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Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA methylation and one-carbon metabolism in the organogenesis-stage rat conceptus.

ABSTRACT: Epigenetic modifications, including DNA methylation, contribute to the transcriptional regulation of developmental genes that control growth and differentiation during embryogenesis. The methyl donor, S-adenosylmethionine (SAM), is biosynthesized from methionine and adenosine triphosphate by methionine adenosyltransferase 2a (Mat2a) in the one-carbon (C1) metabolism pathway. SAM biosynthesis requires a steady supply of nutrients, vitamins and cofactors obtained by the developing conceptus through histiotrophic nutrition pathways (HNPs). The visceral yolk sac (VYS) captures proteins and their substrate cargos by receptor-mediated endocytosis and degrades them using lysosomal proteases. We hypothesize that leupeptin, a protease inhibitor, reduces the availability of methionine and C1 substrates, restricting SAM biosynthesis and altering patterns of DNA methylation. Rat conceptuses were exposed to 50 and 100 ?M leupeptin in whole embryo culture for periods of 26 h from gestational day (GD) 10 or 6 h on GD11. After 6 h on GD11, the 100-?M leupeptin treatment significantly decreased methionine in embryo (EMB) and VYS, reduced Mat2a protein levels and inhibited Mat2a specific activity, all of which produced a significant 52% reduction of SAM in the VYS. The 50- and 100-?M leupeptin treatments significantly decreased global methylation levels by 6%-9% in EMB and by 11%-15% in VYS following both 6- and 26-h exposure periods. This study demonstrates that HNP disruption alters C1 activity and significantly reduces global DNA methylation during organogenesis. Because epigenetic reprogramming is crucial for normal differentiation and growth, these findings suggest a possible mechanism through which nutrients and environmental factors may alter early developmental regulation.

SUBMITTER: Sant KE

PROVIDER: S-EPMC4142195 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA methylation and one-carbon metabolism in the organogenesis-stage rat conceptus.

Sant Karilyn E KE Dolinoy Dana C DC Nahar Muna S MS Harris Craig C

The Journal of nutritional biochemistry 20130228 8

Epigenetic modifications, including DNA methylation, contribute to the transcriptional regulation of developmental genes that control growth and differentiation during embryogenesis. The methyl donor, S-adenosylmethionine (SAM), is biosynthesized from methionine and adenosine triphosphate by methionine adenosyltransferase 2a (Mat2a) in the one-carbon (C1) metabolism pathway. SAM biosynthesis requires a steady supply of nutrients, vitamins and cofactors obtained by the developing conceptus throug ...[more]

PMID: 23453262

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Project description:BackgroundOver 57 million people in Bangladesh are chronically exposed to arsenic-contaminated drinking water. Ingested inorganic arsenic (InAs) undergoes hepatic methylation generating monomethyl- (MMAs) and dimethyl- (DMAs) arsenic species in a process that facilitates urinary As (uAs) elimination. One-carbon metabolism (OCM), a biochemical pathway that is influenced by folate and vitamin B12, facilitates the methylation of As. OCM also supports nucleotide and amino acid synthesis, particularly during periods of rapid growth such as adolescence. While folate supplementation increases As methylation and lowers blood As (bAs) in adults, little data is available for adolescents.ObjectivesTo examine the associations between OCM-related micronutrients and As methylation in Bangladeshi adolescents chronically exposed to As-contaminated drinking water.MethodsWe conducted a cross-sectional study of 679 Bangladeshi adolescents, including 320 boys and 359 girls aged 14-16 years. Nutritional status was assessed by red blood cell (RBC) folate, plasma folate, plasma B12 and homocysteine (Hcys). Arsenic-related outcomes included blood arsenic (bAs), urinary arsenic (uAs), and urinary arsenic metabolites expressed as a percentage of total urinary As: %InAs, %MMAs, %DMAs.ResultsBoys had significantly lower B12, higher Hcys, higher bAs, higher uAs, higher %MMAs, and a trend toward lower RBC folate compared to girls. Therefore, regression analyses controlling for water As and BMI were sex stratified. Among girls, RBC folate was inversely associated with bAs, plasma B12 was inversely associated with uAs, and plasma Hcys was inversely associated with %MMA. Among boys, plasma folate was inversely associated with %InAs and positively associated with %DMA, RBC folate was inversely associated with %InAs and positively associated with %MMA, while Hcys was positively associated with %InAs.ConclusionsThese findings suggest that associations between OCM nutritional status, bAs, and distribution of As metabolites in adolescents are similar to previously reported observations in adults and in children. The As methylation findings are statistically significant among boys but not among girls; this may be related to estrogen which more strongly influences OCM in females. The inverse association between Hcys and %MMA in girls is somewhat unexpected given that Hcys is known to be an indicator of impaired OCM and low folate/B12 in adults. Overall, these results indicate that the associations between OCM-related micronutrients and arsenic methylation in adolescents are generally similar to prior findings in adults, though these associations may differ by sex. Additionally, these findings suggest that more investigation into the role of Hcys in adolescent physiology is needed, perhaps particularly for girls. Additional studies are needed to evaluate the impact of OCM and As methylation on As-related adverse health outcomes (such as cancer and cardiovascular disease) in people exposed to As during adolescence.

Project description:Abstract Objectives Studies in both animals and humans have shown that maternal dietary restriction and supplementation of one carbon (1C) metabolites (methyl donors), such as methionine and choline, can impact offspring growth, insulin resistance, and DNA methylation. However, there has been limited longitudinal research of 1C metabolite concentrations over the reproduction cycle of human pregnancy. The purpose of this study was to investigate if 1C metabolite concentrations change prior to and during pregnancy and if a preconception lipid-based nutrition supplement (LNS) influences such changes. Methods This study was a secondary analysis as part of the Women First study (clinicaltrials.gov, NCT01883193), a large, randomized controlled trial investigating whether the timing of maternal LNS initiation would impact fetal growth and development. The study arms were supplementation at least 3 months prior to conception (Arm 1), supplementation at ∼12 weeks of gestation (Arm 2), or no supplementation (Arm 3). Dried blood spot (DBS) cards were collected at study enrollment prior to conception, and at 12 and 34 weeks gestation. A targeted 1C metabolite assay (27 metabolites) was performed on a subset of DBS samples from Guatemalan women (n = 134) at each time point using liquid chromatography/tandem mass spectrometry. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time and LNS on these metabolites. Results The concentrations of two metabolites were changed by intervention status: asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Twenty-one of 27 metabolites significantly changed from preconception and across gestation after correcting for multiple testing using the Bonferroni correction (P < 0.00185). Conclusions Preconception LNS significantly decreased the level of ADMA, a metabolite which has been implicated in intrauterine growth restriction and preeclampsia. More work is needed to determine whether this intervention could influence development of these conditions. Funding Sources Bill & Melinda Gates Foundation, National Institutes of Health.

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Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA methylation and one-carbon metabolism in the organogenesis-stage rat conceptus.

Publications

Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA methylation and one-carbon metabolism in the organogenesis-stage rat conceptus.

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