Influence of preconditioning-like hypoxia on the liver of developing methyl-deficient rats.
Deficiency in nutritional determinants of homocysteine (HCY) metabolism, such as vitamin B(12) and folate, during pregnancy is known to influence HCY levels in the progeny, which in turn may exert adverse effects during development, including liver defects. Since short hypoxia has been shown to induce tolerance to subsequent stress in various cells including hepatocytes, and as vitamins B deficiency and hypoxic episodes may simultaneously occur in neonates, we aimed to investigate the influence of brief postnatal hypoxia (100% N(2) for 5 min) on the liver of rat pups born from dams fed a deficient regimen, i.e., depleted in vitamins B(12), B(2), folate, and choline. Four experimental groups were studied: control, hypoxia, deficiency, and hypoxia + deficiency. Although hypoxia transiently stimulated HCY catabolic pathways, it was associated with a progressive increase of hyperhomocysteinemia in deficient pups, with a fall of cystathionine beta-synthase activity at 21 days. At this stage, inducible NO synthase activity was dramatically increased and glutathione reductase decreased, specifically in the group combining hypoxia and deficiency. Also, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio. In parallel, early exposure to the methyl-deficient regimen induced oxidative stress and led to hepatic steatosis, which was found to be more severe in pups additionally exposed to hypoxia. In conclusion, brief neonatal hypoxia may accentuate the long-term adverse effects of impaired HCY metabolism in the liver resulting from an inadequate nutritional regimen during pregnancy, and our data emphasize the importance of early factors on adult disease.
Blaise
Sébastien A
SA
INSERM U724, Faculté de Médecine, 9 Ave. de la Forêt de Haye, BP 184, F-54500 Vandoeuvre-lès-Nancy, France.
Alberto
Jean-Marc
JM
Audonnet-Blaise
Sandra
S
Guéant
Jean-Louis
JL
Daval
Jean-Luc
JL
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D049109:Cell Proliferation; D002796:Choline Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000097:blood; D005494:Folic Acid Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology; D005526:Food, Formulated; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000097:blood / Q000378:metabolism; D000860:Hypoxia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012256:Riboflavin / Q000097:blood; D012257:Riboflavin Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014805:Vitamin B 12 / Q000097:blood; D014806:Vitamin B 12 Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology; D014804:Vitamin B Deficiency / Q000150:complications / Q000378:metabolism* / Q000473:pathology
D006710:Homocysteine; D012436:S-Adenosylmethionine; D005492:Folic Acid; D012435:S-Adenosylhomocysteine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D003541:Cystathionine beta-Synthase; D005978:Glutathione; D014805:Vitamin B 12; D012256:Riboflavin