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Dysfunctional lipid metabolism underlies the effect of the perinatal DDT exposure on the development of metabolic syndrome (part II)

ABSTRACT: This study aims to identify changes in lipid mediators in the hypothalamus with triphenyl phosphate (TPP) exposure. UC Davis type 2 diabetes mellitus (UCD-T2DM) rats were treated with TPP (n=8 per group) or not treated (n=8 per group). Each group was analyzed for oxylipin, nitro lipids, endocannabinoid, and endocannabinoid-like monoacylglycerol and N-acylethanolamide changes to investigate alterations in lipid mediator signaling due to TPP exposure. Targeted metabolomic analysis of lipid mediators in rat hypothalamus samples was performed by the Newman lab.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Brain

DISEASE(S): Metabolic Syndrome

SUBMITTER: John Newman

PROVIDER: ST000598 | MetabolomicsWorkbench | Wed Apr 19 00:00:00 BST 2017

REPOSITORIES: MetabolomicsWorkbench

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Project description:By using a 44k chicken Agilent microarray, we systematically analyzed the chicken hypothalamus transcriptome response to thermal stress. Twelve hypothalamus samples were chosen from three groups (four samples per group) to be used in chicken genome microarray to examine differential gene expression.We compared the expression profiles between each pairs of the three groups using the microarray data. Totally, 2474 genes were found to be differentially expressed in the three comparisons with pM-oM-<M-^\0.05 and fold change (FC) higher than 1.5 and the genes were mainly involved in self-regulation and compensation required to maintain homeostasis, including heat shock protein family, enzyme and the hormone, neurotransmitter, cell-cell signaling, metabolism and cytokines. The transcripts of heat shock protein including Hsp 40 and Hsp 90 were significantly changed respond to thermal stress and genes involved in regulation of cell morphogenesis were significantly upregulated in heat stressed group with comparison to control and temperature recovery group. Additionally, the down-regulated genes in both heat stress and temperature recovery groups compared to control group were enriched in muscle organ development, striated muscle tissue development, cardiac muscle tissue development and muscle tissue development, which indicates that muscle development was inhibited during and in short-term after heat treatment. Most of genes dysregulated in heat stress group were found to be recovered in temperature recovery group, which confirmed their roles they could play in coping with heat stress. The present study provides a broader understanding of molecular mechanisms underlying the stress response in chicken and discovery of novel genes that are regulated in a thermal stress specific manner. Hypothalamus samples were collected from non-heat treated group (reared at 25C, used as control), 24h 34C treated group (heat stress treated group) and temperature recovery group (25C for 24h followed heat stress).

Project description:N-nitroso compounds (NOC) may be implicated in human colon carcinogenesis, but the toxicological mechanisms involved have not been elucidated. Since it was previously demonstrated that nitrosamines and nitrosamides, representing two classes of NOC, induce distinct gene expression effects in colon cells that are particularly related to oxidative stress, we hypothesized that different radical mechanisms are involved. Using ESR spectroscopy, we investigated radical generating properties of genotoxic NOC concentrations in human colon adenocarcinoma cells (Caco-2). Cells were exposed to nitrosamides (N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosurea) or nitrosamines (N-nitrosodiethylamine, N-nitrosodimethylamine, N-nitrosopiperidine, N-nitrosopyrrolidine). Nitrosamines caused formation of reactive oxygen species (ROS) and carbon centered radicals which was further stimulated in presence of Caco-2 cells. N-methyl-N-nitrosurea exposure resulted in a small ROS signal, and formation of nitrogen centered radicals (NCR), also stimulated by Caco-2 cells. N-methyl-N'-nitro-N-nitrosoguanidine did not cause radical formation at genotoxic concentrations, but at increased exposure levels, both ROS and NCR formation was observed. By associating gene expression patterns with ROS formation, several cellular processes responding to nitrosamine exposure were identified, including apoptosis, cell cycle blockage, DNA repair and oxidative stress. These findings suggest that following NOC exposure in Caco-2 cells, ROS formation plays an important role in deregulation of gene expression patterns which may be relevant for the process of chemical carcinogenesis in the human colon, in addition to the role of DNA alkylation. Keywords: Nitrosamines, nitrosamides, N-nitroso compounds, free radicals, toxicogenomics, colon carcinogenesis The study investigated differential gene expression in Caco-2 cell line mRNA following 1, 6 or 24 hours of exposure to six different N-nitroso compounds. Two biological replicates per sample compound. One compound per array, hybridized against vehicle control. Dye-swap between biological replicates.

Project description:Purpose: The purpose of this study was to identify cigarette smoke (CS) induced changes in circulatory microRNA (miRNA) in the plasma and ocular fluids of the Rhesus macaque and compare them to normal age-related changes, with the ultimate goal to develop an animal model of early dry age-related macular degeneration (AMD). AMD is a blinding disease having both genetic and environmental components, with cigarette smoke exposure (CS) as the leading environmental risk factor. Methods: All Rhesus macaques were housed at the California National Primate Research Center (CNPRC) at UC Davis. We used 6 animals of the same gender per group: Group 1 (young, 2-4 years old), Group 2 (old, 20-25 years old), Group 3 (middle aged, 9-12 years old) and Group 4 (9-12 years old, exposed to smoke for 1 month). Group 4 macaques were clinically assessed prior to and following CS exposure. Ocular fluids and plasma samples were collected, miRNA isolated, and expression data obtained from Affymetrix miRNA GeneTitan Array Plates 4.0, followed by bioinformatics analysis on Affymetrix Expression Console (EC) and Transcriptome Analysis Software (TAS), and using ANOVA. Results: Statistically significant changes were seen in miRNA populations in ocular fluids and plasma. In the plasma samples, 45 miRNAs were strongly upregulated (Fold Change >+/-1.5, p<0.05) upon CS exposure, while in aging monkeys different miRNAs in plasma were affected, and downregulated. In the vitreous, 3 miRNAs were downregulated in animals exposed to CS, intriguing enough two of them (miR-6794 and miR-6790) were the same ones downregulated with age. Retinal imaging using OCT did not show any significant changes in retinal thickness. Cotinine assays showed that animals received on average dose of 50-60 ng/ml cotinine, a marker for significant CS exposure. Conclusions: One month of CS exposure of Rhesus macaques resulted in significant changes of expression of circulatory miRNAs. We identified several CS related miRNA changes that are plasma or ocular fluid-specific. Healthy aging changes of miRNAs populations were different from the CS exposure induced changes in plasma, while the ones in vitreous were similar. This data will be utilized to develop an animal model of early dry AMD, using a monkey model exposed to CS.

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Dysfunctional lipid metabolism underlies the effect of the perinatal DDT exposure on the development of metabolic syndrome (part II)

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