Arsenic exposure induces enterocyte lipid accumulation, resulting in the accelerated tissue growth and maturation during the suckling period
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE202602 | GEO | 2022/11/30
REPOSITORIES: GEO
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Project description:Inorganic arsenic, a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 M-oM-^AM--M), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs We used human lymphoblastoid cell line (CL-1), immortalized with Epstein-Barr virus. Cell cultures were propagated in RPMI media supplemented with 10% fetal bovine serum (FBS), L-glutammine 2 mM and antiobiotics penicillin and 10 mg/ml streptomycin) at 37M-BM-:C in an atmosphere of 5% CO2. In the case of primary cultures, 1% phytohemaglutinine were added. Cell cultures (1x106) were treated with 5M-BM-5M sodium arsenite for 2 and 12 hrs while control cultures were incubated with PBS. Nine biological replicates for each condition were used for microarray analysis. After iAs treatment, total RNA from each biological replicate was isolated with Trizol. From the 9 biological replicates performed on each condition, we generated 3 pools at a concentration of 300 ng/M-BM-5L, where each pool was processed to a single microarray platform.
2013-10-24 | E-GEOD-51454 | biostudies-arrayexpress
Project description:Emerging knowledge shows the importance of early life events in programming the intestinal mucosal immune system and development of the intestinal barrier function. These processes depend heavily on close interactions between gut microbiota and host cells in the intestinal mucosa. In turn, development of the intestinal microbiota is largely dependent on available nutrients and substrates required for the specific microbial community structures to expand. It is currently not known what the specificities are of intestinal microbial community structures in relation to the programming of the intestinal mucosal immune system and development of the intestinal barrier function. The objective of the present study was to investigate the effect of a nutritional intervention on intestinal development of suckling piglets by daily oral administration of fructooligosaccharides (FOS) over a period of 12 days. At the microbiota community level a clear “bifidogenic” effect of the FOS administration was observed in colon digesta at day 14. The former, however, did not translate into significant changes of local gene expression in the colonic mucosa. In the jejunum, significant changes were observed for microbiota composition at day 14, and microbiota diversity at day 25. In addition, significant differentially expressed gene sets in mucosal tissues of jejunum were identified at both days 14 and 25 of age. At the age of 14 days, lower activity of cell cycle-related processes and a higher activity of extracellular matrix processes were observed in jejunal scrapings of piglets supplemented with FOS compared to control piglets. At day 25, lower activity of immune-related processes in jejunal tissue were seen in piglets supplemented with FOS. Histological parameters, villi height and crypt depth, were significantly different at day 25 between the experimental and control group, where piglets supplemented with FOS had higher villi and deeper crypts. We conclude that oral FOS administration during the suckling period of piglets has significant bifidogenic effects on the microbiota in the colon and on gene expression in jejunal mucosa scrapings. We hypothesize that FOS supplementation of suckling piglets results in a higher butyrate production in the colon due to the increase in bifidobacteria and lactobacilli in the hindgut. We further speculate that a higher butyrate production in colonic digesta relates to changes in gene expression in the jejunum by thus far unknown mechanisms.
2018-01-29 | GSE101147 | GEO
Project description:Inorganic arsenic, a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 M), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs
2013-10-24 | GSE51454 | GEO
Project description:Transcriptional profiling of 25d old piglets comparing control untreated suckling jejunum with weaned piglets' jejunum. The goal was to gain new insight into the interaction between weaning and intestinal function.A keen interest is paid in deciphering expression changes of apoptosis or cell cycle control genes. The statistical analysis of gene ontology revealed that most of these altered genes are metabolic-related enzymes and regulators which may involved in the biological regulation, developmental process, and cellular process. Weaning also causes alterations in various immune response pathways. Results likely indicate that weaning induced cell cycle arrest, enhanced apoptosis, and inhibited cell proliferation. Two-condition experiment, suckling control piglets' jejunum vs. weaned piglets' jejunum. Biological replicates: 4 control replicates, 4 weaned replicates.
2014-05-01 | E-GEOD-48050 | biostudies-arrayexpress
Project description:Diabetes is a metabolic disorder characterized by fasting hyperglycemia and impaired glucose tolerance. Laboratory and population studies have shown that inorganic arsenic (iAs) can impair these pathways. Other metals including cadmium (Cd) and manganese (Mn) have also been linked to diabetes phenotypes. MicroRNAs, short non-coding RNAs that regulate gene expression, have emerged as potential drivers of metabolic dysfunction. MicroRNAs responsive to metal exposures in vitro have also been reported in independent studies to regulate insulin secretion in vivo. We hypothesize that microRNA dysregulation may associate with and possibly contribute to insulin secretion impairment upon exposure to iAs, Cd, or Mn. We exposed insulin secreting rat insulinoma cells to non-cytotoxic concentrations of iAs (1 µM), Cd (5 µM), and Mn (25 µM) for 24 h followed by small RNA sequencing to identify dysregulated microRNAs. RNA sequencing was then performed to further investigate changes in gene expression caused by iAs exposure. While all three metals significantly inhibited glucose-stimulated insulin secretion, high-throughput sequencing revealed distinct microRNA profiles specific to each exposure. One of the most significantly upregulated microRNAs post-iAs treatment is miR-146a (~ + 2-fold), which is known to be activated by nuclear factor κB (NF-κB) signaling. Accordingly, we found by RNA-seq analysis that genes upregulated by iAs exposure are enriched in the NF-κB signaling pathway and genes down-regulated by iAs exposure are enriched in miR-146a binding sites and are involved in regulating beta cell function. Notably, iAs exposure caused a significant decrease in the expression of Camk2a, a calcium-dependent protein kinase that regulates insulin secretion, has been implicated in type 2 diabetes, and is a likely target of miR-146a. Further studies are needed to elucidate potential interactions among NF-kB, miR-146a, and Camk2a in the context of iAs exposure.
2020-05-21 | GSE131544 | GEO
Project description:There is strong epidemiologic evidence supporting that exposure to inorganic arsenic (iAs) exposure is responsible for a myriad of adverse health effects, including carcinogenesis of the bladder. This research aimed to identify novel epigenetic biomarkers of iAs exposure in target cells within a human population. Here we assessed genome-wide, gene-specific promoter DNA methylation levels assessed in exfoliated human bladder uroepithelial cells (BECs) in relationship to BEC iAs, monomethylated As (MMAs), dimethylated As (DMAs), and total As (tAs) concentrations from 46 individuals with varying levels of As exposure in Chihuahua, Mexico. These analyses identified genes with increased methylation associated with BEC iAs(III+V), MMAs(III+V), and tAs(III+V). These genes were enriched for signaling related to metabolic disease and cancer.
2015-06-01 | GSE58499 | GEO
Project description:Background: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new “humanized” mouse model overcomes this limitation. In this study, we leverage this model to study sex differences in the context of iAs exposure. Objectives: The aim of this study iwas to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure. Methods: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic +3 methyl transferase (human AS3MT) 129S6/SvEvTac mice treated with 400 ppb of iAs via drinking water ad libitum. After 1 month, mice were sacrificed and the liver and epididymales gonadal adipose depot were harvested for iAs quantification as well as sequencing-based microRNA and gene expression analysis. Serum blood was collected for fasting blood glucose, fasting plasma insulin, and HOMA-IR. Results: We detected sex divergence in liver and adipose markers of diabetes (e.g., insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) male mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice. Discussion: Our study underscoreds the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings also suggest suggested that humanized females are protected from metabolic dysfunction relative to humanized males in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence, including the potential role of miR-34a and/or Klf11.
2023-07-03 | GSE236059 | GEO
Project description:In this study, we examined the effect of inorganic arsenic (iAs) on the estrogen response (E2) in MCF-7 cells that are estrogen receptor positive/progesterone receptor positive (ER+/PR+). Understanding the changes in the transcriptomic response after iAs exposure and the retention of such responses during recovery from iAs exposure can identify driver mechanisms of breast cancer progression and improve therapies for patients with ER+ cancers exposed to iAs.
2020-10-21 | E-MTAB-9498 | biostudies-arrayexpress
Project description:Inorganic arsenic (iAs) is a widespread environmental toxin. In addition to being a human carcinogen, its effect on systemic glucose metabolism has started to gain recognition recently. However, its in vivo effect on insulin sensitivity is not clear. Here we use mouse models to dissect the dose-dependent effects of iAs in glucose metabolism. We found that a low-dose exposure (0.25 ppm iAs in drinking water) caused glucose intolerance in adult male C57BL/6 mice, likely by disrupting glucose-induced insulin secretion without affecting peripheral insulin sensitivity. However, a higher-dose exposure (2.5 ppm iAs) has diminished effects on glucose tolerance despite disrupted pancreatic insulin secretion. We performed hyperinsulinemic euglycemic clamp, the gold standard analysis of systemic insulin sensitivity, and found that the 2.5 ppm iAs enhanced systemic insulin sensitivity by simultaneously enhancing insulin-stimulated glucose uptake in skeletal muscles and insulin-mediated suppression of endogenous glucose production. RNA-seq analysis of muscles revealed that 2.5 ppm iAs regulated expression of many genes involved in the metabolism of fatty acids, pyruvate, and amino acids. These findings suggest that iAs has distinct effects on distinct metabolic tissues at different dose thresholds, which could help reconcile some of the conflicting epidemiological results. The study shed light on the complex interactions between an environmental factor and the systemic glucose metabolism.
2018-11-16 | GSE122566 | GEO
Project description:In the present study a 44k oligonucleotide salmonid microarray, qPCR and histology were used to investigate transcriptomic responses in the distal intestine during the first week of oral exposure to soybean meal in order to gain insight into early molecular response mechanisms. Intestinal tissue samples were taken on day one, two, three, five and seven after introduction of a soybean-containing diet and compared to a control group fed fishmeal. Day 1, day 2, day 3, day 5 and day 7 (n=10 per condition) post-soybean meal feeding Atlantic salmon hybridized to common reference and compared against control (day 0 of SBM feeding). Tissue = distal intestine.
2012-12-17 | E-GEOD-37457 | biostudies-arrayexpress