Whole adult organism transcriptional profiling of acute metal exposures in male Zebrafish

BMC Clinical Pharmacology

Jonathan D Stallings⁴  David A Jackson⁶  Danielle L Ippolito¹  Christine E Baer³  John A Lewis⁵  Naissan Hussainzada² 

[1] ORISE, Fort Detrick, Frederick, Maryland 21702-5010, USA;ORISE Postdoctoral Fellow, Ft. Detrick, Frederick, Maryland 21702, USA;Excet Inc., Fort Detrick, Frederick, Maryland 21702-5010, USA;Environmental Health Program, US Army Center for Environmental Health Research, Fort Detrick, Frederick, Maryland, USA;Biomarkers Program, US Army Center for Environmental Health Research, Fort Detrick, Frederick, Maryland 21702-5010, USA;Pulmonary Health Program, US Army Center for Environmental Health Research, Fort Detrick, Frederick, Maryland 21702-5010, USA

关键词: Toxicogenomics;    Cobalt;    Chromium;    Nickel;    Whole organism;    Zebrafish;    Toxicity mechanisms;    Metals;   

Others  :  1228655
DOI  :  10.1186/2050-6511-15-15

 received in 2013-09-26, accepted in 2014-02-27,  发布年份 2014

【 摘 要 】

Background

A convergence of technological breakthroughs in the past decade has facilitated the development of rapid screening tools for biomarkers of toxicant exposure and effect. Platforms using the whole adult organism to evaluate the genome-wide response to toxicants are especially attractive. Recent work demonstrates the feasibility of this approach in vertebrates using the experimentally robust zebrafish model. In the present study, we evaluated gene expression changes in whole adult male zebrafish following an acute 24 hr high dose exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride or sodium dichromate concentrations corresponding to their respective 96 hr LC₂₀, LC₄₀ and LC₆₀. Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal.

Results

Comparative analysis identified subsets of differentially expressed transcripts both overlapping and unique to each metal. Application of gene ontology (GO) and transcription factor (TF) enrichment algorithms revealed a number of key biological processes perturbed by metal poisonings and the master transcriptional regulators mediating gene expression changes. Metal poisoning differentially activated biological processes associated with ribosome biogenesis, proteosomal degradation, and p53 signaling cascades, while repressing oxygen-generating pathways associated with amino acid and lipid metabolism. Despite appreciable effects on gene regulation, nickel poisoning did not induce any morphological alterations in male zebrafish organs and tissues. Histopathological effects of cobalt remained confined to the olfactory system, while chromium targeted the gills, pharynx, and intestinal mucosa. A number of enriched transcription factors mediated the observed gene response to metal poisoning, including known targets such as p53, HIF1α, and the myc oncogene, and novel regulatory factors such as XBP1, GATA6 and HNF3β.

Conclusions

This work uses an experimentally innovative approach to capture global responses to metal poisoning and provides mechanistic insights into metal toxicity.

【 授权许可】

   
2014 Hussainzada et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Hill AJ, Teraoka H, Heideman W, Peterson RE: Zebrafish as a model vertebrate for investigating chemical toxicity. Toxicol Sci 2005, 86(1):6-19.
• [2]Spitsbergen JM, Kent ML: The state of the art of the zebrafish model for toxicology and toxicologic pathology research–advantages and current limitations. Toxicol Pathol 2003, 31(Suppl):62-87.
• [3]Carvan MJ III, Dalton TP, Stuart GW, Nebert DW: Transgenic zebrafish as sentinels for aquatic pollution. Ann N Y Acad Sci 2000, 919:133-147. 133–147
• [4]Carvan MJ III, Sonntag DM, Cmar CB, Cook RS, Curran MA, Miller GL: Oxidative stress in zebrafish cells: potential utility of transgenic zebrafish as a deployable sentinel for site hazard ranking. Sci Total Environ 2001, 274(1–3):183-196.
• [5]Amanuma K, Takeda H, Amanuma H, Aoki Y: Transgenic zebrafish for detecting mutations caused by compounds in aquatic environments. Nat Biotechnol 2000, 18(1):62-65.
• [6]Ng HBG, Lam SH, Sukardi H, Gong Z: Potential applications of transgenic fish to environmental monitoring and toxicology. In Aquaculture Biotechnology. 1st edition. Edited by Fletcher GL, Rise ML. West Sussex: John Wiley & Sons, Ltd; 2012:267-280.
• [7]Reichert K, Menzel R: Expression profiling of five different xenobiotics using a Caenorhabditis elegans whole genome microarray. Chemosphere 2005, 61(2):229-237.
• [8]Ruden DM, Chen L, Possidente D, Possidente B, Rasouli P, Wang L, Lu X, Garfinkel MD, Hirsch HVB, Page GP: Genetical toxicogenomics in Drosophila identifies master-modulatory loci that are regulated by developmental exposure to lead. Neurotoxicology 2009, 30(6):898-914.
• [9]Neumann NF, Galvez F: DNA microarrays and toxicogenomics: applications for ecotoxicology? Biotechnol Adv 2002, 20(5–6):391-419.
• [10]Poynton HC, Varshavsky JR, Chang B, Cavigiolio G, Chan S, Holman PS, Loguinov AV, Bauer DJ, Komachi K, Theil EC: Daphnia magna ecotoxicogenomics provides mechanistic insights into metal toxicity. Environ Sci Technol 2007, 41(3):1044-1050.
• [11]Martyniuk CJ, Houlahan J: Assessing gene network stability and individual variability in the fathead minnow (Pimephales promelas) transcriptome. Comp Biochem Physiol Part D Genomics Proteomics 2013, 8(4):283-291.
• [12]Lam SH, Mathavan S, Tong Y, Li H, Karuturi RKM, Wu Y, Vega VB, Liu ET, Gong Z: Zebrafish whole-adult-organism chemogenomics for large-scale predictive and discovery chemical biology. PLoS Genet 2008, 4(7):e1000121.
• [13]Valko M, Morris H, Cronin MTD: Metals, toxicity and oxidative stress. Curr Med Chem 2005, 12(10):1161-1208.
• [14]Fu H, Boffetta P: Cancer and occupational exposure to inorganic lead compounds - a metaanalysis of published data. Occup Environ Med 1995, 52(2):73-81.
• [15]Steenland K, Loomis D, Shy C, Simonsen N: Review of occupational lung carcinogens. Am J Ind Med 1996, 29(5):474-490.
• [16]Integrated Risk Information System (IRIS) [http://www.epa.gov/iris/ webcite]
• [17]Simmons SO, Fan C-Y, Ramabhadran R: Cellular stress response pathway system as a sentinel ensemble in toxicological screening. Toxicol Sci 2009, 111(2):202-225.
• [18]Beyersmann D, Hechtenberg S: Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol 1997, 144(2):247-261.
• [19]Salnikow K, Zhitkovich A: Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. Chem Res Toxicol 2007, 21(1):28-44.
• [20]Janssens TKS, Roelofs D, van Straalen NM: Molecular mechanisms of heavy metal tolerance and evolution in invertebrates. Insect Science 2009, 16(1):3-18.
• [21]Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005, 102(43):15545-15550.
• [22]Athikesavan S, Vincent S, Ambrose T, Velmurugan B: Nickel induced histopathological changes in the different tissues of freshwater fish, Hypophthalmichthys molitrix (Valenciennes). J Environ Biol 2006, 27(2):391-395.
• [23]Nath K, Kumar N: Nickel-induced histopathological alterations in the gill architecture of a tropical fresh-water perch, colisa-fasciatus (bloch and schn). Sci Total Environ 1989, 80(2–3):293-296.
• [24]Wang H, Tan JT, Emelyanov A, Korzh V, Gong Z: Hepatic and extrahepatic expression of vitellogenin genes in the zebrafish, Danio rerio. Gene 2005, 356:91-100.
• [25]Gong Z, Yan T, Liao J, Lee SE, He J, Hew CL: Rapid identification and isolation of zebrafish cDNA clones. Gene 1997, 201(1–2):87-98.
• [26]Peng X, Wood CL, Blalock EM, Chen KC, Landfield PW, Stromberg AJ: Statistical implications of pooling RNA samples for microarray experiments. BMC Bioinforma 2003, 4:26. BioMed Central Full Text
• [27]Kendziorski C, Irizarry RA, Chen KS, Haag JD, Gould MN: On the utility of pooling biological samples in microarray experiments. Proc Natl Acad Sci U S A 2005, 102(12):4252-4257.
• [28]Kendziorski CM, Zhang Y, Lan H, Attie AD: The efficiency of pooling mRNA in microarray experiments. Biostatistics 2003, 4(3):465-477.
• [29]Zhang SD, Gant TW: A statistical framework for the design of microarray experiments and effective detection of differential gene expression. Bioinformatics 2004, 20(16):2821-2828.
• [30]Chen K, Rajewsky N: The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet 2007, 8(2):93-103.
• [31]Drǎghici S, Khatri P, Martins RP, Ostermeier GC, Krawetz SA: Global functional profiling of gene expression. Genomics 2003, 81(2):98-104.
• [32]Casillas E, Myers M, Ames WE: Relationship of serum chemistry values to liver and kidney histopathology in english sole (Parophrys-vetulus) after acute exposure to carbon-tetrachloride. Aquat Toxicol 1983, 3(1):61-78.
• [33]Ptashynski MD, Klaverkamp JF: Accumulation and distribution of dietary nickel in lake whitefish (Coregonus clupeaformis). Aquat Toxicol 2002, 58(3–4):249-264.
• [34]Ptashynski MD, Pedlar RM, Evans RE, Baron CL, Klaverkamp JF: Toxicology of dietary nickel in lake whitefish (Coregonus clupeaformis). Aquat Toxicol 2002, 58(3–4):229-247.
• [35]Mishra AK, Mohanty B: Chronic exposure to sublethal hexavalent chromium affects organ histopathology and serum cortisol profile of a teleost, Channa punctatus (Bloch). Sci Total Environ 2009, 407(18):5031-5038.
• [36]Parvathi K, Sivakumar P, Sarasu C: Effects of chromium on histological alterations of gill, liver and kidney of fresh water teleost, Cyprinus carpio (L.). J Fisheries Int 2011, 6(1):1-5.
• [37]Bucher JR, Elwell MR, Thompson MB, Chou BJ, Renne R, Ragan HA: Inhalation toxicity studies of cobalt sulfate in F344N rats and B6C3F1 mice. Fundam Appl Toxicol 1990, 15(2):357-372.
• [38]Maines MD, Kappas A: Metals as regulators of heme metabolism. Science 1977, 198(4323):1215-1221.
• [39]Salnikow K, Su W, Blagosklonny MV, Costa M: Carcinogenic metals induce hypoxia-inducible factor-stimulated transcription by reactive oxygen species-independent mechanism. Cancer Res 2000, 60(13):3375-3378.
• [40]Njalsson R, Norgren S: Physiological and pathological aspects of GSH metabolism. Acta Paediatr 2005, 94(2):132-137.
• [41]Koskinen H, Pehkonen P, Vehniainen E, Krasnov A, Rexroad C, Afanasyev S, Molsa H, Oikari A: Response of rainbow trout transcriptome to model chemical contaminants. Biochem Biophys Res Commun 2004, 320(3):745-753.
• [42]Maier MSV, Legare ME, Hanneman WH: The aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl induces distinct patterns of gene expression between hepatoma and glioma cells: chromatin remodeling as a mechanism for selective effects. Neurotoxicology 2007, 28(3):594-612.
• [43]Williams TD, Diab A, Ortega F, Sabine VS, Godfrey RE, Falciani F, Chipman JK, George SG: Transcriptomic responses of European flounder (Platichthys flesus) to model toxicants. Aquat Toxicol 2008, 90(2):83-91.
• [44]Sanchez BC, Carter B, Hammers HR, Sepúlveda MS: Transcriptional response of hepatic largemouth bass (Micropterus salmoides) mRNA upon exposure to environmental contaminants. J Appl Toxicol 2011, 31(2):108-116.
• [45]Romero G, Lasheras B, Sainz Suberviola L, Cenarruzabeitia E: Protective effects of calcium channel blockers in carbon tetrachloride-induced liver toxicity. Life Sci 1994, 55(13):981-990.
• [46]Chung H, Kim H-J, Jang K-S, Kim M, Yang J, Kim JH, Lee Y-S, Kong G: Comprehensive analysis of differential gene expression profiles on diclofenac-induced acute mouse liver injury and recovery. Toxicol Lett 2006, 166(1):77-87.
• [47]Eisler R: Nickel Hazards to Fish, Wildlife, and Invertebrates: A Synoptic Review. Laurel: U.S. Department of the Interior, U.S. Geological Survey, Patuxent Wildlife Research Center; 1998.
• [48]Brix KV, Keithly J, DeForest DK, Laughlin J: Acute and chronic toxicity of nickel to rainbow trout (Oncorhynchus mykiss). Environ Toxicol Chem 2004, 23(9):2221-2228.
• [49]Pane E, Richards J, Wood C: Acute waterborne nickel toxicity in the rainbow trout (Oncorhynchus mykiss) occurs by a respiratory rather than ionoregulatory mechanism. Aquat Toxicol 2003, 63(1):65-82.
• [50]Kubrak OI, Husak VV, Rovenko BM, Storey JM, Storey KB, Lushchak VI: Cobalt-induced oxidative stress in brain, liver and kidney of goldfish Carassius auratus. Chemosphere 2011, 85(6):983-989.
• [51]Zhang Z, Huang CS, Li JX, Leonard SS, Lanciotti R, Butterworth L, Shi XL: Vanadate-induced cell growth regulation and the role of reactive oxygen species. Arch Biochem Biophys 2001, 392(2):311-320.
• [52]Lushchak VI: Environmentally induced oxidative stress in aquatic animals. Aquat Toxicol 2011, 101(1):13-30.
• [53]Koj A: Initiation of acute phase response and synthesis of cytokines. Biochim Biophys Acta 1996, 1317(2):84-94.
• [54]Hütter R, Niederberger P: Biochemical pathways and mechanisms nitrogen, amino acid, and carbon metabolism. Biotechnol Adv 1983, 1(2):179-191.
• [55]Johnson LR, Lichtenberger LM, Copeland EM, Dudrick SJ, Castro GA: Action of gastrin on gastrointestinal structure and function. Gastroenterology 1975, 68(5 Pt 1):1184-1192.
• [56]Bertolo RFP, Chen CZL, Pencharz PB, Ball RO: Intestinal atrophy has a greater impact on nitrogen metabolism than liver by-pass in piglets fed identical diets via gastric, central venous or portal venous routes. J Nutr 1999, 129(5):1045-1052.
• [57]You ZY, Komamura Y, Ishimi Y: Biochemical analysis of the intrinsic Mcm4-Mcm6-Mcm7 DNA helicase activity. Mol Cell Biol 1999, 19(12):8003-8015.
• [58]Madine MA, Swietlik M, Pelizon C, Romanowski P, Mills AD, Laskey RA: The roles of the MCM, ORC, and Cdc6 proteins in determining the replication competence of chromatin in quiescent cells. J Struct Biol 2000, 129(2–3):198-210.
• [59]Musahl C, Holthoff HP, Lesch R, Knippers R: Stability of the replicative Mcm3 protein in proliferating and differentiating human cells. Exp Cell Res 1998, 241(1):260-264.
• [60]Stoeber K, Tisty TD, Happerfield L, Thomas GA, Romanov S, Bobrow L, Williams ED, Williams GH: DNA replication licensing and human cell proliferation. J Cell Sci 2001, 114(11):2027-2041.
• [61]Tu BP, Weissman JS: Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol 2004, 164(3):341-346.
• [62]Tu BP, Ho-Schleyer SC, Travers KJ, Weissman JS: Biochemical basis of oxidative protein folding in the endoplasmic reticulum. Science 2000, 290(5496):1571-1574.
• [63]Iwai K, Naganuma A, Kuge S: Peroxiredoxin Ahp1 acts as a receptor for alkylhydroperoxides to induce disulfide bond formation in the Cad1 transcription factor. J Biol Chem 2010, 285(14):10597-10604.
• [64]Salnikow K, Donald SP, Bruick RK, Zhitkovich A, Phang JM, Kasprzak KS: Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress. J Biol Chem 2004, 279(39):40337-40344.
• [65]Permenter MG, Lewis JA, Jackson DA: Exposure to nickel, chromium, or cadmium causes distinct changes in the gene expression patterns of a rat liver derived cell line. PLoS One 2011, 6(11):e27730.
• [66]Maxwell P, Salnikow K: HIF-1, an oxygen and metal responsive transcription factor. Cancer Biol Ther 2004, 3(1):29-35.
• [67]Gazit G, Hung G, Chen XK, Anderson WF, Lee AS: Use of the glucose starvation-inducible glucose-regulated protein 78 promoter in suicide gene therapy of murine fibrosarcoma. Cancer Res 1999, 59(13):3100-3106.
• [68]Koong AC, Auger EA, Chen EY, Giaccia AJ: The regulation of GRP78 and messenger RNA levels by hypoxia is modulated by protein kinase C activators and inhibitors. Radiat Res 1994, 138(1):S60.
• [69]Lee AS: The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 2005, 35(4):373-381.
• [70]Mori K: Frame switch splicing and regulated intramembrane proteolysis: key words to understand the unfolded protein response. Traffic 2003, 4(8):519-528.
• [71]Schroder M, Kaufman RJ: ER stress and the unfolded protein response. Mutat Res 2005, 569(1–2):29-63.
• [72]Ciechanover A: Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 2005, 6(1):79-86.
• [73]Finley D: Recognition and Processing of Ubiquitin-Protein Conjugates by the Proteasome. In Annu Rev Biochem, Volume 78. Palo Alto: Annual Reviews; 2009:477-513.
• [74]Pickart CM, Cohen RE: Proteasomes and their kin: Proteases in the machine age. Nat Rev Mol Cell Biol 2004, 5(3):177-187.
• [75]Zheng H, Fletcher D, Kozak W, Jiang M, Hofmann KJ, Conn CA, Soszynski D, Grabiec C, Trumbauer ME, Shaw A, Kostura MJ, Stevens K, Rosen H, North RJ, Chen HY, Tocci MJ, Kluger MJ, Van der Ploeg LHT: Resistance to fever induction and impaired acute-phase response in interleukin-1 beta-deficient mice. Immunity 1995, 3(1):9-19.
• [76]Fantuzzi G, Ku G, Harding MW, Livingston DJ, Sipe JD, Kuida K, Flavell RA, Dinarello CA: Response to local inflammation of IL-1 beta-converting enzyme-deficient mice. J Immunol 1997, 158(4):1818-1824.
• [77]Burgess-Beusse BL, Darlington GJ: C/EBP alpha is critical for the neonatal acute-phase response to inflammation. Mol Cell Biol 1998, 18(12):7269-7277.
• [78]Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Kennedy K, Hai T, Bolouri H, Aderem A: Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 2006, 441(7090):173-178.
• [79]Lekstrom-Himes J, Xanthopoulos KG: Biological role of the CCAAT enhancer-binding protein family of transcription factors. J Biol Chem 1998, 273(44):28545-28548.
• [80]Costa RH, Kalinichenko VV, Holterman A-XL, Wang X: Transcription factors in liver development, differentiation, and regeneration. Hepatology 2003, 38(6):1331-1347.
• [81]Morrisey EE, Tang ZH, Sigrist K, Lu MM, Jiang F, Ip HS, Parmacek MS: GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev 1998, 12(22):3579-3590.
• [82]Duncan SA, Navas MA, Dufort D, Rossant J, Stoffel M: Regulation of a transcription factor network required for differentiation and metabolism. Science 1998, 281(5377):692-695.
• [83]Sladek FM, Zhong WM, Lai E, Darnell JE: Liver-enriched transcription factor Hnf-4 is a novel member of the steroid-hormone receptor superfamily. Genes Dev 1990, 4(12B):2353-2365.
• [84]Esterbauer H, Oberkofler H, Linnemayr V, Iglseder B, Hedegger M, Wolfsgruber P, Paulweber B, Fastner G, Krempler F, Patsch W: Peroxisome proliferator-activated receptor-gamma coactivator-1 gene locus - Associations with obesity indices in middle-aged women. Diabetes 2002, 51(4):1281-1286.
• [85]Inoue I, Shinoda Y, Ikeda M, Hayashi K, Kanazawa K, Nomura M, Matsunaga T, Xu HY, Kawai S, Awata T, Komoda T, Katayama S: CLOCK/BMAL1 is involved in lipid metabolism via transactivation of the peroxisome proliferator-activated receptor (PPAR) response element. J Atheroscler Thromb 2005, 12(3):169-174.
• [86]Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ: An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 1996, 383(6602):728-731.
• [87]Hoshizaki DK, Blackburn T, Miles K, Sweis R: Fat-cell determination and differentiation - identification of genes necessary for fat-cell gene-expression. J Cell Biochem 1994, 18a:161-161.
• [88]Zeuzem S: Gut-liver axis. Int J Colorectal Dis 2000, 15(2):59-82.
• [89]Giglia-Mari G, Zotter A, Vermeulen W: DNA damage response. Cold Spring Harb Perspect Biol 2011, 3(1):a000745.
• [90]Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S: RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 2002, 419(6903):135-141.
• [91]Chong JP, Blow JJ: DNA replication licensing factor. Prog Cell Cycle Res 1996, 2:83-90.
• [92]Klaunig JE, Kamendulis LM: The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 2004, 44:239-267.
• [93]Vogelstein B, Lane D, Levine AJ: Surfing the p53 network. Nature 2000, 408(6810):307-310.
• [94]Boge G, Ndiaye P, Roche H, Peres G: Effects of Non lethal concentrations of hexavalent chromium on intestinal enzymology of salmo-gairdneri and dicentrarchus-labrax (pisces). J Physiol Paris 1988, 83(2):57-63.