Organophosphorus diisopropylfluorophosphate (DFP) intoxication in zebrafish larvae causes behavioral defects, neuronal hyperexcitation and neuronal death
- PMID: 33154418
- PMCID: PMC7645799
- DOI: 10.1038/s41598-020-76056-8
Organophosphorus diisopropylfluorophosphate (DFP) intoxication in zebrafish larvae causes behavioral defects, neuronal hyperexcitation and neuronal death
Erratum in
-
Author Correction: Organophosphorus diisopropylfluorophosphate (DFP) intoxication in zebrafish larvae causes behavioral defects, neuronal hyperexcitation and neuronal death.Sci Rep. 2021 Mar 9;11(1):5917. doi: 10.1038/s41598-021-85547-1. Sci Rep. 2021. PMID: 33750890 Free PMC article. No abstract available.
Abstract
With millions of intoxications each year and over 200,000 deaths, organophosphorus (OP) compounds are an important public health issue worldwide. OP poisoning induces cholinergic syndrome, with respiratory distress, hypertension, and neuron damage that may lead to epileptic seizures and permanent cognitive deficits. Existing countermeasures are lifesaving but do not prevent long-lasting neuronal comorbidities, emphasizing the urgent need for animal models to better understand OP neurotoxicity and identify novel antidotes. Here, using diisopropylfluorophosphate (DFP), a prototypic and moderately toxic OP, combined with zebrafish larvae, we first showed that DFP poisoning caused major acetylcholinesterase inhibition, resulting in paralysis and CNS neuron hyperactivation, as indicated by increased neuronal calcium transients and overexpression of the immediate early genes fosab, junBa, npas4b, and atf3. In addition to these epileptiform seizure-like events, DFP-exposed larvae showed increased neuronal apoptosis, which were both partially alleviated by diazepam treatment, suggesting a causal link between neuronal hyperexcitation and cell death. Last, DFP poisoning induced an altered balance of glutamatergic/GABAergic synaptic activity with increased NR2B-NMDA receptor accumulation combined with decreased GAD65/67 and gephyrin protein accumulation. The zebrafish DFP model presented here thus provides important novel insights into the pathophysiology of OP intoxication, making it a promising model to identify novel antidotes.
Conflict of interest statement
The authors declare no competing interests.
Figures
Similar articles
-
Microglia Remodelling and Neuroinflammation Parallel Neuronal Hyperactivation Following Acute Organophosphate Poisoning.Int J Mol Sci. 2022 Jul 26;23(15):8240. doi: 10.3390/ijms23158240. Int J Mol Sci. 2022. PMID: 35897817 Free PMC article.
-
Diisopropylfluorophosphate (DFP) volatizes and cross-contaminates wells in a common 96-well plate format used in zebrafish larvae toxicology studies.J Pharmacol Toxicol Methods. 2022 May-Jun;115:107173. doi: 10.1016/j.vascn.2022.107173. Epub 2022 May 8. J Pharmacol Toxicol Methods. 2022. PMID: 35545188 Free PMC article.
-
Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication.Neurobiol Dis. 2020 Jan;133:104431. doi: 10.1016/j.nbd.2019.03.019. Epub 2019 Mar 21. Neurobiol Dis. 2020. PMID: 30905768 Free PMC article. Review.
-
Novel therapeutics for treating organophosphate-induced status epilepticus co-morbidities, based on changes in calcium homeostasis.Neurobiol Dis. 2020 Jan;133:104418. doi: 10.1016/j.nbd.2019.03.006. Epub 2019 Mar 12. Neurobiol Dis. 2020. PMID: 30872159 Free PMC article. Review.
-
Pretreatment with pyridostigmine bromide has no effect on seizure behavior or 24 hour survival in the rat model of acute diisopropylfluorophosphate intoxication.Neurotoxicology. 2019 Jul;73:81-84. doi: 10.1016/j.neuro.2019.03.001. Epub 2019 Mar 7. Neurotoxicology. 2019. PMID: 30853371 Free PMC article.
Cited by
-
Transcriptomic and behavioral analyses reveal unique target tissues and molecular pathways associated with embryonic exposure to low level glyphosate and metal mixtures in zebrafish.Sci Total Environ. 2024 Feb 20;912:169271. doi: 10.1016/j.scitotenv.2023.169271. Epub 2023 Dec 17. Sci Total Environ. 2024. PMID: 38114029
-
Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning.Sci Rep. 2022 Nov 25;12(1):20329. doi: 10.1038/s41598-022-24472-3. Sci Rep. 2022. PMID: 36434021 Free PMC article.
-
Microglia Remodelling and Neuroinflammation Parallel Neuronal Hyperactivation Following Acute Organophosphate Poisoning.Int J Mol Sci. 2022 Jul 26;23(15):8240. doi: 10.3390/ijms23158240. Int J Mol Sci. 2022. PMID: 35897817 Free PMC article.
-
Diisopropylfluorophosphate (DFP) volatizes and cross-contaminates wells in a common 96-well plate format used in zebrafish larvae toxicology studies.J Pharmacol Toxicol Methods. 2022 May-Jun;115:107173. doi: 10.1016/j.vascn.2022.107173. Epub 2022 May 8. J Pharmacol Toxicol Methods. 2022. PMID: 35545188 Free PMC article.
References
-
- Mew EJ, et al. The global burden of fatal self-poisoning with pesticides 2006–15: systematic review. J. Affect. Disord. 2017;219:93–104. - PubMed
-
- Jett DA. Neurological aspects of chemical terrorism. Ann. Neurol. 2007;61:9–13. - PubMed
-
- Lotti M. Clinical toxicology of anticholinesterase agents in humans. In: Krieger R, editor. Hayes’ Handbook of Pesticide Toxicology. Amsterdam: Elsevier; 2010. pp. 1543–1589.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous