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Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain.

ABSTRACT: One carbon metabolism is regulated by the availability of nutrients known as methyl donors, and disruption of this pathway can affect multiple physiological systems. DNA methylation, critical for the regulation of gene expression, is linked to one carbon metabolism, and can be altered by perinatal diet. In this study, dams (n = 12/group) were fed HF or standard control (SC) diet through pregnancy and lactation, and male and female offspring were then fed either SC or methyl donor-supplemented diet (MDS) between 3 and 6 weeks of age (n = 20-26/group). Concentration of one carbon intermediates and other related metabolites were assessed within brain tissue (prefrontal cortex, PFC) through the use of mass spectrometry at 6 weeks of age. In addition, the expression of target genes and enzymes that participate in DNA methylation or are relevant to one carbon metabolism were measured. We found that MDS increases the concentration of folate intermediates in the PFC, and that this increase is blunted in male offspring from dams fed a HF diet. In addition, perinatal HF diet increased the concentration of cysteine in the PFC of both male and female offspring, consistent with oxidative stress. Furthermore, both maternal HF diet and postnatal MDS altered global DNA methylation in the PFC in males but not females. Collectively, these data demonstrate sex differences in changes in one carbon metabolites in the prefrontal cortex in response to early life high fat diet and methyl donor supplementation. Read the Editorial Highlight for this article on page 358.

SUBMITTER: McKee SE

PROVIDER: S-EPMC6288810 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain.

McKee Sarah E SE Zhang Sisi S Chen Li L Rabinowitz Joshua D JD Reyes Teresa M TM

Journal of neurochemistry 20180416 5

One carbon metabolism is regulated by the availability of nutrients known as methyl donors, and disruption of this pathway can affect multiple physiological systems. DNA methylation, critical for the regulation of gene expression, is linked to one carbon metabolism, and can be altered by perinatal diet. In this study, dams (n = 12/group) were fed HF or standard control (SC) diet through pregnancy and lactation, and male and female offspring were then fed either SC or methyl donor-supplemented di ...[more]

PMID: 29423909

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Project description:Between October 2016 and June 2017, a C57BL/6J mouse colony that was undergoing a pre- and perinatal methyl donor supplementation diet intervention to study the impact of parental nutrition on offspring susceptibility to disease was found to suffer from an epizootic of unexpected deaths. Necropsy revealed the presence of severe colitis, and further investigation linked these outbreak deaths to a Clostridium difficile strain of ribotype 027 that we term 16N203. C. difficile infection (CDI) is associated with antibiotic use in humans. Current murine models of CDI rely on antibiotic pretreatment to establish clinical phenotypes. In this report, the C. difficile outbreak occurs in F1 mice linked to alterations in the parental diet. The diagnosis of CDI in the affected mice was confirmed by cecal/colonic histopathology, the presence of C. difficile bacteria in fecal/colonic culture, and detection of C. difficile toxins. F1 mice from parents fed the methyl supplementation diet also had significantly reduced survival (P < 0.0001) compared with F1 mice from parents fed the control diet. When we tested the 16N203 outbreak strain in an established mouse model of antibiotic-induced CDI, we confirmed that this strain is pathogenic. Our serendipitous observations from this spontaneous outbreak of C. difficile in association with a pre- and perinatal methyl donor diet suggest the important role that diet may play in host defense and CDI risk factors.IMPORTANCE Clostridium difficile infection (CDI) has become the leading cause of infectious diarrhea in hospitals worldwide, owing its preeminence to the emergence of hyperendemic strains, such as ribotype 027 (RT027). A major CDI risk factor is antibiotic exposure, which alters gut microbiota, resulting in the loss of colonization resistance. Current murine models of CDI also depend on pretreatment of animals with antibiotics to establish disease. The outbreak that we report here is unique in that the CDI occurred in mice with no antibiotic exposure and is associated with a pre- and perinatal methyl supplementation donor diet intervention study. Our investigation subsequently reveals that the outbreak strain that we term 16N203 is an RT027 strain, and this isolated strain is also pathogenic in an established murine model of CDI (with antibiotics). Our report of this spontaneous outbreak offers additional insight into the importance of environmental factors, such as diet, and CDI susceptibility.

Project description:BackgroundLow chronic vitamin B-6 status can occur in a subset of women who use oral contraceptives (OCs) with uncertain metabolic consequences. An insufficiency of cellular pyridoxal 5'-phosphate (PLP), which is the coenzyme form of vitamin B-6, may impair many metabolic processes including one-carbon and tryptophan metabolism.ObjectiveWe investigated the effects of vitamin B-6 supplementation on the in vivo kinetics of one-carbon metabolism and the concentration of one-carbon and tryptophan metabolites in vitamin B-6-deficient OC users.DesignA primed, constant infusion of [(13)C5]methionine, [3-(13)C]serine, and [(2)H3]leucine was performed on 10 OC users (20-40 y old; plasma PLP concentrations <30 nmol/L) before and after 28 d of supplementation with 10 mg pyridoxine hydrochloric acid/d. In vivo fluxes of total homocysteine remethylation, the remethylation of homocysteine from serine, and rates of homocysteine and cystathionine production were assessed. Targeted metabolite profiling was performed, and data were analyzed by using orthogonal partial least-squares-discriminant analysis and paired t tests adjusted for multiple testing.ResultsPyridoxine supplementation increased the mean ± SD plasma PLP concentration from 25.8 ± 3.6 to 143 ± 58 nmol/L (P < 0.001) and decreased the leucine concentration from 103 ± 17 to 90 ± 20 nmol/L (P = 0.007) and glycine concentration from 317 ± 63 to 267 ± 58 nmol/L (P = 0.03). Supplementation did not affect in vivo rates of homocysteine remethylation or the appearance of homocysteine and cystathionine. A multivariate analysis showed a clear overall effect on metabolite profiles resulting from supplementation. Leucine, glycine, choline, cysteine, glutathione, trimethylamine N-oxide, and the ratios glycine:serine, 3-hydroxykynurenine:kynurenine, 3-hydroxykynurenine:3-hydroxyanthranilic acid, and 3-hydroxykynurenine:anthranilic acid were significant discriminating variables.ConclusionsConsistent with previous vitamin B-6-restriction studies, fluxes of one-carbon metabolic processes exhibited little or no change after supplementation in low-vitamin B-6 subjects. In contrast, changes in the metabolic profiles after supplementation indicated perturbations in metabolism, suggesting functional vitamin B-6 deficiency. This study was registered at clinicaltrials.gov as NCT01128244.

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Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain.

Publications

Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain.

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