Abstract
Epidemiological and experimental studies indicate that the altered fetal and neonatal environment influences physiological functions and may increase the risk of developing chronic diseases in adulthood. Because homocysteine (Hcy) metabolic imbalance is considered a risk factor for neurodegenerative diseases, we investigated whether maternal Vitamin B deficiency during early development alters the offspring's methionine-homocysteine metabolism in their brain. To this end, the dams were submitted to experimental diet one month before and during pregnancy or pregnancy/lactation. After birth, the offspring were organized into the following groups: control (CT), deficient diet during pregnancy and lactation (DPL) and deficient diet during pregnancy (DP). The mice were euthanized at various stages of development. Hcy, cysteine, glutathione (GSH), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), folate and cobalamin concentrations were measured in the plasma and/or brain. At postnatal day (PND) 0, total brain of female and male offspring exhibited decreased SAM/SAH ratios. Moreover, at PND 28, we observed decreased GSH/GSSG ratios in both females and males in the DPL group. Exposure to a Vitamin B-deficient diet during the ontogenic plasticity period had a negative impact on plasma folate and brain cortex SAM concentrations in aged DPL males. We also observed decreased plasma GSH concentrations in both DP and DPL males (PND 210). Additionally, this manipulation seemed to affect the female and male offspring differently. The decreased plasma GSH concentration may reflect redox changes in tissues and the decreased brain cortex SAM may be involved in changes of gene expression, which could contribute to neurodegenerative diseases over the long term.
Highlights
Homocysteine (Hcy) is a sulfur-containing amino acid derived from the metabolism of methionine [1,2]
To evaluate the effect of Vitamin B deficiency during pregnancy on brain methyl metabolism in the offspring, SAM and SAH were measured after birth (PND 0) in the DP and CT groups
Similar results were observed in males, which showed increased Hcy concentration in the during pregnancy and lactation (DPL) group when compared to the DP (P,0.001) and CT (P,0.001) groups, respectively, and a significant decrease in plasma folate concentration when compared to the DP (P,0.001) and CT (P,0.001) groups
Summary
Homocysteine (Hcy) is a sulfur-containing amino acid derived from the metabolism of methionine [1,2]. The methionine adenosyltransferase enzyme produces an intermediate metabolite called S-adenosylmethionine (SAM), which has an important biological function as methyl donor in a multitude of cellular methylation reactions [3]. SAH is hydrolyzed to adenosine and Hcy by the enzyme SAH hydrolase [4]. The reaction catalyzed by SAH hydrolase is reversible, and thermodynamics favors AdoHcy ( named SAH) synthesis rather that Hcy production. Under normal conditions Hcy will be quickly metabolized and the reaction proceeds in the direct way. The Hcy may be remethylated to methionine by the ubiquitously distributed methionine synthase (MS), or by betaine-homocysteine methyltransferase (BHMT) in the liver and kidney of some species. Increasing evidence supports the importance of the transsulfuration pathway of Hcy in the maintenance of the redox homeostasis [6]
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