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Acute inhalation of ozone induces DNA methylation of apelin in lungs of Long-Evans rats.
Citation:
Miller, C., J. Dye, M. Schladweiler, J. Richards, A. Ledbetter, E. Stewart, AND U. Kodavanti. Acute inhalation of ozone induces DNA methylation of apelin in lungs of Long-Evans rats. INHALATION TOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, 30(4):178-186, (2018). https://doi.org/10.1080/08958378.2018.1483984
Impact/Purpose:
The purpose of this study was to evaluate immediate epigenetic alterations following acute exposure to the oxidant air pollutant, ozone, in rats. We sought to explore changes in the regulation of DNA methylation and changes in hydroxymethylation in a global manner and of an epigenetically regulated candidate gene involved in pulmonary hypertension and edema, namely apelin.
Description:
Apelin has cardiopulmonary protective properties that promote vasodilation and maintenance of the endothelial barrier. While reductions in apelin have been identified as a contributor to various lung diseases, including pulmonary edema, its role in the effect of air pollutants has not been examined. Thus, in the current study we sought to investigate if apelin is a downstream target of inhaled ozone and if such change in expression is related to altered DNA methylation in the lung. Male, Long-Evans rats were exposed to filtered air or 1.0 ppm ozone for four hours. Ventilation changes were assessed using whole-body plethysmography immediately following exposure, and markers of pulmonary edema and inflammation were assessed in the bronchoaveolar lavage (BAL) fluid. The enzymatic regulators of DNA methylation were measured in the lung, along with methylation and hydroxymethylation of the apelin promoter. Data showed that ozone exposure was associated with increased enhanced pause and protein leakage in the BAL fluid. Ozone exposure reduced DNA cytosine-5-methyltransferase (DNMT) activity and Dnmt3a/b gene expression. Exposure induced upregulation of proliferating cell nuclear antigen, indicative of DNA damage, repair, and maintenance methylation. Increased methylation and reduced hydroxymethylation was measured on the apelin promoter. These epigenetic modifications accompanied ozone-induced reduction of apelin expression and development of pulmonary edema. In conclusion, epigenetic regulation, specifically increased methylation of the apelin promoter downstream of DNA damage, may lead to reductions in protective signaling of the apelinergic system, contributing to the pulmonary edema observed following exposure to oxidant air pollution.
URLs/Downloads:
DOI: Acute inhalation of ozone induces DNA methylation of apelin in lungs of Long-Evans rats.