Homocysteine-induced neural tube defects in chick embryos via oxidative stress and DNA methylation associated transcriptional down-regulation of miR-124

Rui Wang; Zhong-Ji Han; Ge Song; Yi Cui; Hong-Fei Xia; Xu Ma

doi:10.1093/toxres/tfab020

Homocysteine-induced neural tube defects in chick embryos via oxidative stress and DNA methylation associated transcriptional down-regulation of miR-124

Toxicol Res (Camb). 2021 Apr 26;10(3):425-435. doi: 10.1093/toxres/tfab020. eCollection 2021 May.

Authors

Rui Wang^{1

2}, Zhong-Ji Han^{3

2}, Ge Song^{3

2}, Yi Cui^{3

2}, Hong-Fei Xia^{3

2}, Xu Ma^{3

2}

Affiliations

¹ Department of Blood Transfusion, First Medical Center, Chinese People's Liberation Army General Hospital, Beijing 100853, China.
² Department of Genetics, National Research Institute for Family Planning, Beijing 100081, China.
³ Graduate School of Peking Union Medical College, Beijing 100730, China.

Abstract

Although moderate homocysteine (HCY) elevation is associated with neural tube defects (NTDs), the underlying mechanisms have not been elucidated. In this study, we aimed to investigate that whether HCY-induced NTDs were associated with oxidative stress and methyl metabolism in chick embryos. The potential role of miR-124 in neurogenesis was also investigated. In this study, increased intracellular oxidative species and alterations in DNA methylation were observed following HCY treatment. This alteration coincided with decreases of Mn superoxide dismutase and glutathione peroxidase activities, as well as the expression of anti-rabbit DNA methyltransferase (DNMT) 1 and 3a. In addition, HCY induced significant decreases of S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) (P < 0.05). N-acetyl-L-cysteine and choline ameliorated global DNA hypomethylation induced by HCY. MiR-124 levels were significantly suppressed by HCY (P < 0.05), while elevated by 5-aza-2'-deoxycytidine (5-aza-dC). MiR-124 knockdown resulted in spina bifida occulta. Our research suggests that HCY-induced NTDs were associated with oxidative stress and methyl metabolism in chick embryos. MiR-124 down-regulation may occur via epigenetic mechanisms and contribute to HCY-induced NTDs in chick embryo models.

Keywords: DNA hypomethylation; homocysteine; miR-124; neural tube defects; oxidative stress.