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Clin Epigenetics. 2018 Mar 20;10:37. doi: 10.1186/s13148-018-0469-0. eCollection 2018.

Neonatal exposure to hyperoxia leads to persistent disturbances in pulmonary histone signatures associated with NOS3 and STAT3 in a mouse model.

Author information

1Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Aulweg 130, 35392 Giessen, Germany.
2University Children's Hospital Gießen, Division of General Pediatrics and Neonatology, Justus-Liebig-University, Gießen, Germany.
3Department of Pediatrics, HELIOS Medical Center Wuppertal, Center for Clinical & Translational Research (CCTR), Center for Biomedical Education & Research (ZBAF), Witten/Herdecke University, Wuppertal, Germany.
4EKO Children's Hospital, Oberhausen, Witten/Herdecke University, Alfred-Herrhausen Str. 40, Witten, Germany.
Contributed equally



Early pulmonary oxygen exposure is one of the most important factors implicated in the development of bronchopulmonary dysplasia (BPD).


Here, we analyzed short- and long-term effects of neonatal hyperoxia on NOS3 and STAT3 expression and corresponding epigenetic signatures using a hyperoxia-based mouse model of BPD.


Early hyperoxia exposure led to a significant increase in NOS3 (median fold change × 2.37, IQR 1.54-3.68) and STAT3 (median fold change × 2.83, IQR 2.21-3.88) mRNA levels in pulmonary endothelial cells with corresponding changes in histone modification patterns such as H2aZac and H3K9ac hyperacetylation at the respective gene loci. No complete restoration in histone signatures at these loci was observed, and responsivity to later hyperoxia was altered in mouse lungs. In vitro, histone signatures in human aortic endothelial cells (HAEC) remained altered for several weeks after an initial long-term exposure to trichostatin A. This was associated with a substantial increase in baseline eNOS (median 27.2, IQR 22.3-35.6) and STAT3α (median 5.8, IQR 4.8-7.3) mRNA levels with a subsequent significant reduction in eNOS expression upon exposure to hypoxia.


Early hyperoxia induced permanent changes in histones signatures at the NOS3 and STAT3 gene locus might partly explain the altered vascular response patterns in children with BPD.

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Conflict of interest statement

All animal experiments were performed in accordance with the National Institutes of Health Guidelines for the Use of Laboratory Animals. Animal experiments were approved by the Federal Authorities for Animal Research of the Regierungspräsidium Giessen, Hessen, Germany, protocol 105/2011. This study was conducted with the approval of the Witten/Herdecke University Ethics board.All authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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