High paternal homocysteine causes ventricular septal defects in mouse offspring

Lian Liu; Xuan Zhang; Hao-Ran Geng; Ya-Nan Qiao; Yong-Hao Gui; Jian-Yuan Zhao

doi:10.1016/j.isci.2024.109447

High paternal homocysteine causes ventricular septal defects in mouse offspring

iScience. 2024 Mar 7;27(4):109447. doi: 10.1016/j.isci.2024.109447. eCollection 2024 Apr 19.

Authors

Lian Liu¹, Xuan Zhang¹, Hao-Ran Geng^{2

3}, Ya-Nan Qiao², Yong-Hao Gui¹, Jian-Yuan Zhao³

Affiliations

¹ Children's Hospital of Fudan University and Shanghai Genitourinary Cancer Institute Fudan University, Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 201102, China.
² School of Life Sciences, Fudan University, Shanghai 200438, China.
³ Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.

Abstract

Maternal hyperhomocysteinemia is widely considered as an independent risk of congenital heart disease (CHD). However, whether high paternal homocysteine causes CHD remains unknown. Here, we showed that increased homocysteine levels of male mice caused decreased sperm count, sperm motility defect and ventricular septal defect of the offspring. Moreover, high levels of paternal homocysteine decrease sperm DNMT3A/3B, accompanied with changes in DNA methylation levels in the promoter regions of CHD-related genes. Folic acid supplement could decrease the occurrence of VSD in high homocysteine male mice. This study reveals that increased paternal homocysteine level increases VSD risk in the offspring, indicating that decreasing paternal homocysteine may be an intervening target of CHD.

Keywords: Cardiovascular medicine; Genetics; Male reproductive endocrinology.