3-Nitropropionic acid

Last updated
β-Nitropropionic acid
3-Nitropropanoic acid.png
Names
Preferred IUPAC name
3-Nitropropanoic acid
Other names
3-NPA
β-Nitropropionic acid
Hiptagenic acid
Bovinocidin
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.007.276 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C3H5NO4/c5-3(6)1-2-4(7)8/h1-2H2,(H,5,6)
    Key: WBLZUCOIBUDNBV-UHFFFAOYSA-N
  • C(C[N+](=O)[O-])C(=O)O
Properties
C3H5NO4
Molar mass 119.076 g·mol−1
Melting point 65–67 °C (149–153 °F; 338–340 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

3-Nitropropionic acid (3-NPA) is a mycotoxin which is severely toxic to humans. It is a potent suicidal inhibitor of succinate dehydrogenase, [1] an enyzme in the citric acid cycle and mitochondrial energy chain. [2] Mild cases of exposure give rise to nausea, vomiting, and stomach ache, while severe cases lead to brain damage or death. [3] There is no known antidote to 3-nitropropionic acid poisoning. [4]

Contents

3-nitropropionic acid is produced by a number of fungi, most notably in the Aspergillus family, and may be found in food such as in sugar cane [4] as well as Japanese fungally fermented staples, including miso, soy sauce, katsuobushi, [5] coconuts [6] and some traditional Chinese medicines. [7] Several outbreaks of 3-nitropropionic acid poisoning have been linked to contamination of shared food crops, particularly in China, where sugar cane is commonly consumed by children. [8] [9]

Health effects

Mechanism of action

3-nitroprionionic acid has a similar molecular structure to the biological molecule succinate, a component of the tricarboxylic acid cycle. [10] As such, 3-nitropropionic acid is able to competitively and irreversibly bind to the flavin component of the succinate dehydrogenase enzyme. [11] Suicidal deactivation by 3-nitropropionic acid permanently disables affected enzymes from catalysing the oxidation of succinate to fumarate. [11] This inhibition interrupts the synthesis of the energy biomolecule adenosine triphosphate (ATP) and triggers energy depletion and oxidative stress in affected cells. [12]

Symptoms

Neuronal death can occur, inducing severe neuromuscular disorders and damage to brain matter, spinal tracts, and the nervous system. [12] [13] Late onset muscle dystonia and neurodegeneration of the caudate putamen have been observed in humans who were exposed to 3-nitropropionic acid. [14] [15] [16] A study on rats further observed dopamine toxicity alongside acute encephalopathy and dystonia. [17]

Use in medical research

Recent studies have found that because 3-nitropropionic acid is a mitochondrial toxin, it can produce striatal alterations in rats similar to those observed in the brain of Huntington's disease (HD) patients. As such, 3-nitropropionic acid has been used as an animal model for HD and other such neurodegenerative diseases. [16] [18] Administration of the cannabinoid receptor agonist WIN55212-2 to rats for six consecutive days, before acid dosage, exerted preventive effects on all alterations elicited by the toxin, like mitochondrial dysfunction and lipid peroxidation, by activation of the CB1 receptor. [19]

In nature

This diagram illustrates the contamination pathway of 3-nitropropionic acid (3-NPA), a mycotoxin produced by Aspergillus flavus. Crops such as sugarcane, coconuts, peanuts, soybeans, rice, and maize serve as host substrates for fungal growth. Once contaminated, these crops can transmit 3-NPA to humans and animals through direct consumption or through derived animal products. Pathway of 3-Nitropropionic Acid Contamination from Crops to Humans and Animals.png
This diagram illustrates the contamination pathway of 3-nitropropionic acid (3-NPA), a mycotoxin produced by Aspergillus flavus. Crops such as sugarcane, coconuts, peanuts, soybeans, rice, and maize serve as host substrates for fungal growth. Once contaminated, these crops can transmit 3-NPA to humans and animals through direct consumption or through derived animal products.

Natural occurrence in food crops

As a mycotoxin, 3-nitropropionic acid is naturally produced by some fungi that infest plants and vegetables. [2] These fungi include Aspergillus flavus, Aspergilllus parasiticus, and of the genus Arthrinium, which grow in soil, decaying vegetation, hay, and grains, and are therefore able to contaminate grains before harvest and in storage. [20] [21] According to the World Health Organization, some of the crops that are commonly affected by Aspergillus and Arthrinium fungi include:

Extreme weather, stressed crop growth conditions, as well as storage conditions (like moisture) [22] give rise to conditions suitable for 3-nitropropionic acid formation in food crops.

Notable cases

Mouldy coconut poisoning in Denmark

Fatal 3-NPA poisoning as a result of drinking coconut water has been reported in a case where a pre-prepared coconut had been stored at room temperature for a month, instead of being refrigerated. [23]

Unexpected 3-NPA identification by LC–MS in Norway

The first reported case of human 3-NPA intoxication in Norway, and the first published human liquid chromatography–mass spectrometry (LC–MS)–based metabolomics study of 3-NPA poisoning worldwide, involved a Norwegian boy with an unknown source of intoxication who was initially suspected of having a mitochondrial disorder. In addition to detecting a large number of altered metabolites, the study identified protective mechanisms that may attenuate the toxic effects of 3-NPA, evidence of increased oxidative stress, and disruption of energy metabolism. The results of the study led to a revision of the toxicological screening panel in Norway, with 3-NPA added to the list of tested compounds. [2]

See also

References

  1. ↑ Roberts, Toby John (2004). "3-Nitropropionic Acid Model of Metabolic Stress: Assessment by Magnetic Resonance Imaging". Stroke Genomics. 104: 203–220. doi:10.1385/1-59259-836-6:203. PMID   15454669.
  2. 1 2 3 Bendiksen Skogvold, Hanne; Yazdani, Mazyar; Sandås, Elise Mørk; Østeby Vassli, Anja; Kristensen, Erle; Haarr, Dagfinn; Rootwelt, Helge; Elgstøen, Katja Benedikte Prestø (2022). "A pioneer study on human 3-nitropropionic acid intoxication: Contributions from metabolomics". Journal of Applied Toxicology. 42 (5): 818–829. doi: 10.1002/jat.4259 . ISSN   1099-1263. PMID   34725838.
  3. ↑ Ming, Li (1995-01-01). "Moldy Sugarcane Poisoning— A Case Report with a Brief Review" . Journal of Toxicology: Clinical Toxicology. 33 (4): 363–367. doi:10.3109/15563659509028924. ISSN   0731-3810. PMID   7629905.
  4. 1 2 Van Hooste, Wim L. C. (2017-02-07). "Myoclonic seizure prior to diagnosis of chronic toxic encephalopathy: a case report". Journal of Medical Case Reports. 11 (1) 36. doi: 10.1186/s13256-016-1188-9 . ISSN   1752-1947. PMC   5296961 . PMID   28173825.
  5. ↑ Hocking, Ailsa D.; Pitt, John I.; Samson, Robert A.; Thrane, Ulf (29 August 2006). Advances in Food Mycology. Springer. ISBN   9780387283913.
  6. ↑ Birkelund, T.; Johansen, R. F.; Illum, D. G.; Dyrskog, S. E.; Østergaard, J. A.; Falconer, T. M.; Andersen, C.; Fridholm, H.; Overballe-Petersen, S.; Jensen, J. S. (2021). "Fatal 3-Nitropropionic Acid Poisoning after Consuming Coconut Water". Emerging Infectious Diseases. 27 (1): 278–280. doi:10.3201/eid2701.202222. PMC   7774558 . PMID   33350928.
  7. ↑ Wang, X.P.; Yang, R.M. (2003). "Movement Disorders Possibly Induced by Traditional Chinese Herbs". European Neurology. 50 (3): 153–159. doi:10.1159/000073056. PMID   14530621. S2CID   43878555.
  8. ↑ Hamilton, Bradley F.; Gould, Daniel H.; Gustine, David L. (2000), "History of 3-Nitropropionic Acid", in Sanberg, Paul R.; Nishino, Hitoo; Borlongan, Cesario V. (eds.), Mitochondrial Inhibitors and Neurodegenerative Disorders , Totowa, NJ: Humana Press, pp. 21–33, doi:10.1007/978-1-59259-692-8_2, ISBN   978-1-59259-692-8 , retrieved 2025-04-29
  9. ↑ Liu, X.; Luo, X.; Hu, W. (June 1992). "Studies on the epidemiology and etiology of moldy sugarcane poisoning in China". Biomedical and Environmental Sciences. 5 (2): 161–177. ISSN   0895-3988. PMID   1642790.
  10. ↑ Upadhayay, Shubham; Yedke, Narhari Gangaram; Rahi, Vikrant; Singh, Surbhi; Kumar, Sachin; Arora, Anchal; Chandolia, Priyanka; Kaur, Prabhsharan; Kumar, Mandeep; Koshal, Prashant; Jamwal, Sumit; Kumar, Puneet (2023-06-01). "An Overview of the Pathophysiological Mechanisms of 3-Nitropropionic Acid (3-NPA) as a Neurotoxin in a Huntington's Disease Model and Its Relevance to Drug Discovery and Development" . Neurochemical Research. 48 (6): 1631–1647. doi:10.1007/s11064-023-03868-1. ISSN   1573-6903. PMID   36738367.
  11. 1 2 Alston, T. A.; Mela, L.; Bright, H. J. (September 1977). "3-Nitropropionate, the toxic substance of Indigofera, is a suicide inactivator of succinate dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America. 74 (9): 3767–3771. Bibcode:1977PNAS...74.3767A. doi: 10.1073/pnas.74.9.3767 . ISSN   0027-8424. PMC   431722 . PMID   269430.
  12. 1 2 Túnez, Isaac; Tasset, Inmaculada; Pérez-De La Cruz, Verónica; Santamaría, Abel (2010-02-10). "3-Nitropropionic Acid as a Tool to Study the Mechanisms Involved in Huntington's Disease: Past, Present and Future". Molecules. 15 (2): 878–916. doi: 10.3390/molecules15020878 . ISSN   1420-3049. PMC   6263191 . PMID   20335954.
  13. ↑ Ludolph, A. C.; He, F.; Spencer, P. S.; Hammerstad, J.; Sabri, M. (November 1991). "3-Nitropropionic Acid - Exogenous Animal Neurotoxin and Possible Human Striatal Toxin". Canadian Journal of Neurological Sciences. 18 (4): 492–498. doi:10.1017/S0317167100032212. ISSN   0317-1671. PMID   1782616.
  14. ↑ Gabrielson, K. L.; Hogue, B. A.; Bohr, V. A.; Cardounel, A. J.; Nakajima, W.; Kofler, J.; Zweier, J. L.; Rodriguez, E. R.; Martin, L. J.; de Souza-Pinto, N. C.; Bressler, J. (October 2001). "Mitochondrial toxin 3-nitropropionic acid induces cardiac and neurotoxicity differentially in mice". The American Journal of Pathology. 159 (4): 1507–1520. doi:10.1016/S0002-9440(10)62536-9. ISSN   0002-9440. PMC   1850498 . PMID   11583977.
  15. ↑ Alexi, Tajrena; Hughes, Paul E.; Faull, Richard L. M.; Williams, Chris E. (1998-08-03). "3-Nitropropionic acid's lethal triplet: cooperative pathways of neurodegeneration" . NeuroReport. 9 (11): R57-64. doi:10.1097/00001756-199808030-00001. ISSN   0959-4965. PMID   9721909.
  16. 1 2 Borlongan, Cesario V.; Koutouzis, Theodore K.; Sanberg, Paul R. (1997-01-01). "3-Nitropropionic acid animal model and Huntington' s disease" . Neuroscience & Biobehavioral Reviews. 21 (3): 289–293. doi:10.1016/S0149-7634(96)00027-9. ISSN   0149-7634. PMID   9168265.
  17. ↑ Johnson, John R; Robinson, Bonnie L; Ali, Syed F; Binienda, Zbigniew (2000-07-27). "Dopamine toxicity following long term exposure to low doses of 3-nitropropionic acid (3-NPA) in rats" . Toxicology Letters. 116 (1): 113–118. Bibcode:2000ToxL..116..113J. doi:10.1016/S0378-4274(00)00214-9. ISSN   0378-4274. PMID   10906428.
  18. ↑ Miller, Paul J.; Zaborszky, Laszlo (1997-07-01). "3-Nitropropionic Acid Neurotoxicity: Visualization by Silver Staining and Implications for Use as an Animal Model of Huntington's Disease" . Experimental Neurology. 146 (1): 212–229. doi:10.1006/exnr.1997.6522. ISSN   0014-4886. PMID   9225755.
  19. ↑ Maya-López, Marisol; Colín-González, Ana Laura; Aguilera, Gabriela; de Lima, María Eduarda; Colpo-Ceolin, Ana; Rangel-López, Edgar; Villeda-Hernández, Juana; Rembao-Bojórquez, Daniel; Túnez, Isaac (2017-02-15). "Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors". American Journal of Translational Research. 9 (2): 261–274. ISSN   1943-8141. PMC   5340665 . PMID   28337258.
  20. ↑ Reddy, K. R. N.; Salleh, B.; Saad, B.; Abbas, H. K.; Abel, C. A.; Shier, W. T. (2010-03-01). "An overview of mycotoxin contamination in foods and its implications for human health" . Toxin Reviews. 29 (1): 3–26. doi:10.3109/15569541003598553. ISSN   1556-9543.
  21. ↑ Wei, D. L.; Chang, S. C.; Lin, S. C.; Doong, M. L.; Jong, S. C. (1994). "Production of 3-nitropropionic acid by Arthrinium species". Current Microbiology. 28: 1–5. doi:10.1007/BF01575978. ISSN   0343-8651. S2CID   41489212.
  22. ↑ Jensen, Ole (Jun 13, 2016). "Management of mycotoxin risk in pig production" (PDF). Powerpoint by Ole Jensen. Archived from the original (PDF) on 2017-10-10. Retrieved 2017-10-09.
  23. ↑ Birkelund, Thomas; Johansen, Rakel F.; Illum, Dorte G.; Dyrskog, Stig Eric; Østergaard, Jakob A.; Falconer, Travis M.; Andersen, Chris; Fridholm, Helena; Overballe-Petersen, Søren; Jensen, Jørgen S. (January 2021). "Fatal 3-Nitropropionic Acid Poisoning after Consuming Coconut Water". Emerging Infectious Diseases. 27 (1): 278–280. doi:10.3201/eid2701.202222. ISSN   1080-6059. PMC   7774558 . PMID   33350928.

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