British Journal of Nutrition

Maternal nicotinamide supplementation causes global DNA hypomethylation, uracil hypo-incorporation and gene expression changes in fetal rats

Yan-Jie Tiana1 , Ning Luoa1 , Na-Na Chena1, Yong-Zhi Luna1, Xin-Yi Gua2, Zhi Lia1, Qiang Maa2 c1 and Shi-Sheng Zhoua1 c1

a1 Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian 116622, People's Republic of China

a2 Department of Neurology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, People's Republic of China


Recent evidence shows that excess nicotinamide can cause epigenetic changes in developing rats. The aim of the present study was to investigate the effects of maternal nicotinamide supplementation on the fetus. Female rats were randomised into four groups fed a standard chow diet (control group) or diets supplemented with 1 g/kg of nicotinamide (low-dose group), 4 g/kg of nicotinamide (high-dose group) or 4 g/kg of nicotinamide plus 2 g/kg of betaine (betaine group) for 14–16 d before mating and throughout the study. Fetal tissue samples were collected on the 20th day of pregnancy. Compared with the control group, the high-dose group had a higher fetal death rate, and the average fetal body weight was higher in the low-dose group but lower in the high-dose group. Nicotinamide supplementation led to a decrease in placental and fetal hepatic genomic DNA methylation and genomic uracil contents (a factor modifying DNA for diversity) in the placenta and fetal liver and brain, which could be completely or partially prevented by betaine. Moreover, nicotinamide supplementation induced tissue-specific alterations in the mRNA expression of the genes encoding nicotinamide N-methyltransferase, DNA methyltransferase 1, catalase and tumour protein p53 in the placenta and fetal liver. High-dose nicotinamide supplementation increased fetal hepatic α-fetoprotein mRNA level, which was prevented by betaine supplementation. It is concluded that maternal nicotinamide supplementation can induce changes in fetal epigenetic modification and DNA base composition. The present study raises the concern that maternal nicotinamide supplementation may play a role in the development of epigenetic-related diseases in the offspring.

(Received July 03 2013)

(Revised November 11 2013)

(Accepted November 18 2013)

(Online publication February 10 2014)

Key Words:

  • Maternal nutrient supplementation;
  • Nicotinamide;
  • Epigenetic changes;
  • DNA hypomethylation


c1 Corresponding authors: S.-S. Zhou, fax +86 411 87402053, email; Q. Ma, email;


  Both authors contributed equally to this work.

  Abbreviations: Afp, α-fetoprotein; betaine group, diet supplemented with 4 g/kg of nicotinamide plus 2 g/kg of betaine; Cat, catalase; control group, standard chow diet; Dnmt-1, DNA methyltransferase 1; high-dose group, diet supplemented with 4 g/kg of nicotinamide; low-dose group, diet supplemented with 1 g/kg of nicotinamide; Nnmt, nicotinamide N-methyltransferase; Tp53, tumour protein p53