2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters Hepatic Polyunsaturated Fatty Acid Metabolism and Eicosanoid Biosynthesis in Female Sprague-Dawley Rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE110294 | GEO | 2018/12/01
REPOSITORIES: GEO
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Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist that elicits a broad spectrum of dose-dependent hepatic effects including lipid accumulation, inflammation, and fibrosis. To determine the role of inflammatory lipid mediators in TCDD-mediated hepatotoxicity, eicosanoid metabolism was investigated. Female Sprague-Dawley (SD) rats were orally gavaged with sesame oil vehicle or 0.01-10 μg/kg TCDD every 4 days for 28 days. Hepatic RNA-Seq data was integrated with untargeted metabolomics of liver, serum, and urine, revealing dose-dependent changes in linoleic acid (LA) and arachidonic acid (AA) metabolism. TCDD also elicited dose-dependent differential gene expression associated with the cyclooxygenase, lipoxygenase, and cytochrome P450 epoxidation/hydroxylation pathways with corresponding changes in ω-6 (e.g. AA and LA) and ω-3 polyunsaturated fatty acids (PUFAs), as well as associated eicosanoid metabolites. Overall, TCDD increased the ratio of ω-6 to ω-3 PUFAs. Phospholipase A2 (Pla2g12a) was induced consistent with increased AA metabolism, while AA utilization by induced lipoxygenases Alox5 and Alox15 increased leukotrienes (LTs). More specifically, TCDD increased pro-inflammatory eicosanoids including leukotriene LTB4, and LTB3, known to recruit neutrophils to damaged tissue. Dose-response modeling suggests the cytochrome P450 hydroxylase/epoxygenase and lipoxygenase pathways are more sensitive to TCDD than the cyclooxygenase pathway. Hepatic AhR ChIP-Seq analysis found little enrichment within the regulatory regions of differentially expressed genes (DEGs) involved in eicosanoid biosynthesis, suggesting TCDD-elicited dysregulation of eicosanoid metabolism is a downstream effect of AhR activation. Overall, these results suggest alterations in eicosanoid metabolism may play a key role in TCDD-elicited hepatotoxicity associated with the progression of steatosis to steatohepatitis.
| S-EPMC7294678 | biostudies-literature
Project description: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.
2018-12-01 | GSE110293 | GEO
Project description: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.
2018-12-01 | GSE110282 | GEO
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters Hepatic Polyunsaturated Fatty Acid Metabolism and Eicosanoid Biosynthesis in Female Sprague-Dawley Rats
| PRJNA433388 | ENA
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters Hepatic Polyunsaturated Fatty Acid Metabolism and Eicosanoid Biosynthesis in Female Sprague-Dawley Rats [RNA-Seq]
| PRJNA433392 | ENA
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters Hepatic Polyunsaturated Fatty Acid Metabolism and Eicosanoid Biosynthesis in Female Sprague-Dawley Rats [ChIP-Seq]
| PRJNA433369 | ENA
Project description:Chronic exposure to 2,3,7,8-tetrachlorodibeno-p-dioxin (TCDD) and related polyhalogenated organic pollutants occurs as a consequence of modern life. Exploring the cellular basis for their action is anticipated to help understand the risk they pose and improve the foundation for their regulation. A basis for the striking change in human keratinocyte colony morphology due to TCDD exposure has been investigated by shotgun proteomics. Concentrating on changes in protein levels among three cell strains has revealed significant decreases in the differentiation markers filaggrin, keratin 1, and keratin 10. EGF treatment in concert with TCDD enhanced the changes in these markers and several other proteins while reducing the levels of certain other proteins. The only protein stimulated by TCDD in all three strains and reversed by EGF in them was vimentin, not previously observed to be in the aryl hydrocarbon receptor response domain. Although TCDD is often proposed to enhance keratinocyte differentiation, proteomic analysis reveals it uncouples the differentiation program and suggests that reduced levels of differentiation marker proteins contribute to the observed excessive stratification it induces.
| S-EPMC4026210 | biostudies-literature
Project description:Previous studies demonstrate that Nrf2, a master regulator of antioxidative responses, is essential in mediating induction of many antioxidative enzymes by acute activation of the AhR. However, the role of Nrf2 in protecting against oxidative stress and DNA damage induced by sustained activation of the AhR remains unknown and was investigated herein. Tissue and blood samples were collected from wild-type (WT) and Nrf2-null mice 21 days after administration of a low-toxic dose (10 ?g/kg ip) of TCDD. Only Nrf2-null mice lost body weight after TCDD treatment; however, blood levels of ALT were not markedly changed in either genotype, indicating a lack of extensive necrosis. Compared to livers of TCDD-treated WT mice, livers of TCDD-treated Nrf2-null mice had: 1) degenerated hepatocytes, lobular inflammation, marked fat accumulation, and higher mRNA expression of inflammatory and fibrotic genes; 2) depletion of glutathione, elevation in lipid peroxidation and marker of DNA damage; 3) attenuated induction of phase-II enzymes Nqo1, Gsta1/2, and Ugt2b35 mRNAs, but higher induction of cytoprotective Ho-1, Prdx1, Trxr1, Gclc, and Epxh1 mRNAs; 4) higher mRNA expression of Fgf21 and triglyceride-synthesis genes, but down-regulation of bile-acid-synthesis genes and cholesterol-efflux transporters; and 5) trend of induction/activation of c-jun and NF-kB. Additionally, TCDD-treated Nrf2-null mice had impaired adipogenesis in white adipose tissue. In conclusion, Nrf2 protects livers of mice against oxidative stress, DNA damage, and steatohepatitis induced by TCDD-mediated sustained activation of the AhR. The aggravated hepatosteatosis in TCDD-treated Nrf2-null mice is due to increased lipogenesis in liver and impaired lipogenesis in white adipose tissue.
| S-EPMC3183285 | biostudies-literature
Project description:2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 µg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1. Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci (bsh, baiCD) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters (Slc10a2, Slc51a) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression (Slco1a1, Slc10a1, Slco2b1, Slco1b2, Slco1a4) and hepatocyte-to-blood transporter induction (Abcc4, Abcc3). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity.
| S-EPMC5517430 | biostudies-literature
Project description:Exposure to dioxins results in a broad range of pathophysiological disorders in human fetuses. In order to evaluate the effects of dioxins on the feto-placental tissues, we analyzed the gene expression in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated primary cultures of human amniotic epithelial cells.Human amniotic epithelial cells were dispersed by trypsin from amniotic membranes and cultured in DME/Ham's F12 medium supplemented with 10% FBS. Two weeks after plating, cells were treated with 50 nM TCDD or DMSO (control), further incubated for 48 hrs, and the gene expression was analyzed by DNA microarray technology and quantitative real-time PCR.Thirty eight TCDD-inducible genes, including cytochromeP4501A1 and cytochromeP4501B1, were identified. One of the remarkable profiles of the gene expression was the prominent up-regulation of interferon-inducible genes. The genes involved in the interferon gene expression and interferon signaling pathways were also up-regulated. Furthermore, the expression of genes related to collagen synthesis or degradation was enhanced by TCDD.Using DNA microarray and quantitative real-time PCR analyses, we identified TCDD-inducible genes, including interferon-inducible genes and genes related to collagen synthesis or degradation, in human amniotic epithelial cells.
| S-EPMC1557667 | biostudies-literature