Low ascorbic acid and increased oxidative stress in gulo(-/-) mice during development.
Vitamin C (ascorbic acid, AA) depletion during prenatal and postnatal development can lead to oxidative stress in the developing brain and other organs. Such damage may lead to irreversible effects on later brain function. We studied the relationship between AA deficiency and oxidative stress during development in gulonolactone oxidase (gulo) knockout mice that are unable to synthesize their own ascorbic acid. Heterozygous gulo(+/-) mice can synthesize AA and typically have similar tissue levels to wild-type mice. Gulo(+/-) dams were mated with gulo(+/-) males to provide offspring of each possible genotype. Overall, embryonic day 20 (E20) and postnatal day 1 (P1) pups were protected against oxidative stress by sufficient AA transfer during pregnancy. On postnatal day 10 (P10) AA levels were dramatically lower in liver and cerebellum in gulo(-/-) mice and malondialdehyde (MDA) levels were significantly increased. In postnatal day 18 pups (P18) AA levels decreased further in gulo(-/-) mice and oxidative stress was observed in the accompanying elevations in MDA in liver, and F(2)-isoprostanes in cortex. Further, total glutathione levels were higher in gulo(-/-) mice in cortex, cerebellum and liver, indicating that a compensatory antioxidant system was activated. These data show a direct relationship between AA level and oxidative stress in the gulo(-/-) mice. They reinforce the critical role of ascorbic acid in preventing oxidative stress in the developing brain in animals that, like humans, cannot synthesize their own AA.
Harrison
Fiona E
FE
Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA. Fiona.Harrison@Vanderbilt.edu
Meredith
M Elizabeth
ME
Dawes
Sean M
SM
Saskowski
Jeanette L
JL
May
James M
JM
D000818:Animals; D000831:Animals, Newborn; D001205:Ascorbic Acid / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D004622:Embryo, Mammalian; D028441:F2-Isoprostanes / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D050544:L-Gulonolactone Oxidase / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics*; D050050:Protein Carbonylation / Q000235:genetics
D028441:F2-Isoprostanes; D005904:Glial Fibrillary Acidic Protein; D008315:Malondialdehyde; D050544:L-Gulonolactone Oxidase; D005978:Glutathione; D001205:Ascorbic Acid