 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Dec 01, 2018 |
| Title |
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters Hepatic Polyunsaturated Fatty Acid Metabolism and Eicosanoid Biosynthesis in Female Sprague-Dawley Rats [RNA-Seq] |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist that elicits a broad spectrum of dose-dependent effects in the liver, including hepatic lipid accumulation coupled with inflammation. To determine the role of inflammatory lipid mediators in TCDD-mediated hepatotoxicity, eicosanoid metabolism was investigated in female Sprague-Dawley (SD) rats. Rats were gavaged with sesame oil vehicle or 0.01-10 µg/kg TCDD every 4 days for 28 days. Hepatic RNA-Seq data from female SD rats was compared with data from female C57BL/6 mice and functionally annotated to determine key toxicogenomic differences between the two species regarding TCDD exposure. Hepatic RNA-Seq data from female SD rats integrated with untargeted metabolomics of liver, serum, and urine identified dose-dependent changes in linoleic acid (LA) and arachidonic acid (AA) metabolism. TCDD also elicited dose-dependent differential gene expression associated with cyclooxygenase, lipoxygenase, and cytochrome P450 epoxidation/ hydroxylation pathways with corresponding changes in omega-6 (e.g. AA and LA) and omega-3 polyunsaturated fatty acids (PUFAs) as well as their eicosanoid metabolites. Overall, total omega-6 PUFAs increased, while total omega-3 PUFAs decreased. Phospholipase A2 (Pla2g12a) was induced 6-fold consistent with increased AA metabolism, while AA utilization by lipoxygenases Alox5 (2-fold) and Alox15 (10-fold) increased leukotrienes (LTs), important mediators signaling an inflammatory response. More specifically, TCDD increased pro-inflammatory eicosanoids, including leukotriene (LT) B4 (3-fold), and LTB3 (5-fold), known signals for the recruitment of neutrophils to areas of tissue damage. Dose-response modeling of metabolite and gene expression changes suggests the cytochrome P450 hydroxylase/epoxygenase and the lipoxygenase pathways are the most sensitive to TCDD. While several differentially expressed genes (DEGs) associated with eicosanoid biosynthesis contained putative dioxin response elements (pDRE) within their regulatory region, ChIP-Seq analysis showed little AhR enrichment, suggesting TCDD-elicited induction of eicosanoid biosynthesis is not a direct effect of AhR activation.
|
| |
|
| Overall design |
Three biological replicates for rats given dose of sesame oil vehicle or 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 μg/kg.
|
| |
|
| Contributor(s) |
Doskey CM, Nault R, Fader KA, Lydic T, Matthews J, Potter D, Sharratt B, Zacharewski TR |
| Citation(s) |
32387183 |
| Submission date |
Feb 07, 2018 |
| Last update date |
Sep 16, 2020 |
| Contact name |
Timothy Zacharewski |
| E-mail(s) |
tzachare@msu.edu
|
| Phone |
517-355-1607
|
| Organization name |
Michigan State University
|
| Department |
Biochemistry and Molecular Biology
|
| Lab |
Zacharewski
|
| Street address |
1129 Farm Lane
|
| City |
East Lansing |
| State/province |
MI |
| ZIP/Postal code |
48824 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18694 |
Illumina HiSeq 2500 (Rattus norvegicus) |
|
| Samples (24)
|
|
| This SubSeries is part of SuperSeries: |
| GSE110294 |
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters Hepatic Polyunsaturated Fatty Acid Metabolism and Eicosanoid Biosynthesis in Female Sprague-Dawley Rats |
|
| Relations |
| BioProject |
PRJNA433392 |
| SRA |
SRP132387 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE110293_RAW.tar |
2.4 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...