{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:36:08Z","timestamp":1776436568121,"version":"3.51.2"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T00:00:00Z","timestamp":1445472000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T00:00:00Z","timestamp":1445472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Terrorist use of organophosphorus-based nerve agents and toxic industrial chemicals against civilian populations constitutes a real threat, as demonstrated by the terrorist attacks in Japan in the 1990\u2009s or, even more recently, in the Syrian civil war. Thus, development of more effective countermeasures against acute organophosphorus poisoning is urgently needed. Here, we have generated and validated zebrafish models for mild, moderate and severe acute organophosphorus poisoning by exposing zebrafish larvae to different concentrations of the prototypic organophosphorus compound chlorpyrifos-oxon. Our results show that zebrafish models mimic most of the pathophysiological mechanisms behind this toxidrome in humans, including acetylcholinesterase inhibition, N-methyl-D-aspartate receptor activation and calcium dysregulation as well as inflammatory and immune responses. The suitability of the zebrafish larvae to <jats:italic>in vivo<\/jats:italic> high-throughput screenings of small molecule libraries makes these models a valuable tool for identifying new drugs for multifunctional drug therapy against acute organophosphorus poisoning.<\/jats:p>","DOI":"10.1038\/srep15591","type":"journal-article","created":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T09:38:59Z","timestamp":1445506739000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Zebrafish Models for Human Acute Organophosphorus Poisoning"],"prefix":"10.1038","volume":"5","author":[{"given":"Melissa","family":"Faria","sequence":"first","affiliation":[]},{"given":"Nat\u00e0lia","family":"Garcia-Reyero","sequence":"additional","affiliation":[]},{"given":"Francesc","family":"Padr\u00f3s","sequence":"additional","affiliation":[]},{"given":"Patrick J.","family":"Babin","sequence":"additional","affiliation":[]},{"given":"David","family":"Sebasti\u00e1n","sequence":"additional","affiliation":[]},{"given":"J\u00e9r\u00f4me","family":"Cachot","sequence":"additional","affiliation":[]},{"given":"Eva","family":"Prats","sequence":"additional","affiliation":[]},{"suffix":"II","given":"Mark","family":"Arick","sequence":"additional","affiliation":[]},{"given":"Eduardo","family":"Rial","sequence":"additional","affiliation":[]},{"given":"Anja","family":"Knoll-Gellida","sequence":"additional","affiliation":[]},{"given":"Guilaine","family":"Mathieu","sequence":"additional","affiliation":[]},{"given":"Florane","family":"Le Bihanic","sequence":"additional","affiliation":[]},{"given":"B. Lynn","family":"Escalon","sequence":"additional","affiliation":[]},{"given":"Antonio","family":"Zorzano","sequence":"additional","affiliation":[]},{"given":"Amadeu M. V. M","family":"Soares","sequence":"additional","affiliation":[]},{"given":"Demetrio","family":"Rald\u00faa","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2015,10,22]]},"reference":[{"key":"BFsrep15591_CR1","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1192\/bjp.bp.105.020834","volume":"189","author":"JM Bertolote","year":"2006","unstructured":"Bertolote, J. M., Fleischmann, A., Eddleston, M. & Gunnell, D. Deaths from pesticide poisoning: a global response. Br J Physchiatry 189, 201\u2013203 (2006).","journal-title":"Br J Physchiatry"},{"key":"BFsrep15591_CR2","doi-asserted-by":"publisher","first-page":"147","DOI":"10.2174\/1573408054022243","volume":"1","author":"S Pe\u00f1a Llopis","year":"2005","unstructured":"Pe\u00f1a Llopis, S. & Pena, L. Antioxidants as Potentially Safe Antidotes for Organophosphorus Poisoning. Current enzyme inhibition 1, 147\u2013156 (2005).","journal-title":"Current enzyme inhibition"},{"key":"BFsrep15591_CR3","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1002\/(SICI)1099-1263(199707)17:4<255::AID-JAT441>3.0.CO;2-D","volume":"17","author":"T\u00c4 Shih","year":"1997","unstructured":"Shih, T. \u00c4. & McDonough, J. H. Neurochemical Mechanisms in Soman-induced Seizures. J Appl Toxicol 17, 255\u2013264 (1997).","journal-title":"J Appl Toxicol"},{"key":"BFsrep15591_CR4","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1177\/019262339502300316","volume":"23","author":"L Tryphonas","year":"1995","unstructured":"Tryphonas, L. & Clement, J. G. Histomorphogenesis of soman-induced encephalocardiomyopathy in Sprague-Dawley rats. Toxicol Pathol 23, 393\u2013409 (1995).","journal-title":"Toxicol Pathol"},{"key":"BFsrep15591_CR5","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.taap.2008.07.005","volume":"232","author":"BA Weissman","year":"2008","unstructured":"Weissman, B. A. & Raveh, L. Therapy against organophosphate poisoning: the importance of anticholinergic drugs with antiglutamatergic properties. Toxicol Appl Pharmacol 232, 351\u2013358 (2008).","journal-title":"Toxicol Appl Pharmacol"},{"key":"BFsrep15591_CR6","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1139\/cjpp-2014-0113","volume":"92","author":"S Kaur","year":"2014","unstructured":"Kaur, S., Singh, S., Chahal, K. S. & Prakash, A. Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity. Can J Physiol Pharmacol 92, 893\u2013911 (2014).","journal-title":"Can J Physiol Pharmacol"},{"key":"BFsrep15591_CR7","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1007\/s12640-013-9388-1","volume":"24","author":"A Eisenkraft","year":"2013","unstructured":"Eisenkraft, A., Falk, A. & Finkelstein, A. The role of glutamate and the immune system in organophosphate-induced CNS damage. Neurotox Res 24, 265\u2013279 (2013).","journal-title":"Neurotox Res"},{"key":"BFsrep15591_CR8","doi-asserted-by":"publisher","first-page":"13220","DOI":"10.1073\/pnas.0605370103","volume":"103","author":"EX Albuquerque","year":"2006","unstructured":"Albuquerque, E. X. et al. Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci USA 103, 13220\u201313225 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep15591_CR9","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1136\/bmj.329.7476.1231","volume":"329","author":"NA Buckley","year":"2004","unstructured":"Buckley, N. A., Roberts, D. & Eddleston, M. Overcoming apathy in research on organophosphate poisoning. BMJ 329, 1231\u20131233 (2004).","journal-title":"BMJ"},{"key":"BFsrep15591_CR10","unstructured":"World Health Organization. Clinical management of acute pesticide intoxication: prevention of suicidal behaviours. Geneva, World Health Organization (2008)."},{"key":"BFsrep15591_CR11","doi-asserted-by":"crossref","unstructured":"Jett, D. A. & Yeung, D. T. Strategies to Enhance Medical Countermeasures After the Use of Chemical Warfare Agents on Civilians. In Handbook of Toxicology of Chemical Warfare Agents (ed Gupta R. C. ) Academic Press (2015).","DOI":"10.1016\/B978-0-12-800159-2.00070-1"},{"key":"BFsrep15591_CR12","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1124\/jpet.114.214932","volume":"350","author":"EF Pereira","year":"2014","unstructured":"Pereira, E. F. et al. Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds. J Pharmacol Exp Ther 350, 313\u2013321 (2014).","journal-title":"J Pharmacol Exp Ther"},{"key":"BFsrep15591_CR13","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.reprotox.2011.09.001","volume":"33","author":"D Rald\u00faa","year":"2012","unstructured":"Rald\u00faa, D., Thienpont, B. & Babin, P. J. Zebrafish eleutheroembryos as an alternative system for screening chemicals disrupting the mammalian thyroid gland morphogenesis and function. Reprod Toxicol 33, 188\u2013197 (2012).","journal-title":"Reprod Toxicol"},{"key":"BFsrep15591_CR14","doi-asserted-by":"publisher","first-page":"7525","DOI":"10.1021\/es202248h","volume":"45","author":"B Thienpont","year":"2011","unstructured":"Thienpont, B. et al. Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis. Environ Sci Technol 45, 7525\u20137532 (2011).","journal-title":"Environ Sci Technol"},{"key":"BFsrep15591_CR15","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.pneurobio.2014.03.001","volume":"118","author":"PJ Babin","year":"2014","unstructured":"Babin, P. J., Goizet, C. & Rald\u00faa, D. Zebrafish models of human motor neuron diseases: Advantages and limitations. Prog Neurobiol 118, 36\u201358 (2014).","journal-title":"Prog Neurobiol"},{"key":"BFsrep15591_CR16","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1074\/jbc.M006308200","volume":"276","author":"C Bertrand","year":"2001","unstructured":"Bertrand, C. et al. Zebrafish acetylcholinesterase is encoded by a single gene localized on linkage group 7\u2014Gene structure and polymorphism; Molecular forms and expression pattern during development. J Biol Chem 276, 464\u2013474 (2001).","journal-title":"J Biol Chem"},{"key":"BFsrep15591_CR17","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1093\/toxsci\/kfh020","volume":"77","author":"M Behra","year":"2004","unstructured":"Behra, M., Etard, C., Cousin, X. & Strahle, U. The use of zebrafish mutants to identify secondary target effects of acetylcholine esterase inhibitors. Toxicol Sci 77, 325\u2013333 (2004).","journal-title":"Toxicol Sci"},{"key":"BFsrep15591_CR18","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.aquatox.2012.09.008","volume":"126","author":"KL Yozzo","year":"2013","unstructured":"Yozzo, K. L., McGee, S. P. & Volz, D. C. Adverse outcome pathways during zebrafish embryogenesis: A case study with paraoxon. Aquat Toxicol 126, 346\u2013354 (2013).","journal-title":"Aquat Toxicol"},{"key":"BFsrep15591_CR19","unstructured":"Hau, J. Animal Models for Human Diseases. In Sourcebook of Models for Biomedical Research (ed Conn P. M. ), Human Press (2008)."},{"key":"BFsrep15591_CR20","first-page":"289","volume":"44","author":"T Namba","year":"1971","unstructured":"Namba, T. Cholinesterase inhibition by organophosphorus compounds and its clinical effects. Bull World Health Organ 44, 289 (1971).","journal-title":"Bull World Health Organ"},{"key":"BFsrep15591_CR21","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1093\/toxsci\/46.2.211","volume":"46","author":"VC Moser","year":"1998","unstructured":"Moser, V. C., Chanda, S. M., Mortensen, S. R. & Padilla, S. Age-and gender-related differences in sensitivity to chlorpyrifos in the rat reflect developmental profiles of esterase activities. Toxicol Sci 46, 211\u2013222 (1998).","journal-title":"Toxicol Sci"},{"key":"BFsrep15591_CR22","doi-asserted-by":"publisher","first-page":"2042","DOI":"10.1016\/j.cub.2012.08.016","volume":"22","author":"AM Fernandes","year":"2012","unstructured":"Fernandes, A. M. et al. Deep brain photoreceptors control light-seeking behavior in zebrafish larvae. Curr Biol 22, 2042\u20132047 (2012).","journal-title":"Curr Biol"},{"key":"BFsrep15591_CR23","doi-asserted-by":"crossref","unstructured":"Fero, K., Yokogawa, T. & Burgess, H. A. The behavioral repertoire of larval zebrafish. In Zebrafish models in neurobehavioral research (eds Kalueff A. V., Cachat J. M. ). Springer (2011).","DOI":"10.1007\/978-1-60761-922-2_12"},{"key":"BFsrep15591_CR24","doi-asserted-by":"publisher","first-page":"19126","DOI":"10.1073\/pnas.0709337104","volume":"104","author":"F Emran","year":"2007","unstructured":"Emran, F. et al. OFF ganglion cells cannot drive the optokinetic reflex in zebrafish. Proc Natl Acad Sci USA 104, 19126\u201319131 (2007).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep15591_CR25","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.neuro.2012.02.002","volume":"33","author":"CN Banks","year":"2012","unstructured":"Banks, C. N. & Lein, P. J. A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation. Neurotoxicology 33, 575\u2013584 (2012).","journal-title":"Neurotoxicology"},{"key":"BFsrep15591_CR26","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.cbi.2005.10.036","volume":"157","author":"JE Casida","year":"2005","unstructured":"Casida, J. E. & Quistad, G. B. Serine hydrolase targets of organophosphorus toxicants. Chem Biol Interact 157, 277\u2013283 (2005).","journal-title":"Chem Biol Interact"},{"key":"BFsrep15591_CR27","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.cardiores.2003.12.012","volume":"61","author":"H Piper","year":"2004","unstructured":"Piper, H., Abdallah, Y. & Sch\u00e4fer, C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res 61, 365\u2013371 (2004).","journal-title":"Cardiovasc Res"},{"key":"BFsrep15591_CR28","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/0272-0590(87)90089-3","volume":"8","author":"RC Gupta","year":"1987","unstructured":"Gupta, R. C. & Dettbarn, W. D. Alterations of high-energy phosphate-compounds in the skeletal-muscles of rats intoxicated with diisopropylphosphorofluoridate (DFP) and soman. Fundam Appl Toxicol 8, 400\u2013407 (1987).","journal-title":"Fundam Appl Toxicol"},{"key":"BFsrep15591_CR29","doi-asserted-by":"publisher","first-page":"S18","DOI":"10.1038\/nrn1434","volume":"5","author":"JK Andersen","year":"2004","unstructured":"Andersen, J. K. Oxidative stress in neurodegeneration: cause or consequence? Nat Med 5, S18\u2013S25 (2004).","journal-title":"Nat Med"},{"key":"BFsrep15591_CR30","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.taap.2012.06.005","volume":"263","author":"JE Lee","year":"2012","unstructured":"Lee, J. E., Park, J. H., Shin, I. C. & Koh, H. C. Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos. Toxicol Appl Pharmacol 263, 148\u2013162 (2012).","journal-title":"Toxicol Appl Pharmacol"},{"key":"BFsrep15591_CR31","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.taap.2013.04.001","volume":"270","author":"S Karami-Mohajeri","year":"2013","unstructured":"Karami-Mohajeri, S. & Abdollahi, M. Mitochondrial dysfunction and organophosphorus compounds. Toxicol Appl Pharmacol 270, 39\u201344 (2013).","journal-title":"Toxicol Appl Pharmacol"},{"key":"BFsrep15591_CR32","doi-asserted-by":"publisher","first-page":"R36","DOI":"10.1186\/gb-2013-14-4-r36","volume":"14","author":"D Kim","year":"2013","unstructured":"Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14, R36 (2013).","journal-title":"Genome Biol"},{"key":"BFsrep15591_CR33","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq\u2013A Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169 (2015).","journal-title":"Bioinformatics"},{"key":"BFsrep15591_CR34","doi-asserted-by":"publisher","first-page":"9546","DOI":"10.1073\/pnas.0914005107","volume":"107","author":"R Bourgon","year":"2010","unstructured":"Bourgon, R., Gentleman, R. & Huber, W. Independent filtering increases detection power for high-throughput experiments. Proc Natl Acad Sci USA 107, 9546\u20139551 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep15591_CR35","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140 (2010).","journal-title":"Bioinformatics"},{"key":"BFsrep15591_CR36","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1186\/1471-2105-10-161","volume":"10","author":"W Luo","year":"2009","unstructured":"Luo, W., Friedman, M. S., Shedden, K., Hankenson, K. D. & Woolf, P. J. GAGE: generally applicable gene set enrichment for pathway analysis. BMC bioinformatics 10, 161 (2009).","journal-title":"BMC bioinformatics"}],"updated-by":[{"DOI":"10.1038\/srep17244","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2016,1,7]],"date-time":"2016-01-07T00:00:00Z","timestamp":1452124800000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep15591.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15591","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15591.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T15:10:59Z","timestamp":1672931459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep15591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,22]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,7]]}},"alternative-id":["BFsrep15591"],"URL":"https:\/\/doi.org\/10.1038\/srep15591","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,22]]},"assertion":[{"value":"17 July 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2016","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15591"}}