Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA252943 | ENA |
REPOSITORIES: ENA
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Project description:Here we investigated the longterm carryover effects of dichloroacetic acid (DCA), a common by-product of drinking water chlorination, on hepatic tumorigenesis in mice. Our findings demonstrate that postnatal exposure to a common drinking water contaminant results in longterm carryover effects on tumorigenesis, potentially via epigenetic events altering cellular respiration and metabolism. The gene expression study followed a stop-promotion design in which 7d male B6C3F1 mice received the following treatments: deionized water alone (dH2O, control); 0.06% phenobarbital (PB), a rodent liver mitogen and tumor promoter; or DCA (3.5g/L) for 10 weeks followed by dH2O for 90 weeks.
2015-02-26 | E-GEOD-58585 | biostudies-arrayexpress
Project description:Early-life environmental factors can increase later-life susceptibility to cancer. Short-term exposure to dichloroacetic acid (DCA), a trace drinking water contaminant with distinctive metabolic effects, increased liver cancer in mice 84 weeks after exposure was stopped. Here we evaluated time course dynamics for key events related to this latent effect. This study followed a stop-exposure design in which 28-day-old male B6C3F1 mice were given the following treatments in drinking water for up to 93 weeks: deionized water (dH20, control); 3.5 g/l DCA continuously; or 3.5 g/l DCA for 4, 10, 26, or 52 weeks followed by dH20. Effects were evaluated at eight interim time points. A short-term biomarker study was used to evaluate DCA effects at 6, 15, and 30 days. Liver tumor incidence was higher in all DCA treatment groups, including carcinomas in 82% of mice previously treated with DCA for only 4 weeks. Direct effects of DCA in the short-term study included decreased liver cell proliferation and marked mRNA changes related to mitochrondrial dysfunction and altered cell metabolism. All observed short-term effects of DCA were reversible. Prior DCA treatment did not alter liver cell proliferation, apoptosis, necrosis, or DNA sequence variants with age. Key intermediate events resulting from early-life DCA exposure do not fit classical cytotoxic, mitogenic, or genotoxic modes of action for carcinogenesis, suggesting a novel epigenetic mechanism related to metabolic disruption.
2017-12-21 | GSE86065 | GEO
Project description:Mechanistic understanding of transient exposures that lead to adverse health outcomes will enhance our ability to recognize biological signatures of disease. Here, we measured the transcriptomic and epigenomic alterations due to exposure to the metabolic reprogramming agent, dichloroacetic acid (DCA). Previously, we showed that exposure to DCA increased liver cancer in B6C3F1 mice after continuous or early life exposures similarly over background level. Measures from these studies did not support direct cytotoxic, mitogenic, or genotoxic modes-of-action of tumorigenesis. Using archived formalin-fixed liver samples, we utilized modern methodologies to measure gene expression and DNA methylation levels to link to previously generated phenotypic measures. Gene expression was measured by targeted RNA sequencing (TempO-seq 1500+ toxicity panel: 2754 total genes) in liver samples collected from 10-, 32-, 57-, and 78-week old mice exposed to deionized water (controls), DCA continuously at 3.5g/L in drinking water (“Direct” group), or DCA at 3.5g/L for 10-, 32-, or 57-weeks followed by control water (“Stop” groups). Genome-scaled alterations in DNA methylation were measured by Reduced Representation Bisulfite Sequencing (RRBS) at 78-weeks. Transcriptomic changes were most robust with concurrent or adjacent timepoints after exposure stoppage. DNA methylation alterations followed a similar pattern, measuring 2720 and 567 differentially methylated regions (DMRs) in 78-week Direct and 10-week “Stop” DCA exposure groups, respectively. Gene pathway analysis indicated cellular effects linked to increased oxidative metabolism, a primary mechanism of action for DCA, closer to exposure windows especially early in life. Conversely, many gene signatures and pathways reversed patterns later in life and reflected more pro-tumorigenic patterns for both current and prior DCA exposures. DNA methylation patterns linked to early gene pathway perturbations, suggesting persistence in the epigenome and possible regulatory effects. In total, results suggested that liver metabolic reprogramming effects of DCA interact with normal age mechanisms to increase tumor burden with both continuous and prior DCA exposure in the B6C3F1 rodent model.
2024-04-29 | GSE242661 | GEO
Project description:Mechanistic understanding of transient exposures that lead to adverse health outcomes will enhance our ability to recognize biological signatures of disease. Here, we measured the transcriptomic and epigenomic alterations due to exposure to the metabolic reprogramming agent, dichloroacetic acid (DCA). Previously, we showed that exposure to DCA increased liver cancer in B6C3F1 mice after continuous or early life exposures similarly over background level. Measures from these studies did not support direct cytotoxic, mitogenic, or genotoxic modes-of-action of tumorigenesis. Using archived formalin-fixed liver samples, we utilized modern methodologies to measure gene expression and DNA methylation levels to link to previously generated phenotypic measures. Gene expression was measured by targeted RNA sequencing (TempO-seq 1500+ toxicity panel: 2754 total genes) in liver samples collected from 10-, 32-, 57-, and 78-week old mice exposed to deionized water (controls), DCA continuously at 3.5g/L in drinking water (“Direct” group), or DCA at 3.5g/L for 10-, 32-, or 57-weeks followed by control water (“Stop” groups). Genome-scaled alterations in DNA methylation were measured by Reduced Representation Bisulfite Sequencing (RRBS) at 78-weeks. Transcriptomic changes were most robust with concurrent or adjacent timepoints after exposure stoppage. DNA methylation alterations followed a similar pattern, measuring 2720 and 567 differentially methylated regions (DMRs) in 78-week Direct and 10-week “Stop” DCA exposure groups, respectively. Gene pathway analysis indicated cellular effects linked to increased oxidative metabolism, a primary mechanism of action for DCA, closer to exposure windows especially early in life. Conversely, many gene signatures and pathways reversed patterns later in life and reflected more pro-tumorigenic patterns for both current and prior DCA exposures. DNA methylation patterns linked to early gene pathway perturbations, suggesting persistence in the epigenome and possible regulatory effects. In total, results suggested that liver metabolic reprogramming effects of DCA interact with normal age mechanisms to increase tumor burden with both continuous and prior DCA exposure in the B6C3F1 rodent model.
2024-05-30 | GSE242664 | GEO
Project description:Here we investigated the longterm carryover effects of dichloroacetic acid (DCA), a common by-product of drinking water chlorination, on hepatic tumorigenesis in mice. Our findings demonstrate that postnatal exposure to a common drinking water contaminant results in longterm carryover effects on tumorigenesis, potentially via epigenetic events altering cellular respiration and metabolism.
2015-02-26 | GSE58585 | GEO
Project description:Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbed cytokine response and mitigated sepsis when exposed to lipopolysaccharide (LPS) challenge, even after 11-month interval of detraining. Metabolomics analysis of serum and liver identified pipecolic acid (a non-encoded amino acid) as a pivotal metabolite responding to early-life regular exercise. We then explored histone epigenetic modifications and observed a significant increase of H3K4me3 expression in the liver of 15-month-old mice exposed to early-life exercise. To further unravel the prolonged increased pipecplic acid production raised by early-life exercise, we conducted ChIP-seq analysis and found H3K4me3 occupancy at Crym (a key enzyme responsible for catalyzing pipecolic acid production) promoter has a significant increase in hepatocytes of early-life exercised mice. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production plays a pivotal role.
2024-03-12 | GSE255161 | GEO
Project description:Background: Exposure to persistent organic pollutants (POPs) and disruptions in the gastrointestinal microbiota have been positively correlated with a predisposition to factors such as obesity, metabolic syndrome, and type 2 diabetes; however, it is unclear how the microbiome contributes to this relationship.
Objective: This study aimed to explore the association between early-life exposure to a potent aryl hydrocarbon receptor (AHR) agonist and persistent disruptions in the microbiota, leading to impaired metabolic homeostasis later in life.
Methods: This study utilized metagenomics, NMR- and mass spectrometry-based metabolomics, and biochemical assays to analyze the gut microbiome composition and function, as well as the physiological and metabolic effects of early-life exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF), and Ahr-null mice. The impact of TCDF on Akkermansia muciniphila (A. muciniphila) in vitro was assessed using optical density (OD 600), flow cytometry, transcriptomics, and mass spectrometry-based metabolomics.
Results: TCDF-exposed mice exhibited disruption in the gut microbiome community structure and function, characterized by lower abundances of A. muciniphila, lower levels of cecal short chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), and a reduction in gut hormones GLP-1 and PYY. Importantly, microbial and metabolic phenotypes associated with early-life POP exposure were transferable to GF recipients in the absence of POP carry-over. In addition, AHR-independent interactions between POPs and the microbiota were observed, significantly affected the growth, physiology, gene expression, and metabolic activity of A. muciniphila, resulting in suppressed activity along the ILA pathway.
Conclusions: These data point to the complex effects of POPs on the host and microbiota, providing strong evidence that early-life, short-term, and self-limiting POP exposure can adversely impact the microbiome, persisting into later life with associated health implications.
2024-03-29 | MSV000094437 | MassIVE
Project description:In this study, we modeled early life air pollution exposure using C57BL/6J male mice on a controlled chow diet, exposed to real-world inhaled concentrated PM2.5 (~10x ambient level/ ~60-120g/m3) or filtered air (FA) over 14 weeks. We investigated PM2.5 effects on phenotype, transcriptome and chromatin accessibility, compared the effects with a prototypical high-fat diet (HFD) stimulus, and examined the effects of cessation of exposure on reversibility of phenotype/genotype.
2020-11-05 | GSE145840 | GEO
Project description:Early-life exposure to high-fat diet (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by Barnes maze test were observed both in 6-month-old male and female mice. Multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies, that were confirmed by regulon analysis, showing that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.
2024-01-26 | PXD045639 | Pride
Project description:Benzo(a)pyrene is a well-established human carcinogen in humans and rodents. In the present study, we sought to determine the dose- and time-dependent changes in gene expression upon oral exposure to benzo(a)pyrene. Adult male B6C3F1 mice were exposed to four doses of benzo(a)pyrene or vehicle control for three days and sacrificed 4 or 24 hours after the final exposure.
2015-07-01 | GSE43633 | GEO