Maternal diabetes in the rat impairs the formation of neural-crest derived cranial nerve ganglia in the offspring.

ABSTRACT

AIMS/HYPOTHESIS: Maternal diabetes mellitus increases the risk for fetal malformations. Several of these malformations are found in organs and tissues derived from the neural crest. Previous studies have shown changes in fetal organs of neural crest origin in experimental diabetes and changes in migration of neural crest cells exposed to high glucose in vitro. METHODS: We used whole-mount neurofilament staining of embryos from normal and diabetic mothers to investigate the development of cranial nerve ganglia. Neural tube explants were cultured in 10 and 40 mmol/l glucose and cell death and caspase activity was measured with flow cytometry. RESULTS: The development of cranial ganglia V, VII, VIII, IX and X was impaired in day 10-11 embryos of diabetic rats. There was also a higher rate of cell death of neural crest derived cells cultured in 40 mmol/l glucose for 20 h (35% compared to 12% in 10 mmol/l). However, exposure of cells to 40 mmol/l glucose in culture did not increase the activation of the cell death effector proteins-caspases-measured as cellular binding of the activated caspase marker VAD-FMK. This suggests that the cell death is not caused by caspase-dependent apoptosis or that the caspases are activated at an earlier stage. CONCLUSION/INTERPRETATION: The development of neural crest-derived structures is disturbed already at the organogenic period in embryos of diabetic rats and this deteriorated development could be due to high-glucose induced increase in cell death of neural crest derived cells.