title: Influence of preconditioning-like hypoxia on the liver of developing methyl-deficient rats.
abstract: 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.
authors.affiliation: INSERM U724, Faculté de Médecine, 9 Ave. de la Forêt de Haye, BP 184, F-54500 Vandoeuvre-lès-Nancy, France.
authors.forename: Sébastien A
authors.initials: SA
authors.lastname: Blaise
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Alberto
authors.forename: Sandra
authors.initials: S
authors.lastname: Audonnet-Blaise
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Daval
mesh_terms: 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
chemical_list: 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