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Functional genomics and metabolomics reveal the toxicological effects of cadmium in Mus musculus mice

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Abstract

Cadmium (Cd) is an environmental pollutant that accumulates in the organisms causing serious health problems. Over the past decades, omics studies have been conducted trying to elucidate changes in the genome, the transcriptome or the proteome after Cd exposure. Metabolomics is relatively new to the omics revolution, but has shown enormous potential for investigating biological systems or their perturbations. When metabolomic data are interpreted in combination with genomic, transcriptomic and proteomic results, in the so-called systems biology approach, a holistic knowledge of the organism/process under investigation can be achieved. In this work, transcriptional and proteomic analysis (functional genomics) were combined with metabolomic workflow to evaluate the biological responses caused in Mus musculus mice by Cd (subcutaneous injection for 10 consecutive days). Animals showed high Cd levels in liver and plasma, drastic lipid peroxidation in liver, increased transcription of hepatic genes involved in oxidative stress, metal transport, immune response and lipid metabolism and moderate decreases of DNA repair genes mRNAs. 2DE-DIGE proteomics confirmed changes of hepatic proteins related to stress and immune responses, or involved in energy metabolism, suggesting a metabolic switch in the liver from oxidative phosphorylation to aerobic glycolysis, that was confirmed by metabolomics analysis, via DIMS and GC–MS. This metabolic alteration is particularly important for highly proliferating cells, like tumor cells, which requires a continuous supply of precursors for the synthesis of lipids, proteins and nucleic acids. The metabolic changes observed in mouse liver by metabolomics and the oxidative stress detected via functional genomics could be in the base of Cd hepatocarcinogenicity.

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References

  • Abdullah, A., Kitteringham, N. R., Jenkins, R. E., Goldring, C., Higgins, L., Yamamoto, M., et al. (2012). Analysis of the role of Nrf2 in the expression of liver proteins in mice using two-dimensional gel-based proteomics. Pharmacological Reports, 64, 680–697.

    Article  CAS  PubMed  Google Scholar 

  • Abril, N., Ruiz-Laguna, J., Garcia-Sevillano, M. A., Mata, A. M., Gomez-Ariza, J. L., & Pueyo, C. (2014). Heterologous microarray analysis of transcriptome alterations in Mus spretus mice living in an industrial settlement. Environmental Science and Technology, 48, 2183–2192.

    Article  CAS  PubMed  Google Scholar 

  • Adiele, R. C., Stevens, D., & Kamunde, C. (2012). Differential inhibition of electron transport chain enzyme complexes by cadmium and calcium in isolated rainbow trout (Oncorhynchus mykiss) hepatic mitochondria. Toxicological Sciences, 127, 110–119.

    Article  CAS  PubMed  Google Scholar 

  • Afolabi, O. K., Oyewo, E. B., Adekunle, A. S., Adedosu, O. T., & Adedeji, A. L. (2012). Impaired lipid levels and inflammatory response in rats exposed to cadmium. EXCLI Journal, 11, 677–687.

    Google Scholar 

  • Agorreta, J., Hu, J., Liu, D., Delia, D., Turley, H., Ferguson, D. J. P., et al. (2014). TRAP1 regulates proliferation, mitochondrial function and has prognostic significance in NSCLC. Molecular Cancer Research, 12(5), 660–669.

    Article  CAS  PubMed  Google Scholar 

  • Asara, Y., Marchal, J. A., Carrasco, E., Boulaiz, H., Solinas, G., Bandiera, P., et al. (2013). Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil. International Journal of Molecular Sciences, 14, 16600–16616.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., et al. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. The Journal of Cell Biology, 171, 603–614.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bravard, A., Campalans, A., Vacher, M., Gouget, B., Levalois, C., Chevillard, S., & Radicella, J. P. (2010). Inactivation by oxidation and recruitment into stress granules of hOGG1 but not APE1 in human cells exposed to sub-lethal concentrations of cadmium. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 685, 61–69.

    Article  CAS  PubMed  Google Scholar 

  • Brzoska, M. M., & Rogalska, J. (2013). Protective effect of zinc supplementation against cadmium-induced oxidative stress and the RANK/RANKL/OPG system imbalance in the bone tissue of rats. Toxicology and Applied Pharmacology, 272, 208–220.

    Article  CAS  PubMed  Google Scholar 

  • Brzoska, M. M., Rogalska, J., & Kupraszewicz, E. (2011). The involvement of oxidative stress in the mechanisms of damaging cadmium action in bone tissue: A study in a rat model of moderate and relatively high human exposure. Toxicology and Applied Pharmacology, 250, 327–335.

    Article  CAS  PubMed  Google Scholar 

  • Cannino, G., Ferruggia, E., Luparello, C., & Rinaldi, A. M. (2009). Cadmium and mitochondria. Mitochondrion, 9, 377–384.

    Article  CAS  PubMed  Google Scholar 

  • Chang, K.-C., Hsu, C.-C., Liu, S.-H., Su, C.-C., Yen, C.-C., Lee, M.-J., et al. (2013). Cadmium induces apoptosis in pancreatic β-cells through a mitochondria-dependent pathway: The role of oxidative stress-mediated C-jun N-terminal kinase activation. PLoS ONE, 8, e54374.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chang, Y. J., Huang, Y. P., Li, Z. L., & Chen, C. H. (2012). GRP78 knockdown enhances apoptosis via the down-regulation of oxidative stress and Akt pathway after epirubicin treatment in colon cancer DLD-1 cells. PLoS ONE, 7, e35123.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cortés, V. A., Curtis, D. E., Sukumaran, S., Shao, X., Parameswara, V., Rashid, S., et al. (2009). Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metabolism, 9, 165–176.

    Article  PubMed Central  PubMed  Google Scholar 

  • Dakubo, G. D. (Ed.). (2010). The Warburg phenomenon and other metabolic alterations of cancer cells. In Mitochondrial genetics and cancer. Berlin: Springer.

  • Davalos, D., & Akassoglou, K. (2012). Fibrinogen as a key regulator of inflammation in disease. Seminars in Immunopathology, 34, 43–62.

    Article  CAS  PubMed  Google Scholar 

  • Desideri, E., Vegliante, R., & Ciriolo, M. R. (2015). Mitochondrial dysfunctions in cancer: Genetic defects and oncogenic signaling impinging on TCA cycle activity. Cancer Letters, 356(2), 217–223.

    Article  CAS  PubMed  Google Scholar 

  • Dettmer, K., & Hammock, B. D. (2004). Metabolomics—A new exciting field within the omics sciences. Environmental Health Perspectives, 112, A396–397.

    PubMed Central  PubMed  Google Scholar 

  • el Jihen, H., Fatima, H., Nouha, A., Baati, T., Imed, M., & Abdelhamid, K. (2010). Cadmium retention increase: A probable key mechanism of the protective effect of zinc on cadmium-induced toxicity in the kidney. Toxicology Letters, 196, 104–109.

    Article  CAS  Google Scholar 

  • Eletto, D., Eletto, D., Dersh, D., Gidalevitz, T., & Argon, Y. (2014). Protein disulfide isomerase A6 controls the decay of ire1α signaling via disulfide-dependent association. Molecular Cell, 53, 562–576.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fang, L., & Miller, Y. I. (2012). Emerging applications for zebrafish as a model organism to study oxidative mechanisms and their roles in inflammation and vascular accumulation of oxidized lipids. Free Radical Biology and Medicine, 53, 1411–1420.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fang, Y., Yang, H., Wang, T., Liu, B., Zhao, H., & Chen, M. (2010). Metallothionein and superoxide dismutase responses to sublethal cadmium exposure in the clam Mactra veneriformis. Comparative Biochemistry and Physiology, 151, 325–333.

    PubMed  Google Scholar 

  • Fiehn, O. (2002). Metabolomics—The link between genotypes and phenotypes. Plant Molecular Biology, 48, 155–171.

    Article  CAS  PubMed  Google Scholar 

  • Filipič, M. (2012). Mechanisms of cadmium induced genomic instability. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 733, 69–77.

    Article  PubMed  Google Scholar 

  • Fuentes-Almagro, C. A., Prieto-Alamo, M. J., Pueyo, C., & Jurado, J. (2012). Identification of proteins containing redox-sensitive thiols after PRDX1, PRDX3 and GCLC silencing and/or glucose oxidase treatment in Hepa 1-6 cells. Journal of Proteomics, 77, 262–279.

    Article  CAS  PubMed  Google Scholar 

  • Galano, E., Arciello, A., Piccoli, R., Monti, D. M., & Amoresano, A. (2014). A proteomic approach to investigate the effects of cadmium and lead on human primary renal cells. Metallomics, 6, 587–597.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Sevillano, M. A., Contreras-Acuna, M., Garcia-Barrera, T., Navarro, F., & Gomez-Ariza, J. L. (2014a). Metabolomic study in plasma, liver and kidney of mice exposed to inorganic arsenic based on mass spectrometry. Analytical and Bioanalytical Chemistry, 406, 1455–1469.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Sevillano, M. A., Garcia-Barrera, T., Abril, N., Pueyo, C., Lopez-Barea, J., & Gomez-Ariza, J. L. (2014b). Omics technologies and their applications to evaluate metal toxicity in mice M. spretus as a bioindicator. Journal of Proteomics, 104, 4–23.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Sevillano, M. A., Garcia-Barrera, T., Navarro, F., & Gomez-Ariza, J. L. (2013). Analysis of the biological response of mouse liver (Mus musculus) exposed to As2O3 based on integrated -omics approaches. Metallomics, 5, 1644–1655.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Sevillano, M. A., Garcia-Barrera, T., Navarro-Roldan, F., Montero-Lobato, Z., & Gomez-Ariza, J. L. (2014c). A combination of metallomics and metabolomics studies to evaluate the effects of metal interactions in mammals. Application to Mus musculus mice under arsenic/cadmium exposure. Journal of Proteomics, 104, 66–79.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Sevillano, M. A., Gonzalez-Fernandez, M., Jara-Biedma, R., Garcia-Barrera, T., Lopez-Barea, J., Pueyo, C., & Gomez-Ariza, J. L. (2012). Biological response of free-living mouse Mus spretus from Donana National Park under environmental stress based on assessment of metal-binding biomolecules by SEC–ICP–MS. Analytical and Bioanalytical Chemistry, 404, 1967–1981.

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Fernandez, M., Garcia-Barrera, T., Jurado, J., Prieto-Álamo, M. J., Pueyo, C., Lopez-Barea, J., & Gomez-Ariza, J. L. (2008). Integrated application of transcriptomics, proteomics and metallomics in environmental studies. Pure and Apllied Chemistry, 12, 2609–2626.

    Google Scholar 

  • Goyer, R. A., & Clarkson, T. (2001). Toxic effects of metals. In C. D. Klaassen (Ed.), Casarett and Doull’s toxicology the basic science of poisons (pp. 811–867). New Yok: McGraw-Hill.

    Google Scholar 

  • Habeebu, S. S., Liu, J., Liu, Y., & Klaassen, C. D. (2000). Metallothionein-null mice are more sensitive than wild-type mice to liver injury induced by repeated exposure to cadmium. Toxicological Sciences, 55, 223–232.

    Article  CAS  PubMed  Google Scholar 

  • Hamann, I., König, C., Richter, C., Jahnke, G., & Hartwig, A. (2012). Impact of cadmium on hOGG1 and APE1 as a function of the cellular p53 status. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 736, 56–63.

    Article  CAS  PubMed  Google Scholar 

  • Han, E. S., Muller, F. L., Perez, V. I., Qi, W., Liang, H., Xi, L., et al. (2008). The in vivo gene expression signature of oxidative stress. Physiological Genomics, 34, 112–126.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hegde, M. L., Hazra, T. K., & Mitra, S. (2008). Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Research, 18, 27–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hoeferlin, L. A., Fekry, B., Ogretmen, B., Krupenko, S. A., & Krupenko, N. I. (2013). Folate stress induces apoptosis via p53-dependent de novo ceramide synthesis and up-regulation of ceramide synthase 6. Journal of Biological Chemistry, 288, 12880–12890.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jara-Biedma, R., Gonzalez-Dominguez, R., Garcia-Barrera, T., Lopez-Barea, J., Pueyo, C., & Gomez-Ariza, J. L. (2013). Evolution of metallotionein isoforms complexes in hepatic cells of Mus musculus along cadmium exposure. Biometals, 26, 639–650.

    Article  CAS  PubMed  Google Scholar 

  • Jo, E. J., Lee, H.-Y., Lee, Y.-N., Kim, J. I., Kang, H.-K., Park, D.-W., et al. (2004). Group IB secretory phospholipase A2 stimulates CXC chemokine ligand 8 production via ERK and NF-κB in human neutrophils. The Journal of Immunology, 173, 6433–6439.

    Article  CAS  PubMed  Google Scholar 

  • Jozkowicz, A., Was, H., & Dulak, J. (2007). Heme oxygenase-1 in tumors: Is it a false friend? Antioxidants and Redox Signaling, 9, 2099–2117.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jurado, J., Fuentes-Almagro, C. A., Prieto-Alamo, M. J., & Pueyo, C. (2007). Alternative splicing of c-fos pre-mRNA: Contribution of the rates of synthesis and degradation to the copy number of each transcript isoform and detection of a truncated c-Fos immunoreactive species. BMC Molecular Biology, 8, 83–96.

    Article  PubMed Central  PubMed  Google Scholar 

  • Jurczuk, M., Brzóska, M. M., Moniuszko-Jakoniuk, J., Gałażyn-Sidorczuk, M., & Kulikowska-Karpińska, E. (2004). Antioxidant enzymes activity and lipid peroxidation in liver and kidney of rats exposed to cadmium and ethanol. Food and Chemical Toxicology, 42, 429–438.

    Article  CAS  PubMed  Google Scholar 

  • Jurczuk, M., Brzoska, M. M., Rogalska, J., & Moniuszko-Jakoniuk, J. (2003). Iron body status of rats chronically exposed to cadmium and ethanol. Alcohol and Alcoholism, 38, 202–207.

    Article  CAS  PubMed  Google Scholar 

  • Kang, H. S., Okamoto, K., Kim, Y. S., Takeda, Y., Bortner, C. D., Dang, H., et al. (2011). Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance. Diabetes, 60, 177–188.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annual Review of Pharmacology and Toxicology, 47, 89–116.

    Article  CAS  PubMed  Google Scholar 

  • Kil, I. S., Shin, S. W., Yeo, H. S., Lee, Y. S., & Park, J.-W. (2006). Mitochondrial NADP+-dependent isocitrate dehydrogenase protects cadmium-induced apoptosis. Molecular Pharmacology, 70, 1053–1061.

    Article  CAS  PubMed  Google Scholar 

  • Kim, J. Y., & Ozato, K. (2009). The sequestosome 1/p62 attenuates cytokine gene expression in activated macrophages by inhibiting IFN regulatory factor 8 and TNF receptor-associated factor 6/NF-κB activity. The Journal of Immunology, 182, 2131–2140.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • King, M. A., Halicka, H. D., & Darzynkiewicz, Z. (2004). Pro- and anti-apoptotic effects of an inhibitor of chymotrypsin-like serine proteases. Cell Cycle, 3, 1566–1571.

    Article  CAS  PubMed  Google Scholar 

  • Kothinti, R. K., Blodgett, A. B., Petering, D. H., & Tabatabai, N. M. (2010). Cadmium down-regulation of kidney Sp1 binding to mouse SGLT1 and SGLT2 gene promoters: Possible reaction of cadmium with the zinc finger domain of Sp1. Toxicology and Applied Pharmacology, 244, 254–262.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Koyu, A., Gokcimen, A., Ozguner, F., Bayram, D. S., & Kocak, A. (2006). Evaluation of the effects of cadmium on rat liver. Molecular and Cellular Biochemistry, 284, 81–85.

    Article  CAS  PubMed  Google Scholar 

  • Larregle, E. V., Varas, S. M., Oliveros, L. B., Martinez, L. D., Anton, R., Marchevsky, E., & Gimenez, M. S. (2008). Lipid metabolism in liver of rat exposed to cadmium. Food and Chemical Toxicology, 46, 1786–1792.

    Article  CAS  PubMed  Google Scholar 

  • Lei, T., He, Q.-Y., Cai, Z., Zhou, Y., Wang, Y.-L., Si, L.-S., et al. (2008). Proteomic analysis of chromium cytotoxicity in cultured rat lung epithelial cells. Proteomics, 8, 2420–2429.

    Article  CAS  PubMed  Google Scholar 

  • Li, J., & Lee, A. S. (2006). Stress induction of GRP78/BiP and its role in cancer. Current Molecular Medicine, 6, 45–54.

    Article  CAS  PubMed  Google Scholar 

  • Liu, F., Inageda, K., Nishitai, G., & Matsuoka, M. (2006). Cadmium induces the expression of Grp78, an endoplasmic reticulum molecular chaperone, in LLC-PK1 renal epithelial cells. Environmental Health Perspectives, 114, 859–864.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lu, X. J., Chen, J., Huang, Z. A., Zhuang, L., Peng, L. Z., & Shi, Y. H. (2012). Influence of acute cadmium exposure on the liver proteome of a teleost fish, ayu (Plecoglossus altivelis). Molecular Biology Reports, 39, 2851–2859.

    Article  CAS  PubMed  Google Scholar 

  • Ma, Z., Izumi, H., Kanai, M., Kabuyama, Y., Ahn, N. G., & Fukasawa, K. (2006). Mortalin controls centrosome duplication via modulating centrosomal localization of p53. Oncogene, 25, 5377–5390.

    Article  CAS  PubMed  Google Scholar 

  • Manna, P., Sinha, M., & Sil, P. C. (2009). Taurine plays a beneficial role against cadmium-induced oxidative renal dysfunction. Amino Acids, 36, 417–428.

    Article  CAS  PubMed  Google Scholar 

  • Marth, E., Jelovcan, S., Kleinhappl, B., Gutschi, A., & Barth, S. (2001). The effect of heavy metals on the immune system at low concentrations. International Journal of Occupational Medicine and Environmental Health, 14, 375–386.

    CAS  PubMed  Google Scholar 

  • Matovic, V., Buha, A., Bulat, Z., & Ethukic-Cosic, D. (2011). Cadmium toxicity revisited: Focus on oxidative stress induction and interactions with zinc and magnesium. Archives of Industrial Hygiene and Toxicology, 62, 65–76.

    Article  CAS  PubMed  Google Scholar 

  • McNeill, D. R., Narayana, A., Wong, H. K., & Wilson, D. M, 3rd. (2004). Inhibition of Ape1 nuclease activity by lead, iron, and cadmium. Environmental Health Perspectives, 112, 799–804.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miyazaki, T., & Matsuzaki, Y. (2014). Taurine and liver diseases: A focus on the heterogeneous protective properties of taurine. Amino Acids, 46, 101–110.

    Article  CAS  PubMed  Google Scholar 

  • Moniuszko-Jakoniuk, J., Jurczuk, M., Brzoska, M. M., Rogalska, J., & Galazyn-Sidorczuk, M. (2005). Involvement of some low-molecular thiols in the destructive mechanism of cadmium and ethanol action on rat livers and kidneys. Polish Journal of Environmental Studies, 14, 483–489.

    CAS  Google Scholar 

  • Morrison, N., Cochrane, G., Faruque, N., Tatusova, T., Tateno, Y., Hancock, D., & Field, D. (2006). Concept of sample in OMICS technology. OMICS, 10, 127–137.

    Article  CAS  PubMed  Google Scholar 

  • Murugavel, P., & Pari, L. (2007a). Diallyl tetrasulfide protects cadmium-induced alterations in lipids and plasma lipoproteins in rats. Nutrition Research, 27, 356–361.

    Article  CAS  Google Scholar 

  • Murugavel, P., & Pari, L. (2007b). Effects of diallyl tetrasulfide on cadmium-induced oxidative damage in the liver of rats. Human and Experimental Toxicology, 26, 527–534.

    Article  CAS  PubMed  Google Scholar 

  • Nordberg, G. F. (2009). Historical perspectives on cadmium toxicology. Toxicology and Applied Pharmacology, 238, 192–200.

    Article  CAS  PubMed  Google Scholar 

  • Pelisch, F., Pozzi, B., Risso, G., Muñoz, M. J., & Srebrow, A. (2012). DNA damage-induced heterogeneous nuclear ribonucleoprotein K SUMOylation regulates p53 transcriptional activation. Journal of Biological Chemistry, 287, 30789–30799.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Perez-Enciso, M., & Tenenhaus, M. (2003). Prediction of clinical outcome with microarray data: A partial least squares discriminant analysis (PLS-DA) approach. Human Genetics, 112, 581–592.

    PubMed  Google Scholar 

  • Prieto-Alamo, M. J., Cabrera-Luque, J. M., & Pueyo, C. (2003). Absolute quantitation of normal and ROS-induced patterns of gene expression: An in vivo real-time PCR study in mice. Gene Expression, 11, 23–34.

    Article  PubMed  Google Scholar 

  • Pueyo, C., Jurado, J., Prieto-Alamo, M. J., Monje-Casas, F., & Lopez-Barea, J. (2002). Multiplex reverse transcription-polymerase chain reaction for determining transcriptional regulation of thioredoxin and glutaredoxin pathways. Methods in Enzymology, 347, 441–451.

    Article  CAS  PubMed  Google Scholar 

  • Rana, S. V. (2008). Metals and apoptosis: Recent developments. Journal of Trace Elements in Medicine and Biology, 22, 262–284.

    Article  CAS  PubMed  Google Scholar 

  • Rani, A., Kumar, A., Lal, A., & Pant, M. (2014). Cellular mechanisms of cadmium-induced toxicity: A review. International Journal of Environmental Health Research, 24, 378–399.

    Article  CAS  PubMed  Google Scholar 

  • Ridgway, N. D. (2013). The role of phosphatidylcholine and choline metabolites to cell proliferation and survival. Critical Reviews in Biochemistry and Molecular Biology, 48, 20–38.

    Article  CAS  PubMed  Google Scholar 

  • Satarug, S., Garrett, S. H., Sens, M. A., & Sens, D. A. (2010). Cadmium, environmental exposure, and health outcomes. Environmental Health Perspectives, 118, 182–190.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shimada, H., Funakoshi, T., & Waalkes, M. P. (2000). Acute, nontoxic cadmium exposure inhibits pancreatic protease activities in the mouse. Toxicological Sciences, 53, 474–480.

    Article  CAS  PubMed  Google Scholar 

  • Templeton, D. M., & Liu, Y. (2010). Multiple roles of cadmium in cell death and survival. Chemico-Biological Interactions, 188, 267–275.

    Article  CAS  PubMed  Google Scholar 

  • Tong, W. H., Sourbier, C., Kovtunovych, G., Jeong, S. Y., Vira, M., Ghosh, M., et al. (2011). The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels. Cancer Cell, 20, 315–327.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tretter, L., & Adam-Vizi, V. (2005). Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philosophical transactions of the Royal Society of London Series B, 360, 2335–2345.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Valko, M., Morris, H., & Cronin, M. T. (2005). Metals, toxicity and oxidative stress. Current Medicinal Chemistry, 12, 1161–1208.

    Article  CAS  PubMed  Google Scholar 

  • Wang, L., & Gallagher, E. P. (2013). Role of Nrf2 antioxidant defense in mitigating cadmium-induced oxidative stress in the olfactory system of zebrafish. Toxicology and Applied Pharmacology, 266, 177–186.

    Article  CAS  PubMed  Google Scholar 

  • Weckwerth, W. (2010). Metabolomics: An integral technique in systems biology. Bioanalysis., 2, 829–836.

    Article  CAS  PubMed  Google Scholar 

  • Wu, K. C., Liu, J. J., & Klaassen, C. D. (2012). Nrf2 activation prevents cadmium-induced acute liver injury. Toxicology and Applied Pharmacology, 263, 14–20.

    Article  CAS  PubMed  Google Scholar 

  • Yadav, U. C., & Ramana, K. V. (2013). Regulation of NF-kappaB-induced inflammatory signaling by lipid peroxidation-derived aldehydes. Oxidative Medicine and Cellular Longevity, 2013, 690545.

    Article  PubMed Central  PubMed  Google Scholar 

  • Yang, G., Biswasa, C., Lin, Q. S., La, P., Namba, F., Zhuang, T., et al. (2013). Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: Role of beta-catenin/hnRNPK signaling. Redox Biology, 1, 234–243.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yang, P.-M., Chen, H.-C., Tsai, J.-S., & Lin, L.-Y. (2007). Cadmium induces Ca2+ -dependent necrotic cell death through Calpain-triggered mitochondria depolarization and reactive oxygen species-mediated inhibition of nuclear factor-kB activity. Chemical Research in Toxicology, 20(3), 406–415.

    Article  CAS  PubMed  Google Scholar 

  • Zhai, Q., Wang, G., Zhao, J., Liu, X., Tian, F., Zhang, H., & Chen, W. (2013). Protective effects of Lactobacillus plantarum CCFM8610 against acute cadmium toxicity in mice. Applied and Environmental Microbiology, 79, 1508–1515.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou, Z., Wang, C., Liu, H., Huang, Q., Wang, M., & Lei, Y. (2013). Cadmium induced cell apoptosis, DNA damage, decreased DNA repair capacity, and genomic instability during malignant transformation of human bronchial epithelial cells. International Journal of Medical Sciences, 10, 1485–1496.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This project received Grants CTM2012-38720-C03-01 and CTM2012-38720-C03-02 from the Ministerio de Economia y Competitividad-Spain; BIO1675, P12-FQM-00442 and P09-FQM-04659 from the Consejería de Innovación, Andalusian government. M. A. García-Sevillano thanks to Ministerio de Educación for a predoctoral grant.

Conflict of interest

The authors declare no conflict of interest.

Compliance with Ethical Requirements

Animals were handled according to the directive 2010/63/EU stipulated by the European Community, and the study was approved by the Ethics Committees of University of Córdoba and Huelva Universities (Spain).

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    Authors and Affiliations

    1. Department of Chemistry and Materials Sciences, Faculty of Experimental Science, University of Huelva, Campus de El Carmen, 21007, Huelva, Spain

      M. A. García-Sevillano, T. García-Barrera & J. L. Gómez-Ariza

    2. Agrifood Campus of International Excellence (ceiA3-UHU), University of Huelva, Campus de El Carmen, 21007, Huelva, Spain

      M. A. García-Sevillano, T. García-Barrera & J. L. Gómez-Ariza

    3. Research Center of Health and Environment (CYSMA), University of Huelva, Campus de El Carmen, 21007, Huelva, Spain

      M. A. García-Sevillano, T. García-Barrera & J. L. Gómez-Ariza

    4. Department of Biochemistry and Molecular Biology, University of Córdoba, Severo Ochoa Building, Rabanales Campus, 14071, Córdoba, Spain

      N. Abril, R. Fernández-Cisnal, C. Pueyo & J. López-Barea

    5. Agrifood Campus of International Excellence (ceiA3-UCO), University of Córdoba, Severo Ochoa Building, Rabanales Campus, 14071, Córdoba, Spain

      N. Abril, R. Fernández-Cisnal, C. Pueyo & J. López-Barea

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    1. M. A. García-Sevillano
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    2. N. Abril
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    3. R. Fernández-Cisnal
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    4. T. García-Barrera
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    5. C. Pueyo
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    6. J. López-Barea
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    7. J. L. Gómez-Ariza
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    Corresponding author

    Correspondence to J. L. Gómez-Ariza.

    Additional information

    M. A. García-Sevillano and N. Abril have contributed equally to this work and should be considered first authors.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 21 kb)

    Supplementary material 2 (DOCX 18 kb)

    Supplementary material 3 (DOCX 21 kb)

    11306_2015_801_MOESM4_ESM.pptx

    Supporting Information Fig. 1. Experimental design showing the animals per treatment group ant the pooling of the samples for the different assays. Supplementary material 4 (PPTX 1021 kb)

    11306_2015_801_MOESM5_ESM.pptx

    Supporting Information Fig. 2. Virtual two-dimensional differential in gel electrophoresis (2D-DIGE) images for comparison of control and 10-days Cd-treated liver mice proteomes. Equal amounts of Cy2 (IS, internal standard with equally mixed samples), Cy5 (control, untreated mice), and Cy3 (10-days Cd treated mice) labeled samples were mixed and then separated on analytical 2D-DIGE. Gels were scanned and a set of Cy5, Cy3, and Cy2 (A) images were obtained from each gel. An overlay of three dye scan-images was also obtained (B). The spot intensities and the relative expression ratio were computed using the DeCyder 6.5 software (Amersham Biosciences). Statistical significances were determined with the Student’s t-test. As an example, circles in (B) mark some spots whose intensities increased (red) or decreased (green) in relation to the IS because of the Cd treatment; for these four spots, the symbol of the identified protein and the fold-change variation (statistically significant at a P value of ≤ 0.05) are indicated and the number assigned to the spot, the Mw and the Ip are given in brackets). The remarked sponts are highlated in (C), where the intensity and direction of the change is also shown. Supplementary material 5 (PPTX 1871 kb)

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    García-Sevillano, M.A., Abril, N., Fernández-Cisnal, R. et al. Functional genomics and metabolomics reveal the toxicological effects of cadmium in Mus musculus mice. Metabolomics 11, 1432–1450 (2015). https://doi.org/10.1007/s11306-015-0801-z

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    • DOI: https://doi.org/10.1007/s11306-015-0801-z

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