Abstract
Maternal food intake has a significant effect on the fetal environment, and an inadequate maternal diet may result in intrauterine growth restriction. Intrauterine growth restriction newborn rat pups nursed by normal diet-fed dams exhibited rapid catch-up growth, which plays a critical role in the risk for metabolic and cardiovascular disease in later life. Specifically, one-carbon metabolism in the liver plays a critical role in placental and fetal growth. Impaired functioning of one-carbon metabolism is associated with increased homocysteine levels. In this study, we applied a comprehensive proteomic approach to identify differential expression of proteins related to one-carbon metabolism in the livers of rat offspring as an effect of maternal food restriction during gestation. Data are available via ProteomeXchange with identifier PXD002578. We determined that betaine-homocysteine S-methyltransferase 1, methylenetetrahydrofolate dehydrogenase 1, and ATP synthase subunit beta mitochondrial (ATP5B) expression levels were significantly reduced in the livers of rat offspring exposed to maternal food restriction during gestation compared with in the offspring of rats fed a normal diet (p < 0.05). Moreover, the expression levels of betaine-homocysteine S-methyltransferase 1, methylenetetrahydrofolate dehydrogenase 1, and ATP synthase subunit beta mitochondrial were negatively correlated with serum homocysteine concentration in male offspring exposed to maternal food restriction during gestation and normal diet during lactation. However, in female offspring only expression levels of methylenetetrahydrofolate dehydrogenase 1 were negatively correlated with homocysteine concentration. This study shows that maternal food restriction during late gestation and normal diet during lactation lead to increased homocysteine concentration through disturbance of one-carbon metabolism in the livers of male offspring. This suggests that male offspring have an increased gender-specific susceptibility to disease in later life through fetal programming.
Highlights
From the ‡Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158 –710, Korea; §Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, 158 –710, Korea; ¶Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do 456 –756, Korea
The body and liver weights of the intrauterine growth restriction (IUGR) offspring were lower than those of the ad libitum (AdLib) offspring at birth, the 3-week-old IUGR offspring nursed by AdLib dams showed a marked increase in body and liver weights that exceeded those of the AdLib/AdLib offspring
We identified protein spots in the food restriction (FR)/AdLib offspring that exhibited a 10fold difference in protein expression compared with the livers of AdLib/AdLib offspring (p Ͻ 0.05, Fig. 1)
Summary
Animal Experiments—Studies were approved by the Animal Research Committee of the School of Medicine at Ewha Womans University and were in accordance with the international guidelines for the care of laboratory animals. The proteins were loaded into different 2D-analysis gels for each group. Custom-made chromatographic columns were used to desalt and concentrate the peptide mixture prior to mass spectrophotometric analysis. Electrospray Ionization MS/MS Analysis—MS/MS of the peptides generated by in-gel digestion was performed by nano-electrospray ionization (ESI) using a MicroQ-TOF2 III mass spectrometer (Bruker Daltonics, Bremen, Germany). Serum Hcy concentrations from 3-week-old offspring from the AdLib/AdLib and FR/AdLib (n ϭ 9 males, n ϭ 9 females/group) groups were measured by enzyme-linked immunoassay (ELISA) following the protocol in the Rat Homocysteine ELISA Kit (Cusabio Biotech Co. LTD, China). We used Student’s t test (p Ͻ 0.05) to determine which protein spots were differentially abundant (Ͼ 10-fold) between the livers of 3-week-old offspring from the. Spearman’s correlations were calculated to analyze differences between the expressed proteins and serum Hcy concentration
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