trichothecene

File:Tricothecene Classifications.jpg

Trichothecenes are a group of over 150 chemically related toxic mycotoxins.{{Cite web|url=https://www.apsnet.org/edcenter/intropp/topics/Mycotoxins/Pages/Trichothecenes.aspx|title=American Phytopathological Society|website=American Phytopathological Society|access-date=2018-05-07|archive-date=2018-05-07|archive-url=https://web.archive.org/web/20180507221753/https://www.apsnet.org/edcenter/intropp/topics/Mycotoxins/Pages/Trichothecenes.aspx|url-status=dead}} Each trichothecene displays a core structure consisting of a six-membered ring containing a single oxygen atom, flanked by two carbon rings.{{cite journal | vauthors = McCormick SP, Stanley AM, Stover NA, Alexander NJ | title = Trichothecenes: from simple to complex mycotoxins | journal = Toxins | volume = 3 | issue = 7 | pages = 802–14 | date = July 2011 | pmid = 22069741 | pmc = 3202860 | doi = 10.3390/toxins3070802 | doi-access = free }} This core ring structure contains an epoxide bridging carbons 12 and 13, as well as a double bond between carbons 9 and 10.{{Cite book|url=https://books.google.com/books?id=3UMrAAAAYAAJ&q=trichothecene+classification&pg=PA17|title=Protection Against Trichothecene Mycotoxins|date=1983-01-01|publisher=National Academies |isbn=9780309034302}} These two functional groups are primarily responsible for trichothecenes' ability to inhibit protein synthesis and incur general cytotoxic effects.{{cite journal | vauthors = Bennett JW, Klich M | title = Mycotoxins | journal = Clinical Microbiology Reviews | volume = 16 | issue = 3 | pages = 497–516 | date = July 2003 | pmid = 12857779 | pmc = 164220 | doi = 10.1128/CMR.16.3.497-516.2003 }} Notably, this core structure is amphipathic, containing both polar and nonpolar parts.{{cite journal | vauthors = Middlebrook JL, Leatherman DL | title = Specific association of T-2 toxin with mammalian cells | journal = Biochemical Pharmacology | volume = 38 | issue = 18 | pages = 3093–102 | date = September 1989 | pmid = 2783163 | doi = 10.1016/0006-2952(89)90020-8 }} All trichothecenes are related through this common structure but are differentiated by the substitution pattern of oxygen-containing functional groups on carbons 3, 4, 7, 8, and 15. These functional groups govern the properties of an individual trichothecene and also serve as the basis for the most commonly used classification system for this family of toxins. This classification system breaks up the trichothecene family into four groups: Type A, B, C, and D.

• Type A trichothecenes have hydroxyl or O-linked ester substitutions around the core ring structure. Common examples of these are neosolaniol with a hydroxyl substitution at carbon 8, and T-2 toxin with an ester substitution at carbon 8.

• Type B trichothecenes are classified by the presence of oxo-substitutions around the core ring structure. Common examples of these include nivalenol and trichothecene, which both have a ketone functional group at carbon 8.

• Type C trichothecenes have an additional epoxide bridging the carbons 7 and 8. A common example of this is crotocin, which also has an O-linked ester functional group at carbon 4.

• Type D trichothecenes have an additional macrocylic ring between carbon 4 and carbon 15. These rings can have varied additional functional groups. Common examples of these are roridin A and satratoxin H.

Although the distinct functional groups of these classification types give each trichothecene unique chemical properties, their classification type does not explicitly indicate their relative toxicity. While the type D group is thought to contain the most toxic trichothecenes, type A and B trichothecenes vary considerably in their toxicity.

The classification system described above is the most commonly used to group molecules of the trichothecene family. However, a variety of alternative classification systems also exist for these complex molecules. Trichothecenes can also be generally described as simple or macrocyclic. Simple trichothecenes include types A, B, and C, whereas macrocyclic trichothecenes include Type D and are characterized by the presence of a carbon 4 – carbon 15 bridge. Additionally, J. F. Grove proposed a classification of trichothecenes into three groups that was also based upon the functional substitution patterns of the ring skeleton.{{Cite journal | vauthors = Grove JF |date=1988|title=Non-macrocyclic trichothecenes|journal=Natural Product Reports|language=en|volume=5|issue=2|pages=187–209|doi=10.1039/NP9880500187|pmid=3062504|issn=0265-0568}} Group 1 trichothecenes only have functional groups substituted on the third, fully saturated carbon ring. Group 2 trichothecenes contain additional functional groups on the core ring containing the 9, 10 carbon double bond. Finally, group 3 trichothecenes contain a ketone functional group at carbon 8; this is the same criteria for type B trichothecenes.

Advances in the field of evolutionary genetics have also led to the proposal of trichothecene classification systems based on the pathway of their biosynthesis. Genes responsible for the biosynthesis of a mycotoxin are typically located in clusters; in Fusariumi these are known as TRI genes.{{Cite journal|date=2003-03-27|title=The trichothecene biosynthesis gene cluster of Fusarium graminearum F15 contains a limited number of essential pathway genes and expressed non-essential genes |journal=FEBS Letters|language=en|volume=539|issue=1–3|pages=105–110|doi=10.1016/S0014-5793(03)00208-4 |pmid=12650935 |last1=Kimura |first1=Makoto |last2=Tokai |first2=Takeshi |last3=o'Donnell |first3=Kerry |last4=Ward |first4=Todd J. |last5=Fujimura |first5=Makoto |last6=Hamamoto |first6=Hiroshi |last7=Shibata |first7=Takehiko |last8=Yamaguchi |first8=Isamu |s2cid=19787988 |doi-access=free |bibcode=2003FEBSL.539..105K }} TRI genes are each responsible for producing an enzyme that carries out a specific step in the biosynthesis of trichothecenes. Mutations in these genes can lead to the production of variant trichothecenes and therefore these molecules could be grouped based on shared biosynthesis steps. For example, a shared step in the biosynthesis of trichothecenes is controlled by the gene TRI4.{{cite journal | vauthors = McCormick SP, Alexander NJ, Proctor RH | title = Fusarium Tri4 encodes a multifunctional oxygenase required for trichothecene biosynthesis | journal = Canadian Journal of Microbiology | volume = 52 | issue = 7 | pages = 636–42 | date = July 2006 | pmid = 16917519 | doi = 10.1139/w06-011 }} This enzyme product controls the addition of either three or four oxygen atoms to trichodiene to form either isotrichodiol or isotrichotriol respectively. A variety of trichothecenes can then be synthesized from either of these intermediates and they could therefore be classified as either t-type if synthesized from isotrichotriol or d-type if synthesized from isotrichodiol.

File:Control Of The Apoptosis Mecanisms.pdf

The toxicity of trichothecenes is primarily due to their action as protein synthesis inhibitors; this inhibition occurs at ribosomes during all three stages of protein synthesis: initiation, elongation, and termination.{{Cite journal|last=Kiessling|first=Karl-Heinz | name-list-style = vanc |date=1986|title=Biochemical mechanism of action of mycotoxins|url = https://www.iupac.org/publications/pac/1986/pdf/5802x0327.pdf|journal=Pure and Applied Chemistry|volume=58|issue=2 |pages=327–338 |doi=10.1351/pac198658020327 |s2cid=94777285 }} During initiation, trichothecenes can either inhibit the association of the two ribosomal subunits or inhibit the function of the mature ribosome by preventing the association of the first tRNA with the start codon. Inhibition at elongation most likely occurs due to trichothecenes preventing the function of peptidyl transferase, the enzyme which catalyzes the formation of new peptide bonds on the 60s ribosomal subunit. Inhibition during termination can also be the result of peptidyl transferase inhibition or the ability of trichothecenes to prevent the hydrolysis required at this final step.

The substitution pattern of the ring core of trichothecenes influences the toxin's action as either an inhibitor of initiation or as an inhibitor of elongation/termination. Trichothecenes also can affect general cellular enzyme function as the 12,13-epoxy moiety is susceptible to nucleophilic attack by active-site thiol groups.{{cite journal | vauthors = Ueno Y, Matsumoto H | title = Inactivation of some thiol-enzymes by trichothecene mycotoxins from Fusarium species | journal = Chemical & Pharmaceutical Bulletin | volume = 23 | issue = 10 | pages = 2439–42 | date = October 1975 | pmid = 1212759 | doi = 10.1248/cpb.23.2439 | doi-access = free }} These inhibitory effects are seen most dramatically in actively proliferating cells such as in the gastrointestinal tract or the bone marrow.

Protein synthesis occurs in both the cytoplasm of the cell as well as in the matrix of the mitochondria, the cytoplasmic organelle responsible for producing the cell's energy. This is done through an enzymatic pathway that generates highly oxidized molecules called reactive oxygen species, for example hydrogen peroxide.{{cite journal | vauthors = Zorov DB, Juhaszova M, Sollott SJ | title = Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release | journal = Physiological Reviews | volume = 94 | issue = 3 | pages = 909–50 | date = July 2014 | pmid = 24987008 | pmc = 4101632 | doi = 10.1152/physrev.00026.2013 }} Reactive oxygen species can react with and cause damage to many critical parts of the cell, including membranes, proteins, and DNA.{{cite journal | vauthors = Fang H, Wu Y, Guo J, Rong J, Ma L, Zhao Z, Zuo D, Peng S | title = T-2 toxin induces apoptosis in differentiated murine embryonic stem cells through reactive oxygen species-mediated mitochondrial pathway | journal = Apoptosis | volume = 17 | issue = 8 | pages = 895–907 | date = August 2012 | pmid = 22614820 | doi = 10.1007/s10495-012-0724-3 | s2cid = 17446994 }} Trichothecene inhibition of protein synthesis in the mitochondria allows reactive oxygen species to build up in the cell which inevitably leads to oxidative stress and induction of the programmed cell death pathway, apoptosis.

Additionally, trichothecenes such as T-2 have also been shown to increase the c-Jun N-Terminal Kinase signaling pathway in cells.{{cite journal | vauthors = Li M, Pestka JJ | title = Comparative induction of 28S ribosomal RNA cleavage by ricin and the trichothecenes deoxynivalenol and T-2 toxin in the macrophage | journal = Toxicological Sciences | volume = 105 | issue = 1 | pages = 67–78 | date = September 2008 | pmid = 18535001 | pmc = 2734305 | doi = 10.1093/toxsci/kfn111 }} Here, c-Jun N-Terminal Kinase is able to increase to phosphorylation of its target, c-Jun, into its active form. Activated c-jun acts as a transcription factor in the cell nucleus for proteins important for facilitating the downstream apoptotic pathway.

The trichothecene mycotoxins are toxic to humans, other mammals, birds, fish, a variety of invertebrates, plants, and eukaryotic cells. The specific toxicity varies depending on the particular toxin and animal species, however the route of administration plays a significantly higher role in determining lethality. The effects of poisoning will depend on the concentration of exposure, length of time and way the person is exposed. Exposure to a concentrated solution or aerosolized toxin is more likely to cause severe effects, including death. Upon consumption, the toxin inhibits ribosomal protein, DNA and RNA synthesis,{{cite book | vauthors = McLaughlin C, Vaughan M, Campbell I, Wei CM, Stafford M, Hansen B | year = 1977 | chapter = Inhibition of protein synthesis by trichothecenes. | title = Mycotoxins in human and animal health | location = Park Forest South, IL | publisher = Pathotox Publishers | pages = 263–75 }}{{cite book | vauthors = Wannemacher R, Wiener SL, Sidell FR, Takafuji ET, Franz DR | year = 1997 | title = Trichothecene mycotoxins | chapter= Medical Aspects of Chemical and Biological Warfare | volume = 6 | pages = 655–76 | isbn = 978-9997320919 | publisher = United States Government Printing | edition = 1st }}{{cite journal | vauthors = Desjardins AE, Hohn TM, McCormick SP | title = Trichothecene biosynthesis in Fusarium species: chemistry, genetics, and significance | journal = Microbiological Reviews | volume = 57 | issue = 3 | pages = 595–604 | date = September 1993 | doi = 10.1128/MMBR.57.3.595-604.1993 | pmid = 8246841 | pmc = 372927 }} mitochondrial functions{{cite journal | vauthors = Fried HM, Warner JR | title = Cloning of yeast gene for trichodermin resistance and ribosomal protein L3 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 1 | pages = 238–42 | date = January 1981 | pmid = 7017711 | doi = 10.1073/pnas.78.1.238 | pmc = 319027 | bibcode = 1981PNAS...78..238F | doi-access = free }}{{cite journal | vauthors = Bouaziz C, Martel C, Sharaf el dein O, Abid-Essefi S, Brenner C, Lemaire C, Bacha H | title = Fusarial toxin-induced toxicity in cultured cells and in isolated mitochondria involves PTPC-dependent activation of the mitochondrial pathway of apoptosis | journal = Toxicological Sciences | volume = 110 | issue = 2 | pages = 363–75 | date = August 2009 | pmid = 19541794 | doi = 10.1093/toxsci/kfp117 | doi-access = free }}{{cite journal | vauthors = Bin-Umer MA, McLaughlin JE, Basu D, McCormick S, Tumer NE | title = Trichothecene mycotoxins inhibit mitochondrial translation--implication for the mechanism of toxicity | journal = Toxins | volume = 3 | issue = 12 | pages = 1484–501 | date = December 2011 | pmid = 22295173 | pmc = 3268453 | doi = 10.3390/toxins3121484 | doi-access = free }} cell division{{cite journal | vauthors = Azcona-Olivera JI, Ouyang Y, Murtha J, Chu FS, Pestka JJ | title = Induction of cytokine mRNAs in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol): relationship to toxin distribution and protein synthesis inhibition | journal = Toxicology and Applied Pharmacology | volume = 133 | issue = 1 | pages = 109–20 | date = July 1995 | pmid = 7597700 | doi = 10.1006/taap.1995.1132 | bibcode = 1995ToxAP.133..109A }}{{cite journal | vauthors = Thompson WL, Wannemacher RW | title = Structure-function relationships of 12,13-epoxytrichothecene mycotoxins in cell culture: comparison to whole animal lethality | journal = Toxicon | volume = 24 | issue = 10 | pages = 985–94 | date = 1986 | pmid = 3824405 | doi = 10.1016/0041-0101(86)90004-8 | bibcode = 1986Txcn...24..985T }} while simultaneously activating a cellular stress response named ribotoxic stress response.{{cite journal | vauthors = Shifrin VI, Anderson P | title = Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis | journal = The Journal of Biological Chemistry | volume = 274 | issue = 20 | pages = 13985–92 | date = May 1999 | pmid = 10318810 | doi = 10.1074/jbc.274.20.13985 | doi-access =free }} The trichothecene mycotoxins can be absorbed though topical, oral, and inhalational routes.

Trichothecenes differ from most other potential weapon toxins since they can act through the skin, which is attributed to their amphipathic and lipophilic characteristics. The small amphipathic nature of trichothecenes allows them to easily cross cell membranes and interact with different organelles such as the mitochondria,{{cite journal | vauthors = Cundliffe E, Cannon M, Davies J | title = Mechanism of inhibition of eukaryotic protein synthesis by trichothecene fungal toxins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 1 | pages = 30–4 | date = January 1974 | pmid = 4521056 | pmc = 387925 | doi = 10.1073/pnas.71.1.30 | bibcode = 1974PNAS...71...30C | doi-access = free }}{{cite journal | vauthors = Cundliffe E, Davies JE | title = Inhibition of initiation, elongation, and termination of eukaryotic protein synthesis by trichothecene fungal toxins | journal = Antimicrobial Agents and Chemotherapy | volume = 11 | issue = 3 | pages = 491–9 | date = March 1977 | pmid = 856003 | pmc = 352012 | doi = 10.1128/AAC.11.3.491 }} endoplasmic reticulum (ER).{{cite journal | vauthors = Ueno Y | title = The toxicology of mycotoxins | journal = Critical Reviews in Toxicology | volume = 14 | issue = 2 | pages = 99–132 | date = 1985 | pmid = 3158480 | doi = 10.3109/10408448509089851 }} and chloroplast{{cite journal | vauthors = Pace JG, Watts MR, Canterbury WJ | title = T-2 mycotoxin inhibits mitochondrial protein synthesis | journal = Toxicon | volume = 26 | issue = 1 | pages = 77–85 | date = 1988 | pmid = 3347933 | doi = 10.1016/0041-0101(88)90139-0 | bibcode = 1988Txcn...26...77P }} The lipophilic nature of trichothecenes allow them to be easily absorbed through skin{{cite journal | vauthors = Coulombe RA | title = Biological action of mycotoxins | journal = Journal of Dairy Science | volume = 76 | issue = 3 | pages = 880–91 | date = March 1993 | pmid = 8463495 | doi = 10.3168/jds.S0022-0302(93)77414-7 | url = https://digitalcommons.usu.edu/cgi/viewcontent.cgi?article=1034&context=advs_facpub | doi-access = free }} pulmonary mucosa, and gut. Direct dermal application or oral ingestion of trichothecene causes rapid irritation to the skin or intestinal mucosa. As a dermal irritant and blistering agent, it is alleged to be 400 times more intoxicating than sulfur mustard.

File:Alimentary_Toxic_Aleukia.png

The response in the body to the mycotoxin, alimentary toxic aleukia, occurs several days after consumption, in four stages:

1. The first stage includes inflammation of the gastric and intestinal mucosa.
2. The second stage is characterized by leukopenia, granulopenia, and progressive lymphocytosis.
3. The third stage is characterized by the appearance of a red rash on the skin of the body, as well as hemorrhage of the skin and mucosa. If severe, aphonia and death by strangulation can occur.
4. By the fourth stage, cells in the lymphoid organs and erythropoiesis in the bone marrow and spleen are depleted and immune response is down.

Infection can be triggered by an injury as minor as a cut, scratch, or abrasion.{{cite book | vauthors = Schwarzer K | year = 2009 | chapter = Harmful effects of mycotoxins on animal physiology | title = 17th Annual ASAIM SEA Feed Technology and Nutrition Workshop | location = Hue, Vietnam }}

The following symptoms are exhibited:

• Severe itching and redness of the skin, sores, shedding of the skin
• Distortion of any of the senses, loss of the ability to coordinate muscle movement
• Nausea, vomiting and diarrhea
• Nose and throat pain, discharge from the nose, itching and sneezing
• Coughing, difficulty breathing, wheezing, chest pain and spitting up blood
• Temporary bleeding disorders
• Elevated body temperature{{cite web|url=http://www.dph.illinois.gov/topics-services/emergency-preparedness-response/public-health-care-system-preparedness/trichothecene-mycotoxin|title=Trichothecene Mycotoxin {{!}} IDPH|website=www.dph.illinois.gov |access-date=2018-05-07}}{{cite journal | vauthors = Ueno Y | title = Toxicological features of T-2 toxin and related trichothecenes | journal = Fundamental and Applied Toxicology | volume = 4 | issue = 2 Pt 2 | pages = S124–32 | date = April 1984 | pmid = 6609858 | doi = 10.1016/0272-0590(84)90144-1 }}

When it comes to animal and human food, type A trichothecenes (e.g. T-2 toxin, HT-2 toxin, diacetoxyscirpenol) are of special interest because they are more toxic than the other foodborne trichothecenes, e.g. type B group (e.g. deoxynivalenol, nivalenol, 3- and 15-acetyldeoxynivalenol). However, deoxynivalenol is of concern as it is the most prevalent trichothecene in Europe.{{cite book | vauthors = Miller JD | date = 2003 | chapter = Aspects of the ecology of fusarium toxins in cereals. | title = Mycotoxins and Food Safety. | veditors = de Vries JW, Trucksess MW, Jakson LS | publisher = Kluwer Academic/Plenum Publishers | location = New York | pages = 19–27 }} The major effects of trichothecenes are reduced feed uptake, vomiting, and immuno-suppression.

Relatively few countries, primarily in the European Union, have recommended maximum limits for these mycotoxins in food and animal feed. However, trichothecenes are often tested for elsewhere, in order to prevent them from entering the food chain and to prevent losses in animal production.

Trichothecenes are believed to have been discovered in 1932 in Orenburg, Russia, during World War II, by the Soviet Union. Around 100,000 people (60% mortality rate) began to suffer and die from alimentary toxic aleukia, a lethal disease with symptoms resembling radiation poisoning. It is believed that the Soviet civilians had become ill from ingesting contaminated bread, and inhaling mold through contaminated hay, dusts, and ventilation systems. The culprit is believed to be the toxins Fusarium sporotrichioides and Fusarium poae which are high producers of T-2 toxin.{{cite thesis | vauthors = Joffe AZ | date = 1950 | title = Toxicity of fungi on cereals overwintered in the field: on the etiology of alimentary toxic aleukia. | type = Ph.D. | publisher = Inst. Bot. Acad. Sci. | location = Leningrad | page = 205 }} Fusarium species are probably the most commonly cited and among the most abundant of the trichothecene-producing fungi.{{cite journal | vauthors = Rocha O, Ansari K, Doohan FM | title = Effects of trichothecene mycotoxins on eukaryotic cells: a review | journal = Food Additives and Contaminants | volume = 22 | issue = 4 | pages = 369–78 | date = April 2005 | pmid = 16019807 | doi = 10.1080/02652030500058403 | s2cid = 1534222 }}

Trichothecenes make an ideal biological warfare agent, being lethal and inexpensive to produce in large quantities, stable as an aerosol for dispersion, and without effective vaccination/treatment.{{cite journal | vauthors = Henghold WB | title = Other biologic toxin bioweapons: ricin, staphylococcal enterotoxin B, and trichothecene mycotoxins | journal = Dermatologic Clinics | volume = 22 | issue = 3 | pages = 257–62, v | date = July 2004 | pmid = 15207307 | doi = 10.1016/j.det.2004.03.004 }} Evidence suggests that mycotoxins have already been utilized in biological warfare.

• 1964 there are unconfirmed reports that Egyptian or Russian forces used T-2 with mustard gas
• 1974–1981 "yellow rain" incidents in southeast Asia (Laos, Cambodia) and Afghanistan{{cite journal | vauthors = Heyndrickx A, Sookvanichsilp N, Van den Heede M | title = Detection of trichothecene mycotoxins (yellow rain) in blood, urine and faeces of Iranian soldiers treated as victims of a gas attack | journal = Archives Belges = Belgisch Archief | volume = Suppl | pages = 143–6 | date = 1984 | pmid = 6535464 }}{{cite journal | vauthors = Mirocha CJ, Pawlosky RA, Chatterjee K, Watson S, Hayes W | title = Analysis for Fusarium toxins in various samples implicated in biological warfare in Southeast Asia | journal = Journal of the Association of Official Analytical Chemists | volume = 66 | issue = 6 | pages = 1485–99 | date = November 1983 | pmid = 6643363 }}{{cite journal | vauthors = Spyker MS, Spyker DA | title = Yellow rain: chemical warfare in Southeast Asia and Afghanistan | journal = Veterinary and Human Toxicology | volume = 25 | issue = 5 | pages = 335–40 | date = October 1983 | pmid = 6636506 }}{{cite book | vauthors = Wannemacher JR, Wiener SL | chapter = Chapter 34,: Trichothecene Mycotoxins | title = Medical Aspects Of Chemical And Biological Warfare | veditors = Sidell FR, Takafuji ET, Franz DR | series = Textbook of Military Medicine series | publisher = Office of The Surgeon General, Department of the Army, United States of America }}
• 1975 and 1981 during the Vietnam War, the Soviet Union was alleged to have provided mycotoxins to the armies of Vietnam and Laos for use against resistance forces in Laos and Cambodia{{cite report | vauthors = Haig AM | title = Special Report 98: Chemical Warfare in Southeast Asia and Afghanistan: Report to the Congress from Secretary of State Haig | date = March 22, 1982 | publisher = US Government Printing Office | location = Washington, DC }}{{cite journal | vauthors = Tucker JB | year = 2001 | title = The yellow rain controversy: lessons for arms control compliance. | journal = Nonproliferation Rev. | volume = 8 | pages = 25–39 | doi = 10.1080/10736700108436836 | s2cid = 22473397 }}
• 1979–1989 during the Soviet-Afghan War{{Cite web|url=https://www.jstor.org/stable/20671950|title=World Affairs Vol. 145, No. 3, Afghanistan |jstor=20671950 }}
• 1985–1989 Iran–Iraq War, reports of mycotoxin shipments to Iraq (in form of powder and smoke){{Cite web|url=http://cns.miis.edu/research/wmdme/flow/iraq/seed.htm|title=CNS - Obtain Microbial Seed Stock for Standard or Novel Agent|website=webarchive.loc.gov|access-date=2018-05-06|url-status=dead|archive-url=http://webarchive.loc.gov/all/20011127074853/http://cns.miis.edu/research/wmdme/flow/iraq/seed.htm|archive-date=2001-11-27}}

Since then, trichothecenes have been reported throughout the world.{{cite journal | vauthors = Dohnal V, Jezkova A, Jun D, Kuca K | title = Metabolic pathways of T-2 toxin | journal = Current Drug Metabolism | volume = 9 | issue = 1 | pages = 77–82 | date = January 2008 | pmid = 18220574 | doi = 10.2174/138920008783331176 }} They have had a significant economic impact on the world due to loss of human and animal life, increased health care and veterinary care costs, reduced livestock production, disposal of contaminated foods and feeds, and investment in research and applications to reduce severity of the mycotoxin problem. These mycotoxins account for millions of dollars annually in losses, due to factors that are often beyond human control (environmental, ecological, or storage method).{{Cite journal|date=2011-04-01|title=Impact of mycotoxins on humans and animals|journal=Journal of Saudi Chemical Society|language=en|volume=15|issue=2|pages=129–144|doi=10.1016/j.jscs.2010.06.006|issn=1319-6103|last1=Zain|first1=Mohamed E.|doi-access=free}}

Hazardous concentrations of trichothecenes have been detected in corn, wheat, barley, oats, rice, rye, vegetables, and other crops. Diseases resulting from infection include seed rot, seedling blight, root rot, stalk rot, and ear rot.{{cite journal | vauthors = Schollenberger M, Müller HM, Ernst K, Sondermann S, Liebscher M, Schlecker C, Wischer G, Drochner W, Hartung K, Piepho HP | title = Occurrence and distribution of 13 trichothecene toxins in naturally contaminated maize plants in Germany | journal = Toxins | volume = 4 | issue = 10 | pages = 778–87 | date = October 2012 | pmid = 23162697 | pmc = 3496988 | doi = 10.3390/toxins4100778 | doi-access = free }} Trichothecenes are also common contaminants of poultry feeds and their adverse effects on poultry health and productivity have been studied extensively.{{cite book | vauthors = Leeson S, Dias GJ, Summers JD | year = 1995 | chapter = Tricothecenes | title = Poultry Metabolic Disorders | location = Guelph, Ontario, Canada | pages = 190–226 }}

Several studies have shown that optimal conditions for fungal growth are not necessarily optimum for toxin production.{{cite book | vauthors = Hesseltine CW, Shotwell OL, Smith M, Ellis JJ, Vandegraft E, Shannon G | year = 1970 | chapter = Production of various aflatoxins by strains of the Aspergillis flavus series. | title = Proc. first US–Japan Conf. Toxic Microorg. | location = Washington }} Toxin production is greatest with high humidity and temperatures of 6–24 °C. The fungal propagation and production is enhanced in tropical conditions with high temperatures and moisture levels; monsoons, flash floods and unseasoned rains during harvest.{{cite book | title = Food Safety in the 21st Century: Public Health Perspective | editor-first1 = Puja | editor-last1 = Dudeja | editor-first2 = Rajul K | editor-last2 = Gupta | editor-first3 = Amarjeet Singh | editor-last3 = Minhas | name-list-style = vanc }} Trichothecenes have been detected in air samples suggesting that they can be aerosolized on spores or small particles{{cite journal | vauthors = Brasel TL, Douglas DR, Wilson SC, Straus DC | title = Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins on particulates smaller than conidia | journal = Applied and Environmental Microbiology | volume = 71 | issue = 1 | pages = 114–22 | date = January 2005 | pmid = 15640178 | pmc = 544211 | doi = 10.1128/AEM.71.1.114-122.2005 | bibcode = 2005ApEnM..71..114B }}{{cite journal|last1=Cho|first1=Seung-Hyun|last2=Seo|first2=Sung-Chul|last3=Schmechel|first3=Detlef|last4=Grinshpun|first4=Sergey A.|last5=Reponen|first5=Tiina | name-list-style = vanc |title=Aerodynamic characteristics and respiratory deposition of fungal fragments|journal=Atmospheric Environment|date=September 2005|volume=39|issue=30|pages=5454–5465|doi=10.1016/j.atmosenv.2005.05.042|bibcode=2005AtmEn..39.5454C}}

Natural occurrence of TCT has been reported in Asia, Africa, South America, Europe, and North America{{cite book | veditors = Beasley VR | title = Tricothecene Mycotoxicosis: Pathophysiologic Effects | volume = 1 | publisher = CRC Press | location = Boca Raton | year = 1989 | pages = 1–26 }}

• Akakabibyo, a disease of similar etiology, has also been associated with trichothecene contaminated grains in Japan.{{cite journal | vauthors = Ueno Y, Ishii K, Sakai K, Kanaeda S, Tsunoda H | year = 1972 | title = Toxicological approaches to the metabolites of Fusaria. IV. Microbial survey on "bean-hulls poisoning of horses" with the isolation of toxic trichothecenes, neosolaniol and T-2 toxin of Fusarium solani M-1-1. | journal = Japanese J. Exp. Med. | volume = 42 | issue = 3 | pages = 187–203 | pmid = 4538152 }}
• In China, cereals or their products contaminated with trichothecenes including DON, T-2 toxin, and NIV, have also been associated with outbreaks of gastrointestinal disorders.{{cite journal | vauthors = Lou XY | year = 1988 | title = Fusarium toxins contamination of cereals in China. | journal = Proc. Japanese Assoc. Mycotoxicology | volume = Suppl. 1 | pages = 97–98 }}
• In Yugoslavia, studies on mycotoxigenic fungi in raw milk have indicated that 91% of the samples tested were contaminated{{cite journal | vauthors = Skrinjar M, Danev M, Dimic G | title = Investigation on the presence of toxigenic fungi and aflatoxins in raw milk. | journal = Acta Aliment. | volume = 24 | year = 1995 | pages = 395–402 }}
• In the US, a study was conducted in seven Midwestern states in 1988–1989 and found mycotoxins in 19.5–24.7% of corn samples.{{cite journal | vauthors = Russell L, Cox DF, Larsen G, Bodwell K, Nelson CE | title = Incidence of molds and mycotoxins in commercial animal feed mills in seven midwestern states, 1988–1989 | journal = Journal of Animal Science | volume = 69 | issue = 1 | pages = 5–12 | date = January 1991 | pmid = 1825995 | doi = 10.2527/1991.6915| doi-access = free }} Since the early 1900s, the occurrence of emesis in animals and humans after consumption of cereals infected with Fusarium species have been described.{{cite journal | vauthors = Naumov NA | year = 1916 | title = Intoxicating bread. | journal = Min. Yeml. (Russia), Trudy Ruiri Miwel. I. Fitopatol. Uchen, Kom.| page = 216 }}{{cite journal | vauthors = Dounin M | year = 1930 | title = The fusariosis of cereal crops in European-Russia in 1923. | journal = Phytopathol. | volume = 16 | pages = 305–308 }}
• In a study in the Bihar region of India from 1985 to 1987, 51% of the samples tested were contaminated with molds.{{Cite journal|last1=Ranjan|first1=Kumar S|last2=Sinha|first2=Ashok K | name-list-style = vanc |date=1991|title=Occurrence of mycotoxigenic fungi and mycotoxins in animal feed from bihar, India |journal=Journal of the Science of Food and Agriculture |volume=56|issue=1|pages=39–47|doi=10.1002/jsfa.2740560105 |bibcode=1991JSFA...56...39R }}
• In another study in the Bihar region,{{Cite journal|last1=Phillips|first1=Sarah I.|last2=Wareing|first2=Peter W.|last3=Dutta|first3=Ambika|last4=Panigrahi|first4=Shantanu|last5=Medlock|first5=Victor | name-list-style = vanc |date=1996-01-01|title=The mycoflora and incidence of aflatoxin, zearalenone and sterigmatocystin in dairy feed and forage samples from Eastern India and Bangladesh|journal=Mycopathologia|language=en|volume=133|issue=1|pages=15–21|doi=10.1007/BF00437094|s2cid=32084324|issn=0301-486X}} high levels were reported in groundnut meal used for dairy cattle.
• In Ludhiana and Punjab researchers found 75% of samples from dairy farms contaminated.{{cite journal | vauthors = Dhand NK, Joshi DB, Jand SK | title = Aflatoxins in dairy feeds/ingredients. | journal = Ind. J. Anim. Nutr. | volume = 15 | year = 1998 | pages = 285–286 }}
• In India, estimated 10 million dollars were lost due to groundnut contamination with mycotoxins.{{cite journal | vauthors = Vasanthi S, Bhat RV | title = Mycotoxins in foods—occurrence, health & economic significance & food control measures | journal = The Indian Journal of Medical Research | volume = 108 | pages = 212–24 | date = November 1998 | pmid = 9863277 }}

There are no known direct antidotes to trichothecene exposure. Therefore, risk management in contaminated areas is primarily defined by the treatment of exposure symptoms as well as prevention of future exposure.

Typical routes of exposure to trichothecene toxins include topical absorption, ingestion, and inhalation. Severity of symptoms depends on the dose and type of exposure, but treatment is primarily focused on supporting bodily systems damaged by the mycotoxin. The first step in most exposure cases is to remove potentially contaminated clothing and to flush the sites of exposure thoroughly with water.{{cite web | url = https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+3544|title=T-2 TOXIN – National Library of Medicine HSDB Database|website=toxnet.nlm.nih.gov|access-date=2018-05-07}} This prevents the victim from repeated exposure. Fluids and electrolytes can be given to victims with high levels of gastrointestinal damage to mitigate the effects of reduced tract absorption. Fresh air and assisted respiration can also be administered upon the development of mild respiratory distress. Increasingly severe symptoms can require the application of advanced medical assistance. The onset of leukopenia, or reduction of white blood cell count, can be treated with a plasma or platelet transfusion. Hypotension can be treated with the administration of norepinephrine or dopamine. Development of severe cardiopulmonary distress may require intubation and additional drug treatments to stabilize heart and lung activity.

Additionally, there are a variety of chemicals that can indirectly reduce the damaging effects of trichothecenes on cells and tissues. Activated charcoal solutions are frequently administered to ingestion cases as an adsorbent.{{cite journal | vauthors = Edrington TS, Kubena LF, Harvey RB, Rottinghaus GE | title = Influence of a superactivated charcoal on the toxic effects of aflatoxin or T-2 toxin in growing broilers | journal = Poultry Science | volume = 76 | issue = 9 | pages = 1205–11 | date = September 1997 | pmid = 9276881 | doi = 10.1093/ps/76.9.1205 | doi-access = free | s2cid = 3648573 }} Here, the charcoal acts as a porous substance for the toxin to bind, preventing its absorption through the gastrointestinal tract and increasing its removal from the body through bowel excretion. Similar detoxifying adsorbents can also be added to animal feed upon contamination to reduce the bioavailability of the toxin upon consumption. Antioxidants are also useful in mitigating the damaging effects of trichothecenes in response to the increase of reactive oxygen species they produce in cells. Generally, a good diet rich in probiotics, vitamins and nutrients, proteins, and lipids is thought to be effective in reducing the symptoms of trichothecene poisoning.{{cite journal |vauthors=Adhikari M, Negi B, Kaushik N, Adhikari A, Al-Khedhairy AA, Kaushik NK, Choi EH |date=May 2017 |title=T-2 mycotoxin: toxicological effects and decontamination strategies |journal=Oncotarget |volume=8 |issue=20 |pages=33933–33952 |doi=10.18632/oncotarget.15422 |pmc=5464924 |pmid=28430618}} For example, vitamin E was found to counteract the formation of lipid peroxides induced by T-2 toxin in chickens.{{cite journal | vauthors = Hoehler D, Marquardt RR | title = Influence of vitamins E and C on the toxic effects of ochratoxin A and T-2 toxin in chicks | journal = Poultry Science | volume = 75 | issue = 12 | pages = 1508–15 | date = December 1996 | pmid = 9000276 | doi = 10.3382/ps.0751508 | doi-access = free }} Similarly, co-supplementation of modified glucomannans and selenium in the diets of chickens also consuming T-2 toxin, reduced the deleterious effects of toxin associated depletion of antioxidants in the liver. Despite not being a direct antidote, these antioxidants may be critical in reducing the severity of trichothecene exposures.

File:Deepoxydation.jpg

Trichothecenes are mycotoxins produced by molds that frequently contaminate stores of grain products. This makes trichothecene contamination a significant public health problem, and many areas have strict limits on permitted trichothecene content. For example, in the European Union, only .025 ppm of T-2 toxin is permissible in bakery products intended for human consumption.{{cite journal | vauthors = Stoev SD | title = Foodborne mycotoxicoses, risk assessment and underestimated hazard of masked mycotoxins and joint mycotoxin effects or interaction | journal = Environmental Toxicology and Pharmacology | volume = 39 | issue = 2 | pages = 794–809 | date = March 2015 | pmid = 25734690 | doi = 10.1016/j.etap.2015.01.022 | bibcode = 2015EnvTP..39..794S }} The molds that can produce trichothecenes grow well in dark, temperate places with high moisture content. Therefore, one of the best ways to prevent trichothecene contamination in food products is to store the resources in the proper conditions to prevent the growth of molds. For example, it is generally advised to only store grains in areas with a moisture content of less than 15%.{{cite journal | vauthors = Devreese M, De Backer P, Croubels S | title = Different methods to counteract mycotoxin production and its impact on animal health. | journal = Vlaams Diergen Tijds. | year = 2013 | volume = 82 | issue = 4 | pages = 181–190 | doi = 10.21825/vdt.v82i4.16695 | doi-access = free }} However, if an area has already been contaminated with trichothecene toxins, there are a variety of possible decontamination strategies to prevent further exposure. Treatment with 1% sodium hypochlorite (NaOCl) in 0.1M sodium hydroxide (NaOH) for 4–5 hours has been shown to inhibit the biological activity of T-2 toxin. Incubation with aqueous ozone at approximately 25 ppm has also been shown to degrade a variety of trichothecenes through a mechanism involving oxidation of the 9, 10 carbon double bond.{{cite journal | vauthors = Young JC, Zhu H, Zhou T | title = Degradation of trichothecene mycotoxins by aqueous ozone | journal = Food and Chemical Toxicology | volume = 44 | issue = 3 | pages = 417–24 | date = March 2006 | pmid = 16185803 | doi = 10.1016/j.fct.2005.08.015 }} UV exposure has also been shown to be effective under the right conditions.

Outside of the strategies for physical and chemical decontamination, advancing research in molecular genetics has also given rise to the potential of a biological decontamination approach. Many microbes, including bacteria, yeast, and fungi, have evolved enzymatic gene products which facilitate the specific and efficient degradation of trichothecene mycotoxins. Many of these enzymes specifically degrade the 12,13 carbon epoxide ring which is important for the toxicity of trichothecenes. For example, the Eubacteria strain BBSH 797 produces de-epoxidase enzymes which reduce the 12,13 carbon epoxide ring to a double bond group. These, along with other microbes expressing trichothecene detoxifying properties, can be used in feed stores to prevent to toxic effect of contaminated feed upon consumption. Furthermore, molecular cloning of the genes responsible for producing these detoxifying enzymes could be useful in producing strains of agricultural products that are resistant to trichothecene poisoning.

Epoxy trichothecenes are a variation of the above, and were once explored for military use in East Germany, and possibly the whole Soviet bloc.Die Chemie der Kampfstoffe, GDR Government publishing, 1988 There is no feasible treatment once symptoms of epoxithichothecene poisoning set in, though the effects can subside without leaving any permanent damage.

Any plans to use the epoxy trichothecenes as a large-scale bioweapon were abandoned. They broke down quickly in the presence of heat, UV light, and chlorine. This meant they would be ineffective or quick to remediate in open attacks or water supply poisoning, where it might be exposed to sunlight, boiled, or conditioned with chlorine. {{Cite journal |last1=Adhikari |first1=Manish |last2=Negi |first2=Bhawana |last3=Kaushik |first3=Neha |last4=Adhikari |first4=Anupriya |last5=Al-Khedhairy |first5=Abdulaziz A. |last6=Kaushik |first6=Nagendra Kumar |last7=Choi |first7=Eun Ha |date=2017-05-16 |title=T-2 mycotoxin: toxicological effects and decontamination strategies |journal=Oncotarget |language=en |volume=8 |issue=20 |pages=33933–33952 |doi=10.18632/oncotarget.15422 |issn=1949-2553 |pmc=5464924 |pmid=28430618}}

{{Reflist|32em}}

• [https://web.archive.org/web/20061030075238/http://www.cbwinfo.com/Biological/Toxins/trichothecene_mycotoxins.htm Structures of some of the Commoner Trichothecene Mycotoxins.]
• [http://www.au.af.mil/au/awc/awcgate/medaspec/Ch-34electrv699.pdf Robert W. Wannemacher and Stanley L. Weiner: Trichothecene mycotoxins, chapter 34, Medical Aspects of Chemical and Biological Warfare] {{Webarchive|url=https://web.archive.org/web/20180418224652/http://www.au.af.mil/au/awc/awcgate/medaspec/Ch-34electrv699.pdf |date=2018-04-18 }}

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