Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish.
Angiogenesis
Developmental toxicity
Untargeted metabolomics
Zebrafish embryo
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
29 Jan 2024
29 Jan 2024
Historique:
received:
20
10
2023
accepted:
29
11
2023
medline:
29
1
2024
pubmed:
29
1
2024
entrez:
29
1
2024
Statut:
aheadofprint
Résumé
Angiogenesis is a key process in embryonic development, a disruption of this process can lead to severe developmental defects, such as limb malformations. The identification of molecular perturbations representative of antiangiogenesis in zebrafish embryo (ZFE) may guide the assessment of developmental toxicity from an endpoint- to a mechanism-based approach, thereby improving the extrapolation of findings to humans. Thus, the aim of the study was to discover molecular changes characteristic of antiangiogenesis and developmental toxicity. We exposed ZFEs to two antiangiogenic drugs (SU4312, sorafenib) and two developmental toxicants (methotrexate, rotenone) with putative antiangiogenic action. Molecular changes were measured by performing untargeted metabolomics in single embryos. The metabolome response was accompanied by the occurrence of morphological alterations. Two distinct metabolic effect patterns were observed. The first pattern comprised common effects of two specific angiogenesis inhibitors and the known teratogen methotrexate, strongly suggesting a shared mode of action of antiangiogenesis and developmental toxicity. The second pattern involved joint effects of methotrexate and rotenone, likely related to disturbances in energy metabolism. The metabolites of the first pattern, such as phosphatidylserines, pterines, retinol, or coenzyme Q precursors, represented potential links to antiangiogenesis and related developmental toxicity. The metabolic effect pattern can contribute to biomarker identification for a mechanism-based toxicological testing.
Identifiants
pubmed: 38285066
doi: 10.1007/s00204-023-03655-5
pii: 10.1007/s00204-023-03655-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Bundesministerium für Bildung und Forschung
ID : 031L0232 A/B
Informations de copyright
© 2024. The Author(s).
Références
Alcázar-Fabra M, Rodríguez-Sánchez F, Trevisson E, Brea-Calvo G (2021) Primary coenzyme Q deficiencies: a literature review and online platform of clinical features to uncover genotype-phenotype correlations. Free Radical Biol Med 167:141–180. https://doi.org/10.1016/j.freeradbiomed.2021.02.046
doi: 10.1016/j.freeradbiomed.2021.02.046
Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138(17):3593–3612. https://doi.org/10.1242/dev.063610
doi: 10.1242/dev.063610
pubmed: 21828089
Antonsson B (1997) Phosphatidylinositol synthase from mammalian tissues1Dedicated to Professor Eugene Kennedy. 1. Biochim et Biophys Acta (BBA) Lipids Lipid Metab. 1348(1):179–186. https://doi.org/10.1016/S0005-2760(97)00105-7
doi: 10.1016/S0005-2760(97)00105-7
Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776. https://doi.org/10.1126/science.284.5415.770
doi: 10.1126/science.284.5415.770
pubmed: 10221902
Beedie SL, Mahony C, Walker HM, Chau CH, Figg WD, Vargesson N (2016) Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model. Sci Rep 6(1):30038. https://doi.org/10.1038/srep30038
doi: 10.1038/srep30038
pubmed: 27443489
pmcid: 4957076
Castanon I, Hannich JT, Abrami L et al (2020) Wnt-controlled sphingolipids modulate anthrax toxin receptor palmitoylation to regulate oriented mitosis in zebrafish. Nat Commun 11(1):3317. https://doi.org/10.1038/s41467-020-17196-3
doi: 10.1038/s41467-020-17196-3
pubmed: 32620775
pmcid: 7335183
R Core Team (2022) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/ . Accessed 02 May 2023
Costaridis P, Horton C, Zeitlinger J, Holder N, Maden M (1996) Endogenous retinoids in the zebrafish embryo and adult. Dev Dyn 205(1):41–51. https://doi.org/10.1002/(sici)1097-0177(199601)205:1%3c41::Aid-aja4%3e3.0.Co;2-5
doi: 10.1002/(sici)1097-0177(199601)205:1<41::Aid-aja4>3.0.Co;2-5
pubmed: 8770550
Czech MP (2000) PIP2 and PIP3: complex roles at the cell surface. Cell 100(6):603–606. https://doi.org/10.1016/S0092-8674(00)80696-0
doi: 10.1016/S0092-8674(00)80696-0
pubmed: 10761925
Dimopoulou M, Verhoef A, Pennings JLA, van Ravenzwaay B, Rietjens IMCM, Piersma AH (2017) A transcriptomic approach for evaluating the relative potency and mechanism of action of azoles in the rat Whole Embryo Culture. Toxicology 392:96–105. https://doi.org/10.1016/j.tox.2017.09.014
doi: 10.1016/j.tox.2017.09.014
pubmed: 28970091
EMA (2007) Nexavar : EPAR Scientific Discussion. In: Use CfMPfH (ed). https://www.ema.europa.eu/en/documents/product-information/nexavar-epar-product-information_en.pdf
EPA US (1987) Review of studies submitted to support registration of rotenone (Reg. No. 6704-Q) Tox. Chem. No. 725: Tox. Project Nos. 1582 and 7–0865. In: Substances OoPaT (ed). https://www3.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-071003_22-Dec-87_010.pdf
Fang L, Choi SH, Baek JS et al (2013) Control of angiogenesis by AIBP-mediated cholesterol efflux. Nature 498(7452):118–122. https://doi.org/10.1038/nature12166
doi: 10.1038/nature12166
pubmed: 23719382
pmcid: 3760669
Fiehn C, Wunder A, Krienke S, Max R, Ho AD, Moehler T (2005) Lack of evidence for inhibition of angiogenesis as a central mechanism of the antiarthritic effect of methotrexate. Rheumatol Int 25(2):108–113. https://doi.org/10.1007/s00296-003-0408-y
doi: 10.1007/s00296-003-0408-y
pubmed: 14618373
Fraher D, Sanigorski A, Mellett NA, Meikle PJ, Sinclair AJ, Gibert Y (2016) Zebrafish embryonic lipidomic analysis. Cell Rep. 14(6):1317–1329. https://doi.org/10.1016/j.celrep.2016.01.016
doi: 10.1016/j.celrep.2016.01.016
pubmed: 26854233
Hachicho N, Reithel S, Miltner A, Heipieper HJ, Küster E, Luckenbach T (2015) Body mass parameters, lipid profiles and protein contents of zebrafish embryos and effects of 2,4-dinitrophenol exposure. PLoS ONE 10(8):e0134755. https://doi.org/10.1371/journal.pone.0134755
doi: 10.1371/journal.pone.0134755
pubmed: 26292096
pmcid: 4546380
Hamilton J, Greiner R, Salem N Jr, Kim H-Y (2000) n−3 Fatty acid deficiency decreases phosphatidylserine accumulation selectively in neuronal tissues. Lipids 35(8):863–869. https://doi.org/10.1007/S11745-000-0595-x
doi: 10.1007/S11745-000-0595-x
pubmed: 10984109
Hill J, Clarke JD, Vargesson N, Jowett T, Holder N (1995) Exogenous retinoic acid causes specific alterations in the development of the midbrain and hindbrain of the zebrafish embryo including positional respecification of the Mauthner neuron. Mech Dev 50(1):3–16. https://doi.org/10.1016/0925-4773(94)00321-d
doi: 10.1016/0925-4773(94)00321-d
pubmed: 7605750
Hoffmann S, Rockenstein A, Ramaswamy A et al (2007) Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells. Mol Cell Endocrinol 264(1–2):74–81. https://doi.org/10.1016/j.mce.2006.10.009
doi: 10.1016/j.mce.2006.10.009
pubmed: 17101211
Hyoun SC, Običan SG, Scialli AR (2012) Teratogen update: methotrexate. Birth Defects Res A 94(4):187–207. https://doi.org/10.1002/bdra.23003
doi: 10.1002/bdra.23003
Joussen AM, Kruse FE, Völcker HE, Kirchhof B (1999) Topical application of methotrexate for inhibition of corneal angiogenesis. Graefes Arch Clin Exp Ophthalmol 237(11):920–927. https://doi.org/10.1007/s004170050387
doi: 10.1007/s004170050387
pubmed: 10541903
Kawamukai M (2009) Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms. Biotechnol Appl Biochem 53(Pt 4):217–226. https://doi.org/10.1042/ba20090035
doi: 10.1042/ba20090035
pubmed: 19531029
Keller J, Mellert W, Sperber S et al (2019) Added value of plasma metabolomics to describe maternal effects in rat maternal and prenatal toxicity studies. Toxicol Lett 301:42–52. https://doi.org/10.1016/j.toxlet.2018.10.032
doi: 10.1016/j.toxlet.2018.10.032
pubmed: 30414988
Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF (1995) Stages of embryonic development of the zebrafish. Dev Dyn 203(3):253–310. https://doi.org/10.1002/aja.1002030302
doi: 10.1002/aja.1002030302
pubmed: 8589427
Knudsen T, Baker N, Spencer R, et al. (2023) AOP 43: disruption of VEGFR signaling leading to developmental defects. In. https://aopwiki.org/aops/43 Accessed September 04, 2023
Kolli VK, Natarajan K, Isaac B, Selvakumar D, Abraham P (2014) Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis. Hum Exp Toxicol 33(10):1051–1065. https://doi.org/10.1177/0960327113515503
doi: 10.1177/0960327113515503
pubmed: 24347301
Li Y, Gao R, Liu X et al (2015) Folate deficiency could restrain decidual angiogenesis in pregnant mice. Nutrients 7(8):6425–6445. https://doi.org/10.3390/nu7085284
doi: 10.3390/nu7085284
pubmed: 26247969
pmcid: 4555123
Liebisch G, Vizcaíno JA, Köfeler H et al (2013) Shorthand notation for lipid structures derived from mass spectrometry. J Lipid Res 54(6):1523–1530. https://doi.org/10.1194/jlr.M033506
doi: 10.1194/jlr.M033506
pubmed: 23549332
pmcid: 3646453
Lu S, Lu LY, Liu MF et al (2012) Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood. Neurobiol Dis 45(1):219–233. https://doi.org/10.1016/j.nbd.2011.08.006
doi: 10.1016/j.nbd.2011.08.006
pubmed: 21871565
Lyu J, Yang EJ, Shim JS (2019) Cholesterol trafficking: an emerging therapeutic target for angiogenesis and cancer. Cells 8(5):389. https://doi.org/10.3390/cells8050389
doi: 10.3390/cells8050389
pubmed: 31035320
pmcid: 6562524
Ma H, Blake T, Chitnis A, Liu P, Balla T (2009) Crucial role of phosphatidylinositol 4-kinase IIIalpha in development of zebrafish pectoral fin is linked to phosphoinositide 3-kinase and FGF signaling. J Cell Sci 122(Pt 23):4303–4310. https://doi.org/10.1242/jcs.057646
doi: 10.1242/jcs.057646
pubmed: 19887586
pmcid: 2779132
Mattes WB, Kamp HG, Fabian E et al (2013) Prediction of clinically relevant safety signals of nephrotoxicity through plasma metabolite profiling. Biomed Res Int 2013:202497. https://doi.org/10.1155/2013/202497
doi: 10.1155/2013/202497
pubmed: 23762827
pmcid: 3673329
Mattes W, Davis K, Fabian E et al (2014) Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma. Toxicol Lett 230(3):467–478. https://doi.org/10.1016/j.toxlet.2014.07.021
doi: 10.1016/j.toxlet.2014.07.021
pubmed: 25086301
McCollum CW, Conde-Vancells J, Hans C et al (2017) Identification of vascular disruptor compounds by analysis in zebrafish embryos and mouse embryonic endothelial cells. Reprod Toxicol 70:60–69. https://doi.org/10.1016/j.reprotox.2016.11.005
doi: 10.1016/j.reprotox.2016.11.005
pubmed: 27838387
Mugoni V, Postel R, Catanzaro V et al (2013) Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell 152(3):504–518. https://doi.org/10.1016/j.cell.2013.01.013
doi: 10.1016/j.cell.2013.01.013
pubmed: 23374346
pmcid: 3574195
Myers OD, Sumner SJ, Li S, Barnes S, Du X (2017) One step forward for reducing false positive and false negative compound identifications from mass spectrometry metabolomics data: new algorithms for constructing extracted ion chromatograms and detecting chromatographic peaks. Anal Chem 89(17):8696–8703. https://doi.org/10.1021/acs.analchem.7b00947
doi: 10.1021/acs.analchem.7b00947
pubmed: 28752754
Nöth J, Busch W, Tal T et al (2024) Analysis of vascular disruption in zebrafish embryos as an endpoint to predict developmental toxicity. Arch Toxicol 98(2):537–549. https://doi.org/10.1007/s00204-023-03633-x
doi: 10.1007/s00204-023-03633-x
pubmed: 38129683
National Research Council (US) Committee on Developmental Toxicology (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment. Washington (DC): National Academies Press (US). https://doi.org/10.17226/9871
OECD (2013) Test No. 236: Fish Embryo Acute Toxicity (FET) Test, OECD Guidelines for the Testing of Chemicals, Section 2, OECD Publishing, Paris. https://doi.org/10.1787/9789264203709-en
Oikawa T, Hirotani K, Nakamura O, Shudo K, Hiragun A, Iwaguchi T (1989) A highly potent antiangiogenic activity of retinoids. Cancer Lett 48(2):157–162. https://doi.org/10.1016/0304-3835(89)90054-2
doi: 10.1016/0304-3835(89)90054-2
pubmed: 2479461
Osmond MK, Butler AJ, Voon FC, Bellairs R (1991) The effects of retinoic acid on heart formation in the early chick embryo. Development 113(4):1405–1417. https://doi.org/10.1242/dev.113.4.1405
doi: 10.1242/dev.113.4.1405
pubmed: 1811952
Palmer G, Horgan DJ, Tisdale H, Singer TP, Beinert H (1968) Studies on the respiratory chain-linked reduced nicotinamide adenine dinucleotide dehydrogenase. XIV. Location of the sites of inhibition of rotenone, barbiturates, and piericidin by means of electron paramagnetic resonance spectroscopy. J Biol Chem. 243(4):844–7
doi: 10.1016/S0021-9258(19)81742-8
pubmed: 4295607
Park D, Ravichandran KS (2010) Emerging roles of brain-specific angiogenesis inhibitor 1. In: Yona S, Stacey M (eds) Adhesion-GPCRs: structure to function. Springer, Boston, pp 167–178
doi: 10.1007/978-1-4419-7913-1_15
Pawlikowski B, Wragge J, Siegenthaler JA (2019) Retinoic acid signaling in vascular development. Genesis 57(7–8):e23287. https://doi.org/10.1002/dvg.23287
doi: 10.1002/dvg.23287
pubmed: 30801891
pmcid: 6684837
Pluskal T, Castillo S, Villar-Briones A, Orešič M (2010) MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinform 11(1):395. https://doi.org/10.1186/1471-2105-11-395
doi: 10.1186/1471-2105-11-395
Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16(2):159–178. https://doi.org/10.1016/j.cytogfr.2005.01.004
doi: 10.1016/j.cytogfr.2005.01.004
pubmed: 15863032
Ramirez-Hincapie S, Birk B, Ternes P et al (2023) A high-throughput metabolomics in vitro platform for the characterization of hepatotoxicity. Cell Biol Toxicol. https://doi.org/10.1007/s10565-023-09809-6
doi: 10.1007/s10565-023-09809-6
pubmed: 37138123
pmcid: 10693528
Ross ME (2010) Gene-environment interactions, folate metabolism and the embryonic nervous system. Wiley Interdiscip Rev Syst Biol Med 2(4):471–480. https://doi.org/10.1002/wsbm.72
doi: 10.1002/wsbm.72
pubmed: 20836042
pmcid: 2981143
Ross EJ, Graham DL, Money KM, Stanwood GD (2015) Developmental consequences of fetal exposure to drugs: what we know and what we still must learn. Neuropsychopharmacology 40(1):61–87. https://doi.org/10.1038/npp.2014.147
doi: 10.1038/npp.2014.147
pubmed: 24938210
Rouwkema J, Khademhosseini A (2016) Vascularization and angiogenesis in tissue engineering: beyond creating static networks. Trends Biotechnol 34(9):733–745. https://doi.org/10.1016/j.tibtech.2016.03.002
doi: 10.1016/j.tibtech.2016.03.002
pubmed: 27032730
Schmid R, Heuckeroth S, Korf A et al (2023) Integrative analysis of multimodal mass spectrometry data in MZmine 3. Nat Biotechnol 41(4):447–449. https://doi.org/10.1038/s41587-023-01690-2
doi: 10.1038/s41587-023-01690-2
pubmed: 36859716
pmcid: 10496610
Schoors S, Bruning U, Missiaen R et al (2015) Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520(7546):192–197. https://doi.org/10.1038/nature14362
doi: 10.1038/nature14362
pubmed: 25830893
pmcid: 4413024
Sperber S, Wahl M, Berger F et al (2019) Metabolomics as read-across tool: an example with 3-aminopropanol and 2-aminoethanol. Regul Toxicol Pharmacol. https://doi.org/10.1016/j.yrtph.2019.104442
doi: 10.1016/j.yrtph.2019.104442
pubmed: 31421187
Sun L, Tran N, Tang F et al (1998) Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J Med Chem 41(14):2588–2603. https://doi.org/10.1021/jm980123i
doi: 10.1021/jm980123i
pubmed: 9651163
Sun S, Gui Y, Wang Y et al (2009) Effects of methotrexate on the developments of heart and vessel in zebrafish. Acta Biochim Biophys Sin (shanghai) 41(1):86–96. https://doi.org/10.1093/abbs/gmn010
doi: 10.1093/abbs/gmn010
pubmed: 19129954
Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N (2009) Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proc Natl Acad Sci U S A 106(21):8573–8578. https://doi.org/10.1073/pnas.0901505106
doi: 10.1073/pnas.0901505106
pubmed: 19433787
pmcid: 2688998
Tickle C, Alberts B, Wolpert L, Lee J (1982) Local application of retinoic acid to the limb bond mimics the action of the polarizing region. Nature 296(5857):564–566. https://doi.org/10.1038/296564a0
doi: 10.1038/296564a0
pubmed: 7070499
van Ravenzwaay B, Sperber S, Lemke O et al (2016) Metabolomics as read-across tool: a case study with phenoxy herbicides. Regul Toxicol Pharmacol 81:288–304. https://doi.org/10.1016/j.yrtph.2016.09.013
doi: 10.1016/j.yrtph.2016.09.013
pubmed: 27637788
Verberne EA, de Haan E, van Tintelen JP, Lindhout D, van Haelst MM (2019) Fetal methotrexate syndrome: a systematic review of case reports. Reprod Toxicol 87:125–139. https://doi.org/10.1016/j.reprotox.2019.05.066
doi: 10.1016/j.reprotox.2019.05.066
pubmed: 31181251
Wang M, Zhao Y, Zhang B (2015) Efficient test and visualization of multi-set intersections. Sci Rep 5(1):16923. https://doi.org/10.1038/srep16923
doi: 10.1038/srep16923
pubmed: 26603754
pmcid: 4658477
Wang M, Carver JJ, Phelan VV et al (2016) Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat Biotechnol 34(8):828–837. https://doi.org/10.1038/nbt.3597
doi: 10.1038/nbt.3597
pubmed: 27504778
pmcid: 5321674
Wilhelm SM, Carter C, Tang L et al (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. https://doi.org/10.1158/0008-5472.Can-04-1443
doi: 10.1158/0008-5472.Can-04-1443
pubmed: 15466206
Wilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835–844. https://doi.org/10.1038/nrd2130
doi: 10.1038/nrd2130
pubmed: 17016424
Wilhelmi P, Giri V, Zickgraf FM et al (2023) A metabolomics approach to reveal the mechanism of developmental toxicity in zebrafish embryos exposed to 6-propyl-2-thiouracil. Chem Biol Interact 382:110565. https://doi.org/10.1016/j.cbi.2023.110565
doi: 10.1016/j.cbi.2023.110565
pubmed: 37236578
Wishart DS, Guo A, Oler E et al (2022) HMDB 5.0: the human metabolome database for 2022. Nucleic Acids Res. 50(D1):D622-d631. https://doi.org/10.1093/nar/gkab1062
doi: 10.1093/nar/gkab1062
pubmed: 34986597
Xu M, Legradi J, Leonards P (2023) A comprehensive untargeted metabolomics study in zebrafish embryos exposed to perfluorohexane sulfonate (PFHxS). Sci Total Environ 887:163770. https://doi.org/10.1016/j.scitotenv.2023.163770
doi: 10.1016/j.scitotenv.2023.163770
pubmed: 37146801
Zimna A, Kurpisz M (2015) Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Biomed Res Int 2015:549412. https://doi.org/10.1155/2015/549412
doi: 10.1155/2015/549412
pubmed: 26146622
pmcid: 4471260
Zinski J, Tajer B, Mullins MC (2018) TGF-β family signaling in early vertebrate development. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a033274
doi: 10.1101/cshperspect.a033274
pubmed: 28600394
pmcid: 5983195