Elevated glucose induces congenital heart defects by altering the expression of tbx5, tbx20, and has2 in developing zebrafish embryos

Birth Defects Res A Clin Mol Teratol. 2010 Jun;88(6):480-6. doi: 10.1002/bdra.20654.

Abstract

Background: Maternal diabetes increases the risk of congenital heart defects in infants, and hyperglycemia acts as a major teratogen. Multiple steps of cardiac development, including endocardial cushion morphogenesis and development of neural crest cells, are challenged under elevated glucose conditions. However, the direct effect of hyperglycemia on embryo heart organogenesis remains to be investigated.

Methods: Zebrafish embryos in different stages were exposed to D-glucose for 12 or 24 hr to determine the sensitive window during early heart development. In the subsequent study, 6 hr post-fertilization embryos were treated with either 25 mmol/liter D-glucose or L-glucose for 24 hr. The expression of genes was analyzed by whole-mount in situ hybridization.

Results: The highest incidence of cardiac malformations was found during 6-30 hpf exposure periods. After 24 hr exposure, D-glucose-treated embryos exhibited significant developmental delay and diverse cardiac malformations, but embryos exposed to L-glucose showed no apparent phenotype. Further investigation of the origin of heart defects showed that cardiac looping was affected earliest, while the specification of cardiac progenitors and heart tube assembly were complete. Moreover, the expression patterns of tbx5, tbx20, and has2 were altered in the defective hearts.

Conclusions: Our data demonstrate that elevated glucose alone induces cardiac defects in zebrafish embryos by altering the expression pattern of tbx5, tbx20, and has2 in the heart. We also show the first evidence that cardiac looping is affected earliest during heart organogenesis. These research results are important for devising preventive and therapeutic strategies aimed at reducing the occurrence of congenital heart defects in diabetic pregnancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucose / analysis*
  • Glucuronosyltransferase / genetics*
  • Heart Defects, Congenital / etiology*
  • Hyaluronan Synthases
  • In Situ Hybridization
  • T-Box Domain Proteins / genetics*
  • Zebrafish / embryology*
  • Zebrafish Proteins / genetics*

Substances

  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Zebrafish Proteins
  • tbx20 protein, zebrafish
  • Glucuronosyltransferase
  • Hyaluronan Synthases
  • has2 protein, zebrafish
  • Glucose