Gene expression during tumor enhancement by 3,3’-diindolylmethane in rainbow trout: Timecourse
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ABSTRACT:
ORGANISM(S): Oncorhynchus mykiss
PROVIDER: GSE5644 | GEO | 2006/12/31
SECONDARY ACCESSION(S): PRJNA104375
REPOSITORIES: GEO
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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:Indole-3-carbinol (I3C), from cruciferous vegetables, has been found to suppress or enhance tumors in several animal models. We previously reported that dietary I3C promotes hepatocarcinogenesis in rainbow trout (Oncorhynchus mykiss) at concentrations that differentially activated estrogen receptor (ER) or aryl hydrocarbon receptor (AhR)-mediated responses based on individual protein biomarkers. In this study, we evaluated the relative importance of these pathways as potential mechanisms for I3C on a global scale. Hepatic gene expression profiles were examined in trout after dietary exposure to 500 and 1500 ppm I3C and 3,3,-diindolylmethane (DIM), a major in vivo component of I3C, and were compared to the transcriptional signatures of two model hepatic tumor promoters; 17beta-estradiol (E2), an ER agonist, and beta-naphthoflavone, an AhR agonist. We demonstrate that I3C and DIM acted similar to E2 at the transcriptional level based on correlation analysis of expression profiles and clustering of gene responses. Of the genes regulated by E2 (fold change >2.0 or <0.50), most genes were regulated similarly by DIM (87-92%) and I3C (71%) suggesting a common mechanism of action. Of interest were upregulated genes associated with signaling pathways for cell growth and proliferation, vitellogenesis, and protein folding, stability and transport. Other genes down-regulated by E2, including those involved in acute-phase immune response, were also down-regulated by DIM and I3C. Gene regulation was confirmed by qRT-PCR and western blot. These data indicate I3C promotes hepatocarcinogenesis through estrogenic mechanisms in trout liver and suggest DIM may be an even more potent hepatic tumor promoter in this model. Keywords: dose response
2005-09-28 | GSE3324 | 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: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
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: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: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. Keywords: treatment effect
2007-08-31 | GSE7837 | GEO
Project description:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and its occurrence is associated with a number of environmental factors including ingestion of the dietary contaminant aflatoxin B1 (AFB1). While etiology of the disease is relatively well defined, the molecular mechanisms of tumorigenesis are poorly understood. In this study, we examined, for the first time, gene expression of AFB1-induced HCC by microarray in the rainbow trout (Oncorhynchus mykiss) tumor model. Carcinogenesis was initiated in trout embryos with 50 ppb AFB1 and 13 months later control livers, tumors and tumor-adjacent liver tissues were isolated from juvenile fish. Global gene expression was determined in histologically confirmed HCCs compared to non-cancerous adjacent tissue and sham-initiated control liver utilizing a rainbow trout oligonucleotide array containing approximately 1500 genes of known or probable relevance to toxicology, comparative immunology, carcinogenesis and stress physiology. We observed distinct gene regulation patterns in HCC compared to non-cancerous tissue including upregulation of genes important for cell cycle control, transcription, cytoskeletal formation and the acute phase response and down regulation of genes involved in drug metabolism, lipid metabolism and retinol metabolism. These gene classes have previously been observed to be important in the regulation of HCC in human and rodent models. Overall, these findings contribute to a better understanding of the mechanism of AFB1-induced hepatocarcinogenesis in the trout model and identify conserved genes important for carcinogenesis in species separated evolutionarily by more than 400 million years. Keywords: other
2005-09-06 | GSE2686 | GEO
Project description:The objective of this study was to identify metabolic regulatory mechanisms affected by choline availability in rainbow trout (Oncorhynchus mykiss) broodstock diets associated with increased offspring growth performance. Three customized diets were formulated to have different levels of choline: (a) 0% choline supplementation (Low Choline: 2065 ppm choline), (b) 0.6% choline supplementation (Medium Choline: 5657 ppm choline), and (c) 1.2% choline supplementation (High Choline: 9248 ppm choline). Six all-female rainbow trout families were fed experimental diets beginning 18 months post-hatch until spawning; their offspring were fed a commercial diet. Experimental broodstock diet did not affect overall choline, fatty acid, or amino acid content in the oocytes (p > 0.05), apart from tyrosine (p ≤ 0.05). Offspring body weights from the High and Low Choline diets did not differ from those in the Medium Choline diet (p > 0.05); however, family-by-diet and sire-by-diet interactions on offspring growth were detected (p ≤ 0.05). The High Choline diet did not improve growth performance in the six broodstock families at final harvest (520-days post-hatch, or dph). Numerous genes associated with muscle development and lipid metabolism were identified, including myosin, troponin C, and fatty acid binding proteins, which were associated with key signaling pathways of lipid metabolism, muscle cell development, muscle cell proliferation, and muscle cell differentiation. These findings indicate that supplementing broodstock diets with choline does regulate expression of genes related to growth and nutrient partitioning but does not lead to growth benefits in rainbow trout families selected for disease resistance.
2024-02-09 | GSE243186 | GEO
Project description:Transcriptome sequencing was used to analyze the changes of related signaling pathways and gene expression in multiple myeloma cells after the addition of T6, F2, I3C and DIM.
2023-10-04 | GSE189309 | GEO