WO2009146915A2 - Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances - Google Patents
Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances Download PDFInfo
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- WO2009146915A2 WO2009146915A2 PCT/EP2009/004016 EP2009004016W WO2009146915A2 WO 2009146915 A2 WO2009146915 A2 WO 2009146915A2 EP 2009004016 W EP2009004016 W EP 2009004016W WO 2009146915 A2 WO2009146915 A2 WO 2009146915A2
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- protein
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5073—Stem cells
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5014—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing toxicity
Definitions
- Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances
- the present inventors found out that specific protein biomarkers are diagnostic for developmental toxicity of chemical and pharmaceutical compounds.
- the impact of a substance on these biomarkers is predictive for the developmental toxicity of the substance. Said impact can be determined by contacting a cell sample wherein at least one of the protein biomarkers is produced, with the substance and determining a variation of said protein biomarker(s) in the cell sample as a result of the exposure to the substance.
- the invention provides an in vitro method for the determination of developmental toxicity of a substance, comprising the steps (i) exposing a cell sample to the substance, and (ii) detecting a variation of one or more protein biomarkers in the cell - A - sample as a result of the exposure to the substance.
- the “protein biomarkers” of the invention are selected from the group consisting of heat shock protein beta-1 (HspB1), Ras-GTPase-activating protein SH3-domain binding protein (G3BP), Ran binding protein 5 (RanBP ⁇ ), Calreticulin (CaIr), Dihydropyrimidinase-like 2 (DRP2), stress- induced phosphoprotein 1 (STIP1 ), U2af2 protein (U2AF), calcium binding protein 39, isoform CRA_b (Cab39), NmrA-like family domain containing 1 (NMRL1) and post-translational isoforms thereof.
- HspB1 heat shock protein beta-1
- G3BP Ras-GTPase-activating protein SH3-domain binding protein
- RanBP ⁇ Ran binding protein 5
- CaIr Calreticulin
- DSP2 Dihydropyrimidinase-like 2
- DSP1 Dihydropyrimidinase-like 2
- STIP1 stress- induced
- the biomarkers of the invention are well known proteins.
- the common nomenclature of the proteins is summarized in Table 1 :
- developmental toxicity relates to any adverse effects induced during pregnancy, or as a result of parental exposure.
- developmental toxicity encompasses embryotoxicity.
- a "cell sample” suitable for use in the method of the invention is any sample comprising cells or cell components capable to produce at least one of the above protein biomarkers.
- the cell sample may e.g. be selected from organs, organ samples, tissues, body fluids, cells, and cell lysates.
- the cell sample is preferably of vertebrate origin. Particularly preferred are cell samples of mammalian and in particular human origin.
- a cell sample comprises stem cells.
- the stem cells may be omnipotent, pluripotent, multipotent and/or oligopotent stem cells. Particularly preferred are embryonic stem cells. Most preferably the stem cells are human embryonic stem cells (hESC).
- step (i) a cell sample is exposed to a substance to be tested for developmental toxicity.
- the baseline value of the one or more biomarkers in the sample is determined.
- step (H) a variation of one or more protein biomarkers in the cell sample as a result of the exposure to the substance is detected.
- the detection may comprise qualitative and/or quantitative determination of the one or more protein biomarkers.
- the biomarkers of the invention are well known proteins, the detection of which is within common knowledge in the art.
- the detection may be effected by means of an immunological assay or immunoassay.
- an immunoassay the presence of one or more protein biomarkers is measured using the reaction of an antibody or antibodies to its antigen.
- the assay takes advantage of the specific binding of an antibody to its antigen.
- the biomarkers represent the antigens.
- monoclonal antibodies are used for their detection, as they usually only bind to one site of a particular molecule, and therefore provide a more specific and accurate test, which is less easily confused by the presence of other molecules.
- biomarkers of the invention it is also possible to determine the activity thereof and in particular the variation of the activity upon contacting the cell sample with the substance to be tested.
- the quantity of a protein biomarker of the invention can be achieved by a variety of methods known in the art.
- the antibody for the protein biomarker may be labeled.
- the label may consist of an enzyme, radioisotope, magnetic label or fluorescent label.
- suitable techniques for the detection of a protein biomarker of the invention include Western Blot and ELISA.
- the variation of the one or more biomarkers upon contacting the cell sample with the substance to be tested is continuously detected.
- continuous assays are spectrophotometric assays, flourimetric assays or chemiluminescence assays.
- the one or more protein biomarkers are determined discontinuously one ore more times after contacting the cell sample with the substance to be tested.
- the cell sample or an extract thereof may be subjected to chromatographic separation such as two or three dimensional gel electrophoresis like SDS-PAGE.
- the separated proteins may be visualized by means of staining.
- a molecular analysis of the proteins may be effected e.g. by mass spectroscopy.
- At least one additional biomarker is determined.
- the one or more additional biomarkers are preferably markers for general cytotoxicity. It is thus possible to differentiate between developmental toxicity and general toxicity. Exemplary markers which behave independently of substance application but are correlated to EC 50 measurements are: Heart shock protein 8 (HSP8), Stress-induced phosphoprotein 1 (P-lsoform 2), fascin homolog 1 actin bundling protein (Fscni ), Heterologous nuclear ribonuclear ribonucleoprotein A/B isoform 2, and posttranslational isoforms thereof.
- HSP8 Heart shock protein 8
- P-lsoform 2 Stress-induced phosphoprotein 1
- Fadling protein Fadling protein
- Heterologous nuclear ribonuclear ribonucleoprotein A/B isoform 2 Heterologous nuclear ribonuclear ribonucleoprotein A/B isoform 2
- posttranslational isoforms thereof The common nomenclature of the
- a further embodiment of the invention relates to the use of one or more protein biomarkers as defined above as markers for the assessment of developmental toxicity of a substance.
- the protein biomarkers may be monitored in any known in vivo or in vitro model for toxicity, developmental toxicity or embryotoxicity.
- kits for the determination of developmental toxicity of a substance comprising one or more cell samples, wherein preferred cell samples are as defined above.
- the kit further comprises means for the determination of one or more protein biomarkers.
- the kit further comprises means for determining at least one additional biomarker.
- the one or more additional biomarkers are preferably markers for general cytotoxicity.
- the kit comprises means for determining the additional markers Heart shock protein 8 (HSP8), Stress-induced phosphoprotein 1 (P-lsoform 2), fascin homolog 1 actin bundling protein (Fscni), Heterologous nuclear ribonuclear ribonucleoprotein A/B isoform 2, and/or posttranslational isoforms thereof.
- HSP8 Heart shock protein 8
- P-lsoform 2 Stress-induced phosphoprotein 1
- Fscni fascin homolog 1 actin bundling protein
- Heterologous nuclear ribonuclear ribonucleoprotein A/B isoform 2 Heterologous nuclear ribonuclear ribonucleoprotein A/B isoform 2
- posttranslational isoforms thereof are examples of the kits.
- the protein biomarkers of the invention are well known proteins. However, the invention for the first time describes that the specific proteins are diagnostic biomarkers for developmental toxicity of chemical and pharmaceutical compounds.
- the inventors have applied a differential proteomic technology to the quantitative and statistical analysis of protein biomarkers from rodent and human samples related to developmental toxicity. These samples included: Protein lysates from a variety of experiments carried out for the validation of the EST test in two independent laboratories. Cardiomyocytes differentiated from murine embryonic stem cells according to a standardized protocol (ECVAM validated alternative test) were exposed to sets of substances with known embryotoxic potency and functionally controlled in dose-dependent manner.
- High quality lysates from neurally differentiated human embryonic stem cell have been submitted to this type differential proteomic analysis.
- the hESC cultures have been treated with methyl mercury and valproic acid.
- Samples (including treated and non-treated undifferentiated hESC and respective neural precursors) have been radiolabeled and submitted to a differential quantitative pattern analysis using high resolution 2D-PAGE as described previously (e.g. Schrattenholz & Groebe 2007; Groebe et al., 2007; Wozny et al., 2007): 177 protein spots have been found to be differentially affected by the treatment, among them many redundant posttranslational isoforms, have been identified so far using automated high-throughput MALDI-TOF mass spectrometry.
- Substances tested at the two sites included Dinoseb, Nitrofen, Ochratoxin-A, Lovastatin, MAM 1 ⁇ -aminoproprionitril, Metoclopramide, Doxylamine, D- Penicillamine, Pravastatin, Warfarin and Furosemide.
- 380 differential proteins were found and identified by automated high-throughput MALDI-TOF mass spectrometry. There was a substantial number of redundant protein isoforms pointing to extensive posttranslational modifications.
- the molecular signatures are able to assort substance effects.
- cytoskeletal proteins show a uniform behaviour for all conditions, independent of substance or cluster: We interpret these as more likely to be representative for general cytotoxicity or cell stress.
- the determined protein biomarkers for embryotoxicity are shown in Table 3.
- Cluster 1 shows the alterations of corresponding marker proteins after treatment of the EST model with highly embryotoxic substances Dinoseb, Ochratoxin, Nitrofen, Lovastatin;
- Cluster 2 shows the situation when non- embryotoxic substances were used in this model ( ⁇ -aminoproprionitril, metoclopramide, doxylamine, D-penicillamine) and cluster 3 the effects of application of moderately embryotoxic substances like pravastatin and furosemide. The combination of these markers will allow to discriminate in vitro embryotoxic properties of substances.
- Receptor tyrosine Kinase (RTK)/Ras GTPase/MAP kinase (MAPK) signaling pathways are used ubiquitously during development to control many different biological processes.
- Small GTPases of the Ras superfamily are key regulators of diverse cellular and developmental events, including differentiation, cell division, vesicle transport, nuclear assembly, and control of the cytoskeleton during differentiation (some recent reviews: Omerovic et al., 2007; Wodarz and Nathke, 2007; Kratz et al., 2007).
- RanBP karyopherin or transportin imports numerous RNA binding proteins into the nucleus binding substrates in the cytoplasm and targeting them through the nuclear pore complex, where RanGTP dissociates them in the nucleus (e.g. Cansizoglu and Chook 2007). Again a role on differentiation, development and carcinogenesis is apparent (Teng et al., 2007).
- DRP-2 has been reported to contribute to the pathfinding of growing axons during brain development (Weitzdoerfer et al., 2001 ; lnagaki et al., 2000). DRP2 has also been shown to play role in the response to neuronal stress (e.g. Sommer et al., 2004; Butterfield et al., 2006).
- HspB1 a key role in differentiation of trophoblast cells, which is a critical process for the proper establishment of the placenta and therefore necessary to maintain embryonic development, has been reported recently (Winger et al., 2007). HspB1 is part of the mitogen-activated protein kinase (MAPK) pathways mediating some important cellular processes likely regulating preimplantation development (Natale et al., 2004).
- MAPK mitogen-activated protein kinase
- Fig. 1 shows a cluster analysis of proteins differentially affected by substance treatment in the EST model. Red indicates up, and green down regulation of expression in the protein lysates. There are only a few proteins which clearly behave in a substance- and cluster-dependent way across all conditions; these are promising candidates for markers of embryo toxicity.
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2009254181A AU2009254181A1 (en) | 2008-06-04 | 2009-06-04 | Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances |
JP2011512024A JP2011522265A (en) | 2008-06-04 | 2009-06-04 | Protein biomarkers for in vitro testing of developmental and embryonic toxicity of chemicals |
CA2726563A CA2726563A1 (en) | 2008-06-04 | 2009-06-04 | Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances |
US12/996,445 US20110143366A1 (en) | 2008-06-04 | 2009-06-04 | Protein biomarkers for in vitro testing of developmental toxicity and enbryotoxicity of chemical substances |
CN2009801264837A CN102089658A (en) | 2008-06-04 | 2009-06-04 | Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances |
EP09757298A EP2304434A2 (en) | 2008-06-04 | 2009-06-04 | Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances |
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US12909308P | 2008-06-04 | 2008-06-04 | |
US61/129,093 | 2008-06-04 |
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WO2009146915A2 true WO2009146915A2 (en) | 2009-12-10 |
WO2009146915A3 WO2009146915A3 (en) | 2010-03-04 |
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PCT/EP2009/004016 WO2009146915A2 (en) | 2008-06-04 | 2009-06-04 | Protein biomarkers for in vitro testing of developmental toxicity and embryotoxicity of chemical substances |
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US (1) | US20110143366A1 (en) |
EP (1) | EP2304434A2 (en) |
JP (1) | JP2011522265A (en) |
CN (1) | CN102089658A (en) |
AU (1) | AU2009254181A1 (en) |
CA (1) | CA2726563A1 (en) |
WO (1) | WO2009146915A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012123419A1 (en) | 2011-03-11 | 2012-09-20 | Vib Vzw | Molecules and methods for inhibition and detection of proteins |
JP2013524220A (en) * | 2010-04-01 | 2013-06-17 | バンヤン・バイオマーカーズ・インコーポレイテッド | Markers and assays for detecting neurotoxicity |
US10646555B2 (en) | 2010-01-26 | 2020-05-12 | Bioregency, Inc. | Compositions and methods relating to argininosuccinate synthetase |
Families Citing this family (4)
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US8524458B2 (en) * | 2009-11-09 | 2013-09-03 | Abbvie Inc. | Secretory protein biomarkers for high efficiency protein expression |
HUE039900T2 (en) * | 2010-03-22 | 2019-02-28 | Stemina Biomarker Discovery Inc | Predicting human developmental toxicity of pharmaceuticals using human stem-like cells and metabolomics |
US20140171522A1 (en) * | 2011-07-09 | 2014-06-19 | Astute Medical, Inc | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
US9958433B2 (en) | 2012-09-28 | 2018-05-01 | Agency For Science, Technology And Research | Method and system for in vitro developmental toxicity testing |
Citations (1)
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WO2008107912A2 (en) * | 2007-03-06 | 2008-09-12 | Reliance Life Sciences Pvt. Ltd. | In vitro assay methods for classifying embryotoxicity of compounds |
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US7705197B2 (en) * | 2005-01-19 | 2010-04-27 | University Of Tennessee Research Foundation | Embryo development and survival |
US20090220996A1 (en) * | 2007-03-06 | 2009-09-03 | Reliance Life Sciences Pvt Ltd. | In vitro Assay Methods for Classifying Embryotoxicity of Compounds |
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- 2009-06-04 EP EP09757298A patent/EP2304434A2/en not_active Withdrawn
- 2009-06-04 CN CN2009801264837A patent/CN102089658A/en active Pending
- 2009-06-04 CA CA2726563A patent/CA2726563A1/en not_active Abandoned
- 2009-06-04 AU AU2009254181A patent/AU2009254181A1/en not_active Abandoned
- 2009-06-04 WO PCT/EP2009/004016 patent/WO2009146915A2/en active Application Filing
- 2009-06-04 US US12/996,445 patent/US20110143366A1/en not_active Abandoned
- 2009-06-04 JP JP2011512024A patent/JP2011522265A/en active Pending
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WO2008107912A2 (en) * | 2007-03-06 | 2008-09-12 | Reliance Life Sciences Pvt. Ltd. | In vitro assay methods for classifying embryotoxicity of compounds |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10646555B2 (en) | 2010-01-26 | 2020-05-12 | Bioregency, Inc. | Compositions and methods relating to argininosuccinate synthetase |
JP2013524220A (en) * | 2010-04-01 | 2013-06-17 | バンヤン・バイオマーカーズ・インコーポレイテッド | Markers and assays for detecting neurotoxicity |
WO2012123419A1 (en) | 2011-03-11 | 2012-09-20 | Vib Vzw | Molecules and methods for inhibition and detection of proteins |
EP3384939A1 (en) | 2011-03-11 | 2018-10-10 | Vib Vzw | Molecules and methods for inhibition and detection of proteins |
Also Published As
Publication number | Publication date |
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EP2304434A2 (en) | 2011-04-06 |
CN102089658A (en) | 2011-06-08 |
WO2009146915A3 (en) | 2010-03-04 |
US20110143366A1 (en) | 2011-06-16 |
AU2009254181A1 (en) | 2009-12-10 |
JP2011522265A (en) | 2011-07-28 |
CA2726563A1 (en) | 2009-12-10 |
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