Archives of Toxicology

, Volume 92, Issue 4, pp 1563–1579 | Cite as

Maternal NO2 exposure induces cardiac hypertrophy in male offspring via ROS-HIF-1α transcriptional regulation and aberrant DNA methylation modification of Csx/Nkx2.5

  • Yingying Zhang
  • Wei Yan
  • Xiaotong Ji
  • Huifeng Yue
  • Guangke Li
  • Nan Sang
Reproductive Toxicology


Maternal exposure to nitrogen dioxide (NO2) poses a risk for morbidity and mortality in infantile congenital heart diseases and even adult cardiovascular diseases. However, the experimental evidence supporting these effects is insufficient, and the related regulatory mechanisms are unknown. In the present study, we aimed to determine whether maternal NO2 exposure causes cardiac hypertrophy-related consequences in offspring, and if so, how these adverse effects occur in the postnatal heart. The results indicate that in mice, maternal NO2 exposure causes cardiac hypertrophy in male offspring. This altered phenotype was accompanied by increased expression of atrial natriuretic peptide, B-type natriuretic peptide, bone morphogenetic protein 10 and β-myosin heavy chain and elevated activities of cardiomyocyte injury markers, including serum glutamate-oxaloacetate transaminase, lactate dehydrogenase and kinases creatine phosphokinase (CK-MB) in serum. The cardiac-specific transcription factor Csx/Nkx2.5 played an important role in the induction of cardiac hypertrophy and cardiomyocyte injury, and the action was associated with ROS-HIF-1α transcriptional regulation and DNA hypomethylation modification.


Maternal NO2 exposure Cardiac hypertrophy Csx/Nkx2.5 ROS-HIF-1α transcriptional regulation DNA hypomethylation modification 



This study was supported by National Science Foundation of PR China (NSFC, No. 21377076, 21477070, 91543203, 21222701), Research Project for Young Sanjin Scholarship of Shanxi, Program for the Outstanding Innovative Teams of Higher Learning Institutions of Shanxi, and Research Project Supported by Shanxi Scholarship Council of China (No. 2015-006).

Compliance with ethical standards

Conflict of interest

The authors have no conflicts to disclose.

Supplementary material

204_2018_2166_MOESM1_ESM.doc (506 kb)
Supplementary material 1 (DOC 506 KB)


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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of Environment and Resource, Research Center of Environment and HealthShanxi UniversityTaiyuanPeople’s Republic of China

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