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Maternal high-fat (HF) diets during gestation and lactation have been shown to contribute to metabolic disorders in offspring. Molecular and epigenetic mechanisms underlying this connection may be essential for the prevention and treatment of the fetal origins of metabolic diseases. The current study examined the impact of maternal HF diets on Wnt signaling and histone modification in offspring. Time-pregnant Sprague-Dawley rats were fed either control diet or HF diet during gestation and lactation and then the neonatal offspring of both groups were investigated. The neonatal offspring born to dams fed on HF diets exhibited increases in serum glucose and liver triglyceride levels. Maternal exposure to the HF diet also repressed the mRNA expression of Wnt1 and nuclear b-catenin protein in the liver of offspring. The altered Wnt1 gene expression may be due to the changes of acetylation of H4 at its promoter as well as acetylation of H4 and methylation of H3K9 at coding region. Maternal exposure to the HF diet induced suppression of the Wnt/b-catenin signaling pathway through histone modification, potentially increasing the risk of metabolic syndrome.

Maternal exposure to environmental agents throughout pregnancy may change certain metabolic processes during the offspring's mammary gland development and alter the epigenome. This may predispose the offspring to breast cancer later in life. The purpose of the present study was to examine the effect of maternal protein restriction on the regulation of cyclin-dependent kinase inhibitor 1 (p21) gene expression in the mammary gland of rat offspring. Timed-mated Sprague -Dawley rats were fed one of the two isoenergetic diets, control (C, 18 % casein) or low protein (LP, 9 % casein), during gestation. Compared with the C group, LP offspring showed a decrease of p21 in the mammary gland at both the mRNA and protein levels. Chromatin immunoprecipitation assay demonstrated that the down-regulation of p21 transcription in LP offspring was associated with reduced acetylation of histone H3 and dimethylation of H3K4 within the p21 promoter region, but was not associated with acetylation of histone H4 or histone methylation. DNA methylation analysis using bisulphite sequencing did not detect differences in methylation at the p21 promoter between the offspring of the C and LP groups. We conclude that maternal protein restriction inhibits p21 gene expression in the mammary gland of offspring through histone modifications at the promoter region of the p21 gene.

Genetic, dietary, and inflammatory factors contribute to the etiology of major mood disorders (MMD), thus impeding the identification of specific biomarkers to assist in diagnosis and treatment. We tested association of vitamin D and inflammatory markers in 36 adolescents with bipolar disorder (BD) and major depressive disorder (MDD) forms of MMD and without MMD (non-mood control). We also assessed the overall level of inflammation using a cell-based reporter assay for nuclear factor kappa-B (NFκB) activation and measuring antibodies to oxidized LDL. We found that these factors were similar between non-mood and MMD youth. To identify potential biomarkers, we developed a screening immunoprecipitation-sequencing approach based on inflammatory brain glia maturation factor beta (GMFβ). We discovered that a homolog of GMFβ in human plasma is vitamin D-binding protein (DBP) and validated this finding using immunoprecipitation with anti-DBP antibodies and mass spectrometry/sequencing analysis. We quantified DBP levels in participants by western blot. DBP levels in BD participants were significantly higher (136%) than in participants without MMD (100%). The increase in DBP levels in MDD participants (121.1%) was not statistically different from these groups. The DBP responds early to cellular damage by binding of structural proteins and activating inflammatory cells. A product of enzymatic cleavage of DBP has been described as macrophage-activating factor. Circulating DBP is comprised of heterogenous high and low molecular fractions that are only partially recognized by mono- and polyclonal ELISA and are not suitable for the quantitative comparison of DBP in non-mood and MDD participants. Our data suggest DBP as a marker candidate of BD warranting its validation in a larger cohort of adolescent and adult MMD patients.

To prospectively examine intakes of folate, vitamin B 6 , and vitamin B 12 in relation to diabetes incidence in a large U.S. cohort. RESEARCH DESIGN AND METHODSA total of 4,704 American adults aged 18-30 years and without diabetes were enrolled in 1985-1986 and monitored until 2015-2016 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Dietary assessment was conducted by a validated dietary history questionnaire at baseline, in 1992-1993, and in 2005-2006. The cumulative average intakes of folate, vitamin B 6 , and vitamin B 12 were used in the analyses. Incident diabetes was ascertained by plasma glucose levels, oral glucose tolerance tests, hemoglobin A 1c concentrations, and/or antidiabetic medications. RESULTSDuring 30 years (mean 20.5 6 8.9) of follow-up, 655 incident cases of diabetes occurred. Intake of folate, but not vitamin B 6 or vitamin B 12 , was inversely associated with diabetes incidence after adjustment for potential confounders. Compared with the lowest quintile of total folate intake, the multivariable-adjusted hazard ratios (95% CI) in quintiles 2-5 were 0.85 (0.67-1.08), 0.78 (0.60-1.02), 0.82 (0.62-1.09), and 0.70 (0.51-0.97; P trend 5 0.02). Higher folate intake was also associated with lower plasma homocysteine (P trend < 0.01) and insulin (P trend < 0.01). Among supplement users, folate intake was inversely associated with serum C-reactive protein levels (P trend < 0.01). CONCLUSIONSIntake of folate in young adulthood was inversely associated with diabetes incidence in midlife among Americans. The observed association may be partially explained by mechanisms related to homocysteine level, insulin sensitivity, and systemic inflammation.The high prevalence of type 2 diabetes mellitus (T2DM) is a severe public health concern worldwide (1). Hyperhomocysteinemia has emerged as a risk factor for T2DM due to its association with insulin resistance (IR) (2). Hyperhomocysteinemia may be caused by genetic defects (3), renal dysfunction (3), or dietary factors, including low intakes of folate, vitamin B 6 , and B 12 (4). These B vitamins play a pivotal role in homocysteine (Hcy) degradation by acting as a prerequisite substrate donor (folate) or

BackgroundRecent studies have shown that vitamin D deficiency may contribute to the high prevalence of food allergy but the underlying mechanisms are far from clear.ObjectiveThe present study was designed to investigate the effect of maternal and early-life vitamin D deficiency in the development of food allergy.DesignBALB/c mice were treated with ovalbumin (OVA) to trigger allergic reactions, under vitamin D-deficient (by maternal and early-life feeding of vitamin D deprived chow diet) or vitamin D-sufficient conditions.ResultsIncreased occurrence and severity of allergic diarrhea as well as decreased rectal temperature were observed after OVA sensitization. For vitamin D deficiency groups, OVA-specific IgE and IL-4 levels were significantly increased, while IFN-γ levels were unchanged. Vitamin D deficiency also attenuated the structure of small intestinal villi and decreased the expression of the tight junction protein between adjacent epithelial cells and the percentages of CD4+CD25+Foxp3+Treg cell in spleen and mesenteric lymph nodes.ConclusionsMaternal and early-life vitamin D deficiency have notable influence on the susceptibility to food allergy, which may relate with the reduced population of Treg cell and the dysfunction of intestinal epithelial barrier.

Some studies suggest a positive association between arsenic exposure and risk of diabetes. However, the findings are inconsistent and inconclusive, particularly at a low to moderate arsenic exposure level, and longitudinal data are lacking. We examined toenail arsenic at low to moderate level in young adulthood in relation to incidence of diabetes later in life. This study included 4,102 black and white participants aged 20-32 at baseline (1987-88) who completed up to 7 follow-up exams through 2015-16. Toenail arsenic was measured by collision-cell inductively-coupledplasma mass-spectrometry. Incident diabetes was defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, 2-hour postchallenge glucose ≥200 mg/dL, hemoglobin A1c ≥6.5%, or use of glucose-lowering medications. Cox proportional hazards model and generalized estimating equations (GEEs) were used to determine the associations of quintiles of toenail arsenic with incident diabetes and other metabolic parameters. The median (inter-quartile range) toenail