Congenital malformations are a common adverse outcome in pregnancies complicated by pregestational
obesity, although the underlying mechanisms are still unrevealed. Our aim was to study the effect of oxidative stress in
obesity-induced
teratogenesis. Wistar rats were fed a high-fat diet for 13 weeks, with (OE group) or without (O group)
vitamin E supplementation. Then, rats were mated and sacrificed at day 11.5 of gestation. Embryos from O dams presented a 25.9 ± 3.5% rate of malformations (vs. 8.7 ± 3.4% in C rats), which was reduced in the OE group (11.5 ± 2.3%). Pregestational
obesity induced hepatic
protein and
DNA oxidation and a decline in
antioxidant enzymes. Importantly,
glutathione content was also decreased, limiting the availability of this
antioxidant in the embryos.
Vitamin E supplementation efficiently maintained
glutathione levels in the obese mothers, which could be used in their embryos to prevent oxidation-induced malformations. To test the effect of decreasing
glutathione levels alone in a cell culture model of neuroepithelium, murine embryonic stem cells (ESC) were induced to form neuronal precursors and
glutathione synthesis was inhibited with the
gamma-glutamylcysteine synthesis inhibitor,
buthionine sulfoximine (BSO). BSO inhibited the expression of Pax3, a gene required for neural tube closure that is also inhibited by oxidative stress. Taken together, our data indicate that
obesity causes malformations through the depletion of maternal
glutathione, thereby decreasing
glutathione-dependent
free radical scavenging in embryos, which can be prevented by
vitamin E supplementation.