Tumorigenic carryover effects of early life exposure to dichloroacetic acid in male B6C3F1 mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Susan Hester
PROVIDER: E-GEOD-58585 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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: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:Genetic analysis of women from the Andes Mountains that are exposed to arsenic in drinking water.
| EGAS00001001168 | EGA
Project description:Colorectal cancer (CRC) was induced in Foxp3/eGFP reporter mice by the azoxymethane/dextran sulphate sodium salt (AOM/DSS) protocol. Mice were injected i.p. with the procarcinogen AOM (12.5 mg/kg of body weight). After 1 week, mice received drinking water supplemented with 2.5% DSS for 5 to 7 days, followed by 2 weeks of regular water. The DSS administration was repeated twice with 2% DSS. Mice were sacrificed at week 11 and lamina propia lymphocytes (LPLs) from the colon were isolated. CD4+FOXP3+ (eGFP+) ST2+ or ST2- Tregs were separated from colonic LPLs of CRC induced mice using a FACSAria II cell sorter. Microarray analysis was performed to analyze if ST2+ FOXP3+ Tregs from the colon of CRC mice present a distinct transcription pattern compared to ST2- FOXP3+ Tregs. By this, the role of ST2 for Treg function during intestinal tumorigenesis should be characterized.
2019-05-31 | E-MTAB-6842 | biostudies-arrayexpress
Project description:Perfluoroalkyl acid carboxylates and sulfonates (PFAAs) have many consumer and industrial applications. The persistence and widespread distribution of these compounds in humans have brought them under intense scrutiny. Limited pharmacokinetic data is available in humans; however, human data exists for two communities with drinking water contaminated by PFAAs. Also, there is toxicological and pharmacokinetic data for monkeys, which can be quite useful for cross-species extrapolation to humans. The goal of this research was to develop a physiologically-based pharmacokinetic (PBPK) model for PFOA and PFOS for monkeys and then scale this model to humans in order to describe available human drinking water data. The monkey model simulations were consistent with available PK data for monkeys. The monkey model was then extrapolated to the human and then used to successfully simulate the data collected from residents of two communities exposed to PFOA in drinking water. Human PFOS data is minimal; however, using the half-life estimated from occupational exposure, our model exhibits reasonable agreement with the available human serum PFOS data. It is envisioned that our PBPK model will be useful in supporting human health risk assessments for PFOA and PFOS by aiding in understanding of human pharmacokinetics.
Model is encoded by Ruby and submitted to BioModels by Ahmad Zyoud
2020-03-20 | MODEL2003190002 | BioModels
Project description:Liver RNA samples from C57BL6 mice drinking Hydrogen water for 4 weeks We used microarrays to detail the gene expression after drinking hydrogen water.
2017-09-19 | GSE103941 | GEO
Project description:To induce tumorigenesis in the esophagus, 100 mg/mL of the water-soluble carcinogen 4NQO (Sigma-Aldrich) was added to the drinking water of 6-week-old mice for 16 weeks. The mice were sacrificed when body weight loss >1/3; otherwise, they were sacrificed 12 weeks after completion of 4NQO treatment.Total RNA from murine esophageal squamous cell carcinoma (Ptpro-/- vs. Ptpro+/+, N=3/group) was extracted and purified, transcriptome profiles were generated by deep sequencing, using Illumina HiSeq 2500 sequencer.
2018-10-02 | GSE120688 | GEO
Project description:In utero exposure to arsenic via drinking water increases the risk of lower respiratory tract infections during infancy and mortality from bronchiectasis in adulthood. Pregnant mice were exposed to arsenic, and gene expression patterns were profiled in peripheral lung tissue obtained from the offspring at 2 weeks of age. Pregnant Mice (BALB/c, C57BL/6, C3H/HeARC) mice were exposed to arsenic (or control) via drinking water from day 8 of gestation until the birth of their offspring. After giving birth, mothers were given control drinking water. At 2 weeks post-natal age, total RNA was extracted from peripheral lung tissue of the offspring and analysed on Affymetrix microarrays.
2013-06-04 | E-GEOD-37831 | biostudies-arrayexpress