Toxicogenomic profiling of trout tumor promoters
Ontology highlight
ABSTRACT:
ORGANISM(S): Salmo salar Oncorhynchus mykiss
PROVIDER: GSE3324 | GEO | 2005/09/28
SECONDARY ACCESSION(S): PRJNA93221
REPOSITORIES: GEO
Similar Datasets
Project description:Indole-3-carbinol (I3C) and 3,3’-diindolylmethane (DIM), a primary I3C derivative in vivo, are known dietary chemopreventive agents also available as dietary supplements. However, I3C has been found to act as a tumor promoter in rat (multi-organ) and trout (liver) models. I3C and DIM were previously found to be estrogenic in trout liver based on toxicogenomic profiles. In this study, we compare the post-initiation effects of DIM and 17β-estradiol (E2) on aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in trout. Trout were initiated as embryos with 50 ppb AFB1, fed control diet for three months followed by diets containing 0, 120 or 400 ppm DIM or 5 ppm E2 for 18 weeks before returning all groups to control diet. Tumor incidence was determined 13 months later and found to be significantly elevated in AFB1-initiated trout fed either 400 ppm DIM or 5 ppm E2 compared to control animals. To evaluate the mechanism of tumor enhancement, hepatic gene expression profiles were examined in animals fed promotional diets during the course of tumorigenesis and in hepatocellular carcinomas (HCCs) of initiated animals using a rainbow trout 70-mer custom oligonucleotide array. We demonstrate that DIM alters gene expression profiles similar to E2 in liver samples during tumorigenesis and in HCC tumors. Further, HCCs from animals on DIM and E2 promotional diets had a transcriptional signature indicating decreased invasive or metastatic potential compared to HCCs from control animals. Overall, these findings are the first to demonstrate tumor promotion by DIM. They confirm the importance of estrogenic signaling in the mechanism of promotion by dietary indoles in trout liver and indicate a possible dual effect that enhances tumor incidence and decreases potential for metastasis. Keywords: time course
2006-12-31 | GSE5644 | GEO
Project description:Indole-3-carbinol (I3C) and 3,3’-diindolylmethane (DIM), a primary I3C derivative in vivo, are known dietary chemopreventive agents also available as dietary supplements. However, I3C has been found to act as a tumor promoter in rat (multi-organ) and trout (liver) models. I3C and DIM were previously found to be estrogenic in trout liver based on toxicogenomic profiles. In this study, we compare the post-initiation effects of DIM and 17β-estradiol (E2) on aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in trout. Trout were initiated as embryos with 50 ppb AFB1, fed control diet for three months followed by diets containing 0, 120 or 400 ppm DIM or 5 ppm E2 for 18 weeks before returning all groups to control diet. Tumor incidence was determined 13 months later and found to be significantly elevated in AFB1-initiated trout fed either 400 ppm DIM or 5 ppm E2 compared to control animals. To evaluate the mechanism of tumor enhancement, hepatic gene expression profiles were examined in animals fed promotional diets during the course of tumorigenesis and in hepatocellular carcinomas (HCCs) of initiated animals using a rainbow trout 70-mer custom oligonucleotide array. We demonstrate that DIM alters gene expression profiles similar to E2 in liver samples during tumorigenesis and in HCC tumors. Further, HCCs from animals on DIM and E2 promotional diets had a transcriptional signature indicating decreased invasive or metastatic potential compared to HCCs from control animals. Overall, these findings are the first to demonstrate tumor promotion by DIM. They confirm the importance of estrogenic signaling in the mechanism of promotion by dietary indoles in trout liver and indicate a possible dual effect that enhances tumor incidence and decreases potential for metastasis. Keywords: treatment effect
2006-12-31 | GSE5643 | GEO
Project description:Background: Estrogen receptor (ERα) and aryl hydrocarbon receptor (AHR) are two nuclear receptors involved in regulating gene expression. ERα and AHR are regulated by estradiol(E2) and TCDD respectively. They are also regulated by dietary ligands including 3,3´diindolylmethane (DIM) and resveratrol (RES). DIM is an ERα and AHR agonist, while RES is an ERα agonist and AHR antagonist. Few studies have investigated the impact of RES and DIM on ERα and AHR signaling at a genome-wide level. This study assessed ERα and AHR binding and associated gene expression changes after treatment of MCF-7 human breast cancer cells with DIM, RES, E2, TCDD, and E2+TCDD for 1 hour and 6 hours before ChIP and RNA sequencing respectively. Results: 88% and 86% of the ERα bound sites after RES and DIM overlapped with E2 ERα sites. RES and DIM resulted in 577 and 446 differentially expressed genes (DEGs) respectively compared to 866 after E2. 68% and 62.3% of the DEGs after RES and DIM were closest to an ERα binding site. Motif analysis indicated enrichment for AHRE motif among DIM ERα sites but not among E2 or RES ERα sites. Both DIM and E2+TCDD resulted in greater genome wide binding of AHR than TCDD. DIM and E2+TCDD resulted in 10546 and 8904 AHR and ERα co-occupied sites respectively. While co-occupied sites for both enriched for the AHR and ERE motif among others, DIM mediated co-occupied sites enriched for Tcfcp2l1, Tgif1, Gata3 motifs while E2+TCDD mediated ones enriched for the NF1 and Ppara motifs. Overlap of coregulated DEGs after DIM and E2+TCDD indicated 123 were the same among both with 81 and 85 unique coregulated DEGs respectively. Enrichment analysis indicated that more enrichment terms were different than similar for coregulated genes after E2+TCDD and DIM. Conclusions: AHR activation is responsible for DIM mediated reduced regulation of gene expression by ERα relative to E2 and only a subset of the DEG’s after DIM and RES are ERα targets indicating future studies into other transcription factors regulated by DIM and RES are needed for insights into the regulation of gene expression by these ligands.
2023-10-16 | GSE232234 | GEO
Project description:Abstract: Inhibitory crosstalk between estrogen receptor alpha (ERalpha) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signalling. ERalpha and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) respectively. Dietary ligands resveratrol (RES) and 3,3´diindolylmethane (DIM) also activate ERalpha while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome wide targets and AHR and ERalpha regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERalpha as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2 or TCDD alone or E2+TCDD for 1 and 6 hours respectively. ERalpha bound sites after DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERalpha site and 60% of coregulated genes between DIM and E2+TCDD were common. Collectively our data shows that RES and DIM differentially regulate multiple transcriptomic targets via ERalpha and ERalpha/AHR coactivity respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that when both receptors are activated, ERalpha dominates with preferential recruitment of AHR to ERalpha target genes.
2023-10-16 | GSE232233 | GEO
Project description:Inhibitory crosstalk between estrogen receptor alpha (ER alpha ) and aryl hydrocarbon receptor (AHR) regulates 17-estradiol (E2)-dependent breast cancer cell signaling. ER alpha and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,30diindolylmethane (DIM) also activate ER alpha while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and antiinflammatory properties. Studies with genome-wide targets and AHR- and ER alpha-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ER alpha as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ER alpha bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ER alpha site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ER alpha and ER alpha /AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ER alpha dominates with preferential recruitment of AHR to ER alpha target genes.
2023-10-16 | GSE232235 | GEO
Project description:Background: Previously, we reported that perfluorooctanoic acid (PFOA) promotes liver cancer in manner similar to that of 17β-estradiol (E2) in rainbow trout. Also, other perfluoroalkyl acids (PFAAs) are weakly estrogenic in trout and bind the trout liver estrogen receptor (ER). Objectives: The primary objective of this study was to determine whether multiple PFAAs enhance hepatic tumorigenesis in trout, an animal model that represents human insensitivity to peroxisome proliferators. Methods: A two-stage chemical carcinogenesis model was employed in trout to evaluate PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorooctane sulfonate (PFOS) and 8:2 fluorotelomer alcohol (8:2FtOH) as complete carcinogens or promoters of aflatoxin B1 (AFB1)- and/or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced liver cancer. A custom trout DNA microarray was used to assess hepatic transcriptional response to these dietary treatments in comparison to E2 and the classic peroxisome proliferator clofibrate (CLOF). Results: Incidence, multiplicity and size of liver tumors in trout fed diets containing E2, PFOA, PFNA and PFDA were significantly higher compared to AFB1-initiated animals fed control diet, whereas PFOS caused a minor increase in liver tumor incidence. E2 and PFOA also enhanced MNNG-initiated hepatocarcinogenesis. Pearson correlation analyses, unsupervised hierarchical clustering and principal components analyses showed that the hepatic gene expression profiles for E2 and PFOA, PFNA, PFDA and PFOS were overall highly similar, though distinct patterns of gene expression were evident for each treatment, particularly for PFNA. Conclusions: Overall, these data suggest that multiple PFAAs can promote liver cancer and that the mechanism of promotion may be similar to that for E2.
2011-08-02 | GSE31085 | GEO
Project description:Our laboratory observed that indoles (I3C and DIM) suppressed the development of delayed type hypersensitivity (DTH) in mice. Also, we observed differential regulation of regulatory T cells (Tregs) and Th17 cells in mice treated with I3C or DIM. The aim of this experiment was, therefore, to understand the role of I3C or DIM in the regulation of microRNAs (miRs) in immune cells and generation of Tregs and Th17 cells. We also used FICZ, an aryl hydrocarbon receptor (AhR) ligand to understand the role of various ligands in the regulation of Tregs and Th17 cells. To this end, we used draining (inguinal) lymph nodes (LNs) of mice (C57BL/6) with DTH and treated with Vehicle (corn oil, VEH) or I3C or DIM or FICZ. In brief, total RNA including miRs from inguinal LNs were isolated using miRNeasy kit and the protocol of the company was followed (QIAGEN, Valencia, CA). Next, miR arrays were performed at Johns Hopkins University Microarray and Sequencing Core facility using platform.
2019-01-02 | E-MTAB-4076 | biostudies-arrayexpress
Project description:Background: Previously, we reported that perfluorooctanoic acid (PFOA) promotes liver cancer in manner similar to that of 17β-estradiol (E2) in rainbow trout. Also, other perfluoroalkyl acids (PFAAs) are weakly estrogenic in trout and bind the trout liver estrogen receptor (ER). Objectives: The primary objective of this study was to determine whether multiple PFAAs enhance hepatic tumorigenesis in trout, an animal model that represents human insensitivity to peroxisome proliferators. Methods: A two-stage chemical carcinogenesis model was employed in trout to evaluate PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorooctane sulfonate (PFOS) and 8:2 fluorotelomer alcohol (8:2FtOH) as complete carcinogens or promoters of aflatoxin B1 (AFB1)- and/or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced liver cancer. A custom trout DNA microarray was used to assess hepatic transcriptional response to these dietary treatments in comparison to E2 and the classic peroxisome proliferator clofibrate (CLOF). Results: Incidence, multiplicity and size of liver tumors in trout fed diets containing E2, PFOA, PFNA and PFDA were significantly higher compared to AFB1-initiated animals fed control diet, whereas PFOS caused a minor increase in liver tumor incidence. E2 and PFOA also enhanced MNNG-initiated hepatocarcinogenesis. Pearson correlation analyses, unsupervised hierarchical clustering and principal components analyses showed that the hepatic gene expression profiles for E2 and PFOA, PFNA, PFDA and PFOS were overall highly similar, though distinct patterns of gene expression were evident for each treatment, particularly for PFNA. Conclusions: Overall, these data suggest that multiple PFAAs can promote liver cancer and that the mechanism of promotion may be similar to that for E2. A total of 40 samples were analyzed using a a dye-swap, reference sample hybridization protocol. Rainbow trout were exposed to the following experimental treatments via the diet for two weeks (number in parenthesis is assigned group #): (1) Control; (2) 5 mg/kg diet estradiol (E2); (3) 2000 mg/kg diet perfluorooctanoic acid (PFOA); (4) 2000 mg/kg diet perfluorononanoic acid (PFNA); (5) 2000 mg/kg diet perfluorodecanoic acid (PFDA); (6) 200 mg/kg diet perfluorooctane sulfonate; (7) 2000 mg/kg 8:2 fluorotelomer alcohol (FTOH); and (8) 2000 mg/kg diet clofibrate. A total of 40 total hepatic mRNA samples were analyzed using a dye-swap, reference sample hybridization protocol. A reference RNA pool was made by combining equal amounts of RNA from all control RNA samples, with one exception. A separate time-matched reference pool was utilized for group 6 samples (PFOS treatment). Five hybridizations were performed for each treatment group in the following pattern: Replicate A Cy5/Reference Cy3; Replicate A Cy3/Reference Cy 5; Replicate B Cy5/Reference Cy3; Replicate B Cy3/Reference Cy5; Replicate C Cy5/Reference Cy3. Thus, the experiment consisted of three biological replicates, for two of which were replicated technically.
2011-08-01 | E-GEOD-31085 | biostudies-arrayexpress
Project description:These studies aimed to investigate the hepatic transcriptional response of brown trout to the natural estrogen, E2, and the herbicide linuron. We exposed mature male brown trout to three concentrations of each chemical for 4 days and sequenced the hepatic transcriptome of 3 individuals per treatment group in order to determine the global mechanisms of toxicity of these environmental contaminants. We assembled the brown trout transcriptome using a de novo approach. Subsequent differential expression analysis identified a total of 2113 differentially-regulated transcripts in the group exposed to the highest E2 treatment concentration, and 822 differentially-regulated transcripts across all linuron treatments. For E2, differentially-expressed transcripts included those encoding known oestrogen-responsive genes, while regulated processes included those associated with vitellogenesis including lipid metabolism, cellular proliferation and ribosome biogenesis. For linuron, there was a striking down-regulation of transcripts encoding the majority of the enzymes involved in the cholesterol biosynthesis pathway, and also a considerable induction of transcripts involved in cellular stress response including Cyp1a.
2015-05-08 | GSE57490 | GEO
Project description:Perfluorooctanoic acid (PFOA) is a potent hepatocarcinogen and peroxisome proliferator (PP) in rodents. Humans are not susceptible to peroxisome proliferation and are thought to be refractory to carcinogenesis by PFOA and other PPs. However, previous studies with rainbow trout have shown that they are also insensitive to peroxisome proliferation by the PP, dehydroepiandrosterone (DHEA), but are still susceptible to enhanced hepatocarcinogenesis after chronic exposure. In this study, we determined whether PFOA is also a tumor promotor in trout and then examined hepatic gene expression profiles to further investigate possible mechanisms of action. Trout were initiated as fry to the hepatocarcinogen, aflatoxin B1, and then fed 200-1800 ppm PFOA in the diet for 30 weeks. Two structurally diverse PPs, clofibrate (CLOF) and DHEA, were included for comparison. Hepatic gene expression profiles were subsequently examined in animals exposed to similar doses of PFOA, DHEA and CLOF along with 5 ppm 17β-estradiol (E2; a known tumor promotor) in the diet. PFOA (1800 ppm) and DHEA treatments resulted in enhanced liver tumor incidence and multiplicity while CLOF showed no effect. Carcinogenesis seemed independent of peroxisome proliferation as no induction of peroxisomal β-oxidation and catalase activity were observed. Alternately, plasma VTG was elevated in fish fed PFOA and DHEA suggesting that estrogenic mechanisms may play a role. Both tumor promotors, PFOA and DHEA, resulted in strong correlation of transcriptional profiles with E2 by Pearson correlation (R=0.81 and 0.78, respectively). In comparison, CLOF regulated no genes in common with E2. Overall, these data suggest that the tumor promoting activities of DHEA and PFOA in trout are independent of peroxisome proliferation and may involve estrogenic mechanisms. Juvenile trout, 12-18 months old, were fed experimental diets containing 500 or 1800 ppm PFOA, 1800 ppm CLOF, 750 ppm DHEA, 5 ppm E2 or 0.15 % dimethyl sulfoxide vehicle control for 14 days. Liver samples were collected for microarray analysis. Hybridizations were performed using standard reference design with dye-swapping. For each sample, equal amounts of RNA (µg) were pooled from five fish per tank for every treatment (n=3 biological replicates per treatment). cDNA from two of the three biological replicates was dye-swapped and hybridized to two slides as technical replicates (5 arrays per treatment).
2007-08-31 | E-GEOD-7837 | biostudies-arrayexpress