Molecular and Metabolic Analysis of Arsenic-Exposed Humanized AS3MT Mice
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PROVIDER: PRJNA988520 | ENA |
REPOSITORIES: ENA
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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.
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2009-06-24 | E-GEOD-16772 | biostudies-arrayexpress
Project description:Exposure to high levels of arsenic in drinking water is associated with several types of cancers including lung, bladder and skin, as well as vascular disease and diabetes. Drinking water standards are based primarily on epidemiology and extrapolation from higher dose experiments, rather than measurements of phenotypic changes associated with chronic exposure to levels of arsenic similar to the current standard of 10ppb, and little is known about the difference between arsenic in food as opposed to arsenic in water. Measurement of phenotypic changes at low doses may be confounded by the effect of laboratory diet, in part because of trace amounts of arsenic in standard laboratory chows, but also because of broad metabolic changes in response to the chow itself. Finally, this series contrasts 8hr, 1mg/kg injected arsenic with the various chronic exposures, and also contrasts the acute effects of arsenic, dexamethasone or their combination. Male C57BL/6 mice were fed on two commercially available laboratory diets (LRD-5001 and AIN-76A) were chronically exposed, through drinking water or food, to environmentally relevant concentrations of sodium arsenite, or acutely exposed to dexamethasone. Experiment Overall Design: Male C57BL/6 mice, fed on two commercially available laboratory diets (LRD-5001 and AIN-76A), were chronically exposed through drinking water or food, to environmentally relevant concentrations of sodium arsenite. Another group animals, fed on the AIN 76A diet, was IP injected with dexamethasone (1 mg/kg), sodium arsenite (1mg/kg), both dexamethosone and arsenite, or saline alone.
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Project description:The present study used microarray expression profiling to determine the effects of embryonic arsenic exposure. Fertilized killifish (Fundulus heteroclitus) eggs were exposed to 0, 5, 15, or 25ppm arsenic as sodium arsenite. To examine differentially expressed genes, the microarrays were probed using RNA obtained from the control and 25ppm-exposed killifish just after hatching. No differences were noted in survival or hatching success between any of the groups. After analysis, a set of 332 genes was found to accurately distinguish between the control and 25ppm exposure groups. Expression of several of the genes (CDBP1, Arts1, FetB, and Fbp7) was quantified by qPCR in the lower exposure groups and at earlier time points to examine temporal and dose-responsive expression patterns. These results will enable us to better understand how arsenic impacts development.
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Project description:The present study used microarray expression profiling to determine the effects of embryonic arsenic exposure. Fertilized killifish (Fundulus heteroclitus) eggs were exposed to 0, 5, 15, or 25ppm arsenic as sodium arsenite. To examine differentially expressed genes, the microarrays were probed using RNA obtained from the control and 25ppm-exposed killifish just after hatching. No differences were noted in survival or hatching success between any of the groups. After analysis, a set of 332 genes was found to accurately distinguish between the control and 25ppm exposure groups. Expression of several of the genes (CDBP1, Arts1, FetB, and Fbp7) was quantified by qPCR in the lower exposure groups and at earlier time points to examine temporal and dose-responsive expression patterns. These results will enable us to better understand how arsenic impacts development. Killifish eggs were fertilized, divided into petri dishes containing 40 eggs (n=10 replicate petri dishes), and cultured until hatch in 0 or 25 ppm arsenic as sodium arsenite. Four to five hatchlings within each petri dish were pooled to obtain RNA. A total of 20 arrays were probed, 10 with RNA from control fish and 10 with RNA from the arsenic-exposed fish.
2011-07-31 | E-GEOD-29976 | biostudies-arrayexpress
Project description:Human bronchial epithelial cell BEAS-2B cells were continuously exposed to a vehicel control (DMSO), arsenic (NaAsO2, 1 uM), BaP (2.5 um) alone or arsenic plus BaP for 30 weeks. At the end of exposure, cells were collected and total RNA was extracted for microarray analysis.
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