcription of DNMT1 and methylation of the p16 promoter were inhibited by a mitochondrially targeted antioxidant and a JNK inhibitor. These findings provide a potential mechanism by which PM exposure increases the risk of lung cancer.

Original languageEnglish (US)
Article number275
JournalScientific reports
Volume2
DOIs
StatePublished - Apr 19 2012

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Soberanes, S., Gonzalez, A., Urich, D., Chiarella, S. E., Radigan, K. A., Osornio-Vargas, A., Joseph, J., Kalyanaraman, B., Ridge, K. M., Chandel, N. S., Mutlu, G. M., De Vizcaya-Ruiz, A., & Budinger, G. R. S. (2012). Particulate matter air pollution induces hypermethylation of the p16 promoter Via a mitochondrial ROS-JNK-DNMT1 pathway. Scientific reports, 2, [275]. https://doi.org/10.1038/srep00275