Elevated plasma
homocysteine has been linked to
pregnancy complications and developmental diseases. Whereas
hyperhomocysteinemia is frequently observed in populations at risk of
malnutrition,
hypoxia may alter the remethylation of
homocysteine in hepatocytes. We aimed to investigate the combined influences of early deficiency in nutritional determinants of
hyperhomocysteinemia and of neonatal
hypoxia on
homocysteine metabolic pathways in developing rats. Dams were fed a standard diet or a diet deficient in
vitamins B12, B2,
folate, month, and
choline from 1 mo before pregnancy until weaning of the offspring. The pups were divided into four treatment groups corresponding to "no
hypoxia/standard diet," "
hypoxia (100% N2 for 5 min at postnatal d 1)/standard diet," "no
hypoxia/deficiency," and "
hypoxia/deficiency," and
homocysteine metabolism was analyzed in their liver at postnatal d 21.
Hypoxia increased plasma
homocysteine in deficient pups (21.2 +/- 1.6 versus 13.3 +/- 1.2 microM, p < 0.05). Whereas
mRNA levels of
cystathionine beta-synthase remained unaltered, deficiency reduced the
enzyme activity (48.7 +/- 2.9 versus 83.6 +/- 6.3 nmol/h/mg, p < 0.01), an effect potentiated by
hypoxia (29.4 +/- 4.7 nmol/h/mg, p < 0.05). The decrease in
methylene-tetrahydrofolate reductase activity measured in deficient pups was attenuated by
hypoxia (p < 0.05), and
methionine-adenosyltransferase activity was slightly reduced only in the "
hypoxia/deficiency" group (p < 0.05). Finally,
hypoxia enhanced the deficiency-induced drop of the
S-adenosylmethionine/
S-adenosylhomocysteine ratio, which is known to influence DNA methylation and gene expression. In conclusion, neonatal
hypoxia may increase
homocysteinemia mainly by decreasing
homocysteine transsulfuration in developing rats under methyl-deficient regimen. It could therefore potentiate the well-known adverse effects of
hyperhomocysteinemia.