Abstract
We have shown that aldehydes impact gene expression profiles of bronchial airway associated with pulmonary toxicity. In this study, we aimed to determine whether microRNA (miRNA) plays a role in regulating the airway gene expression response to aldehyde exposure. We analyzed whole genome miRNA and mRNA expression profiles upon nonanal exposure of human alveolar epithelial cells to identify nonanalsensitive miRNAs and to characterize the relationships between miRNAs and the expression of the candidate target genes involved in aldehyde-induced toxicity. Microarray analysis identified six miRNAs that were differentially expressed in nonanal-exposed A549 human alveolar cells. Integrated anti-correlation analyses of miRNA and mRNA expression profiles identified 157 putative target genes. GO analysis of 157 putative target genes demonstrated that the biological category “apoptosis-related pathway” was prominently annotated. Moreover, we detected an increased number of apoptotic cells in the nonanal-exposed group. By integrating the transcriptome and microRNAome, we provide evidence that nonanal can affect apoptosisinduced toxicity signaling. Therefore, this study proves the benefit of an integrated miRNA-mRNA approach for identifying toxicity mechanisms induced by environmental toxicants using an in vitro human model.
Similar content being viewed by others
References
Bernstein, J. A. et al. The health effects of non-industrial indoor air pollution. J Allergy Clin Immunol 121: 585–591 (2008).
Baumann, M. G. D., Lorenz, L. F., Batterman, S. A. & Zhang, G. Z. Aldehyde emissions from particleboard and medium density fiberboard products. Forest Prod J 50:75–82 (2000).
Nazaroff, W. W. & Weschler, C. J. Cleaning products and air fresheners: exposure to primary and secondary air pollutants. Atmos Environ 38:2841–2865 (2004).
O’Brien, P. J., Siraki, A. G. & Shangari, N. Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. Crit Rev Toxicol 35:609–662 (2005).
Lecureur, V. et al. MAPK- and PKC/CREB-dependent induction of interleukin-11 by the environmental contaminant formaldehyde in human bronchial epithelial cells. Toxicology 292:13–22 (2012).
Bein, K. & Leikauf, G. D. Acrolein — a pulmonary hazard. Mol Nutr Food Res 55:1342–1360 (2011).
Tang, M. S. et al. Acrolein induced DNA damage, mutagenicity and effect on DNA repair. Mol Nutr Food Res 55:1291–1300 (2011).
Oyama, T. et al. Susceptibility to inhalation toxicity of acetaldehyde in Aldh2 knockout mice. Front Biosci 12:1927–1934 (2007).
Wolkoffa, P. et al. Risk in cleaning-chemical and physical exposure. Sci Total Environ 215:135–156 (1998).
Fullana, A., Carbonell-Barrachina, A. A. & Sidhu, S. Volatile aldehyde emissions from heated cooking oils. J Sci Food Agr 84:2015–2021 (2004).
Maddalena, R. L. et al. Interim Report: VOC and Aldehyde Emissions in Four FEMA Temporary Housing Units. LBNL Interim Report: FEMA THU Material Emissions (2008).
Sarigiannis, D. A. et al. Exposure to major volatile organic compounds and carbonyls in European indoor environments and associated health risk. Environ Int 37:743–765 (2011).
Clayton, G. D. & Clayton, F. E. (eds.). Patty’s Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981–1982. p. 2633.
NIOSH; NOES. National Occupational Exposure Survey conducted from 1981–1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from http://www.cdc.gov/noes/ as of Feb (2009).
Lim, S. K. et al. Formaldehyde induces apoptosis through decreased Prx 2 via p38 MAPK in lung epithelial cells. Toxicology 271:100–106 (2010).
Kuwano, K. et al. Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosis in mice. J Pathol 190:221–229 (2000).
Iyer, R., Hamilton, R. F., Li, L. & Holian, A. Silicainduced apoptosis mediated via scavenger receptor in human alveolar macrophages. Toxicol Appl Pharmacol 141:84–92 (1996).
Lee, H. S. et al. Analysis of mRNA expression profiles highlights alterations in modulation of the DNA damage-related genes under butanal exposure in A549 human alveolar epithelial cells. Mol Cell Toxicol 9:85–94 (2013).
Fukushima, T., Hamada, Y., Yamada, H. & Horii, I. Changes of micro-RNA expression in rat liver treated by acetaminophen or carbon tetrachloride-regulating role of micro-RNA for RNA expression. J Toxicol Sci 32:401–409 (2007).
Pogribny, I. P. et al. Induction of microRNAome deregulation in rat liver by long-term tamoxifen exposure. Mutat Res 619:30–37 (2007).
Song, M. K., Park, Y. K. & Ryu, J. C. Polycyclic aromatic hydrocarbon (PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5, regulating the activation of p38 MAPK. Toxicol Appl Pharmacol [Epub ahead of print] (2013).
Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835–840 (2010).
Lynam-Lennon, N., Maher, S. G. & Reynolds, J. V. The roles of micro-RNA in cancer and apoptosis. Biol Rev Camb Philos Soc 84:55–71 (2009).
Sun, B. K. & Tsao, H. Small RNAs in development and disease. J Am Acad Dermatol 59:725–737 (2008).
Liu, H. & Kohane, I. S. Tissue and process specific microRNA-mRNA co-expression in mammalian development and malignancy. PLoS One 4:e5436 (2009).
Huang, J. C. et al. Using expression profiling data to identify human microRNA targets. Nat Methods 4: 1045–1049 (2007).
Sonkoly, E. & Pivarcsi, A. MicroRNAs in inflammation and response to injuries induced by environmental pollution. Mutat Res 17:46–53 (2011).
Yokoi, T. & Nakajima, M. Toxicological implications of modulation of gene expression by microRNAs. Toxicol Sci 123:1–14 (2011).
Lema, C. & Cunningham, M. J. MicroRNAs and their implications in toxicological research. Toxicol Lett 198: 100–105 (2010).
Wang, K. et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci USA 106:4402–4407 (2009).
Feltens, R. et al. Chlorobenzene induces oxidative stress in human lung epithelial cells in vitro. Toxicol Appl Pharmacol 242:100–108 (2010).
Koehler, C. et al. Aspects of nitrogen dioxide toxicity in environmental urban concentrations in human nasal epithelium. Toxicol Appl Pharmacol 245:219–225 (2010).
Roggen, E. L., Soni, N. K. & Verheyen, G. R. Respiratory immunotoxicity: an in vitro assessment. Toxicol In Vitro 20:1249–1264 (2006).
Wang, F., Li, C., Liu, W. & **, Y. Modulation of microRNA expression by volatile organic compounds in mouse lung. Environ Toxicol DOI 10.1002 /tox (2012).
Farh, K. K. et al. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310:1817–1821 (2005).
Favaro, E. et al. MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One 5: e10345 (2010).
Roy, J., Pallepati, P., Bettaieb, A. & Averill-Bates, D. A. Acrolein induces apoptosis through the death receptor pathway in A549 lung cells: role of p53. Can J Physiol Pharmacol 88:353–368 (2010).
Chopra, M., Reuben, J. S. & Sharma, A. C. Acute lung injury: apoptosis and signaling mechanisms. Exp Biol Med 34:361–371 (2009).
Levy, M., Khan, E., Careaga, M. & Goldkorn, T. Neutral sphingomyelinase 2 is activated by cigarette smoke to augment ceramide-induced apoptosis in lung cell death. Am J Physiol Lung Cell Mol Physiol 297:125–133 (2009).
Sandikci, M., Seyrek, K., Aksit, H. & Kose, H. Inhalation of formaldehyde and xylene induces apoptotic cell death in the lung tissue. Toxicol Ind Health 25:455–461 (2009).
Kheradmand, F. et al. Transforming growth factoralpha enhances alveolar epithelial cell repair in a new in vitro model. Am J Physiol 267:728–738 (1994).
Geiser, T., Jarreau, P. H., Atabai, K. & Matthay, M. A. Interleukin-1beta augments in vitro alveolar epithelial repair. Am J Physiol Lung Cell Mol Physiol 279:1184–1190 (2000).
Frankel, S. K. et al. TNF-alpha sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis. Am J Respir Cell Mol Biol 34:293–304 (2006).
Gochuico, B. R. et al. Airway epithelial Fas ligand expression: potential role in modulating bronchial inflammation. Am J Physiol 274:L444–449 (1998).
Watanabe-Fukunaga, R., Brannan, C. I., Copeland, N. G., Jenkins, N. A. & Nagata, S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356:314–317 (1992).
McGrath, E. E. et al. Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis. Thorax 67:796–803 (2012).
Hart, K. et al. A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer. Lung Cancer 71:123–129 (2011).
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63 (1983).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Choi, HS., Song, MK. & Ryu, JC. Integrated analysis of microRNA and mRNA expression profiles highlights alterations in modulation of the apoptosis-related pathway under nonanal exposure. Mol. Cell. Toxicol. 9, 351–364 (2013). https://doi.org/10.1007/s13273-013-0044-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13273-013-0044-x