Genetic and environmental influence on diabetic rat embryopathy

• We assessed genetic and environmental influence on fetal outcome in diabetic rat pregnancy. Crossing normal (N) and manifestly diabetic (MD) Wistar Furth (W) and Sprague-Dawley (L) females with W or L males yielded 4 different fetal genotypes (WW, LL, WL, LW) in N or MD rat pregnancies for studies. We also evaluated fetal outcome in litters with enhanced or diminished severity of maternal MD state, denoted MD(+)WL and MD(-)LW. The MDWW litters had less malformations and resorptions (0% and 19%) than the MDLL litters (17% and 30%). The MDWL litters (0% and 8%) were less maldeveloped than the MDLW litters (9% and 22%), whereas the MD(+)WL (3% and 23%) and MD(-)LW (1% and 17%) litters showed increased and decreased dysmorphogenesis (compared to MDWL and MDLW litters). The pregnant MDW rats had lower serum levels of glucose, fructosamine and branched chain amino acids than the pregnant MDL rats, whereas the pregnant MD(+)W and MD(-)L rats had levels comparable to those of the MDL and MDW rats, respectively. The 8-iso-PGF2α levels of the malformed MDLW offspring were increased compared to the non-malformed MDLW offspring. Diabetes decreased fetal heart Ret and increased Bmp-4 gene expression in the MDLW offspring, and caused decreased GDNF and Shh expression in the malformed fetal mandible of the MDLW offspring. We conclude that the fetal (epi)genome controls the embryonic dysmorphogenesis in diabetic pregnancy by instigating a threshold level for the teratological insult, and that the maternal genome controls the teratogenic insult by (dys)regulating the maternal metabolism.

Nyckelord

diabetes in pregnancy

congenital abnormalities

teratology

animal experimentation

aldose reductase

glyceraldehyde-3-phosphate dehydrogenase

sonic hedgehog homologue

ret proto-oncogene

glial-derived neurotrophic factor

antioxidative enzymes

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MEDICIN

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