Zearalenone

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Zearalenone
Zearalenone.svg
Zearalenone-from-xtal-3D-bs-17.png
Names
Preferred IUPAC name
(3S,11E)-14,16-Dihydroxy-3-methyl-3,4,5,6,9,10-hexahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione
Other names
Mycotoxin F2
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.038.043 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C18H22O5/c1-12-6-5-9-14(19)8-4-2-3-7-13-10-15(20)11-16(21)17(13)18(22)23-12/h3,7,10-12,20-21H,2,4-6,8-9H2,1H3/b7-3+/t12-/m0/s1 Yes check.svgY
    Key: MBMQEIFVQACCCH-QBODLPLBSA-N Yes check.svgY
  • InChI=1/C18H22O5/c1-12-6-5-9-14(19)8-4-2-3-7-13-10-15(20)11-16(21)17(13)18(22)23-12/h3,7,10-12,20-21H,2,4-6,8-9H2,1H3/b7-3+/t12-/m0/s1
    Key: MBMQEIFVQACCCH-QBODLPLBBS
  • C[C@H]1CCCC(=O)CCC/C=C/c2cc(cc(c2C(=O)O1)O)O
Properties
C18H22O5
Molar mass 318.369 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Zearalenone (ZEN), also known as RAL and F-2 mycotoxin, is a potent estrogenic metabolite produced by some Fusarium and Gibberella species. [1] Specifically, the Gibberella zeae , the fungal species where zearalenone was initially detected, in its asexual/anamorph stage is known as Fusarium graminearum. [2] Several Fusarium species produce toxic substances of considerable concern to livestock and poultry producers, namely deoxynivalenol, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS) and zearalenone. Particularly, ZEN is produced by Fusarium graminearum , Fusarium culmorum , Fusarium cerealis , Fusarium equiseti , [3] Fusarium verticillioides , [4] and Fusarium incarnatum . Zearalenone is the primary toxin that binds to estrogen receptors, causing infertility, abortion or other breeding problems, especially in swine. [4] Often, ZEN is detected together with deoxynivalenol in contaminated samples and its toxicity needs to be considered in combination with the presence of other toxins. [5]

Contents

Zearalenone is heat-stable and is found worldwide in a number of cereal crops, such as maize, barley, oats, wheat, rice, and sorghum. [6] [7] [8] Its production increases when the climate is warm with air humidity at or above twenty percent. [4] The environmental pH plays also a role in the toxin's production. When temperatures fall to 15oC, alkaline soils still support ZEN production. At the preferred Fusarium temperature, which ranges between 25oC and 30oC, neutral pH results in the greatest toxin production. [9]

In addition to its actions on the classical estrogen receptors, zearalenone has been found to act as an agonist of the GPER (GPR30). [8]

Chemical and physical properties

Zearalenone is a white crystalline solid, with molecular formula C18H22O5 and 318.364 g/mol molecular weight. It is a resorcyclic acid lactone. It exhibits blue-green fluorescence when excited by long wavelength ultraviolet (UV) light (360 nm) and a more intense green fluorescence when excited with short wavelength UV light (260 nm). [4] In methanol, UV absorption maxima occur at 236 (e = 29,700), 274 (e = 13,909) and 316 nm (e = 6,020). Maximum fluorescence in ethanol occurs with irradiation at 314 nm and with emission at 450 nm. Solubility in water is about 0.002 g/100 mL. It is slightly soluble in hexane and progressively more so in benzene, acetonitrile, methylene chloride, methanol, ethanol, and acetone. It is also soluble in aqueous alkali.[ citation needed ]

The naturally occurring isomer trans-zearalenone (trans-ZEN) is transformed by ultraviolet irradiation to cis-zearalenone (cis-ZEN). [10]

Metabolic pathways and products

Zearalenone is metabolically transformed to α-zearalenol (α-Zel) or (α-Zol), β-zearalenol (β-Zel) or (β-Zol), α-zearalanol (α-Zal), β-zearalanol (β-Zal), and zearalanone (ZAN) in animals. [9] [11] The relative composition of these metabolic products varies by species. In pigs, cows and ducks, α-Zel is the dominant form detected. [12] [13] [4] In humans, both α-Zel and β-Zel are seen in urine samples, with the beta form being prevalent. [14] In chickens, β-Zel is the dominant form and in plant cells, the metabolic product zeralenonne-14-O-β-glucoside has been detected. [4] Additionally, in the organs of animals these metabolic products are further modified to yield zearalenone-14-glucuronide (ZEN-14GlcA), α-zearalenol-glucuronide (α-Zel-14G) and β-zearalenol-glucuronide (β-Zel-14G). [15]

Dermal exposure

Zearalenone can permeate through the human skin. [16] However, no significant hormonal effects are expected after dermal contact in normal agricultural or residential environments.

Reproduction

Zearalenone structure is similar to estrogens and α-zearalenol binds with an even greater affinity estrogen receptors, while β-zearalenol's affinity is lower than both the parent compound's and α-Zel's binding affinity. [4] This identifies ZEN and its metabolites as xenoestrogens. [3] The human and livestock exposure to ZEN through the diet poses health concern due to the onset of several sexual disorders and alterations in the development of sexual apparatus. [17] [18] There are reliable case reports of early puberty in girls chronically exposed to ZEN in various regions of the world. [19] In mice, ZEN consumption was linked to a decline of potent sperm and egg cells, an increase to double-stranded breaks in DNA and activation of DNA repair mechanisms, followed by embryonic development challenges that reduced the viability of offspring. [11]

Sampling and analysis

In common with other mycotoxins, sampling food commodities for zearalenone must be carried out to obtain samples representative of the consignment under test. Commonly used extraction solvents are aqueous mixtures of methanol, acetonitrile, or ethyl acetate followed by a range of different clean-up procedures that depend in part on the food and on the detection method in use. Thin-layer chromatography (TLC) methods and high-performance liquid chromatography (HPLC) are commonly used. The TLC method for zearalenone is: normal phase silica gel plates, the eluent: 90% dichloromethane, 10% v/v acetone; or reverse phase C18 silica plates; the eluent: 90% v/v methanol, 10% water. Zearalenone gives unmistakable blue luminiscence under UV. [1] HPLC alone is not sufficient, as it may often yield false positive results. Today, HPLC-MS/MS analysis is used to quantify and confirm the presence of zearalenone.

Typically, the representative sample is commuted and homogenized then few grams are used for extraction with acetonitrile/water mixture. The procedure is the widely used QuEChERS method that quickly and effectively extracts small molecules, like mycotoxins and pesticides, from complex food matrices and animal tissues. The determination step relies on liquid chromatography - mass-spectrometry (LC-MS/MS). [15] Another approach for the analysis of ZEA, without the requirement of expensive instrumentation, is developing specific peptide mimetic with the bioluminescent Gaussia luciferase fused as one protein that can bind specifically to ZEA. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Fusarium ear blight</span> Fungal disease of cereals

Fusarium ear blight (FEB), is a fungal disease of cereals, including wheat, barley, oats, rye and triticale. FEB is caused by a range of Fusarium fungi, which infects the heads of the crop, reducing grain yield. The disease is often associated with contamination by mycotoxins produced by the fungi already when the crop is growing in the field. The disease can cause severe economic losses as mycotoxin-contaminated grain cannot be sold for food or feed.

A mycotoxin is a toxic secondary metabolite produced by fungi and is capable of causing disease and death in both humans and other animals. The term 'mycotoxin' is usually reserved for the toxic chemical products produced by fungi that readily colonize crops.

<span class="mw-page-title-main">Phytoestrogen</span> Plant-derived xenoestrogen

A phytoestrogen is a plant-derived xenoestrogen not generated within the endocrine system, but consumed by eating plants or manufactured foods. Also called a "dietary estrogen", it is a diverse group of naturally occurring nonsteroidal plant compounds that, because of its structural similarity to estradiol (17-β-estradiol), have the ability to cause estrogenic or antiestrogenic effects. Phytoestrogens are not essential nutrients because their absence from the diet does not cause a disease, nor are they known to participate in any normal biological function. Common foods containing phytoestrogens are soy protein, beans, oats, barley, rice, coffee, apples, carrots.

<span class="mw-page-title-main">T-2 mycotoxin</span> Chemical compound

T-2 mycotoxin is a trichothecene mycotoxin. It is a naturally occurring mold byproduct of Fusarium spp. fungus which is toxic to humans and other animals. The clinical condition it causes is alimentary toxic aleukia and a host of symptoms related to organs as diverse as the skin, airway, and stomach. Ingestion may come from consumption of moldy whole grains. T-2 can be absorbed through human skin. Although no significant systemic effects are expected after dermal contact in normal agricultural or residential environments, local skin effects can not be excluded. Hence, skin contact with T-2 should be limited.

<span class="mw-page-title-main">Fumonisin B1</span> Chemical compound

Fumonisin B1 is the most prevalent member of a family of toxins, known as fumonisins, produced by multiple species of Fusarium molds, such as Fusarium verticillioides, which occur mainly in maize (corn), wheat and other cereals. Fumonisin B1 contamination of maize has been reported worldwide at mg/kg levels. Human exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple.

<span class="mw-page-title-main">Trichothecene</span> Large family of chemically related mycotoxins

The trichothecenes are a large family of chemically related mycotoxins. They are produced by various species of Fusarium, Myrothecium,Trichoderma/Podostroma, Trichothecium, Cephalosporium, Verticimonosporium, and Stachybotrys. Chemically, trichothecenes are a class of sesquiterpenes.

<span class="mw-page-title-main">Fumonisin</span> Group of chemical compounds

The fumonisins are a group of mycotoxins derived from Fusarium and their Liseola section. They have strong structural similarity to sphinganine, the backbone precursor of sphingolipids.

Patulin is an organic compound classified as a polyketide. It is named after the fungus from which it was isolated, Penicillium patulum. It is a white powder soluble in acidic water and in organic solvents. It is a lactone that is heat-stable, so it is not destroyed by pasteurization or thermal denaturation. However, stability following fermentation is lessened. It is a mycotoxin produced by a variety of molds, in particular, Aspergillus and Penicillium and Byssochlamys. Most commonly found in rotting apples, the amount of patulin in apple products is generally viewed as a measure of the quality of the apples used in production. In addition, patulin has been found in other foods such as grains, fruits, and vegetables. Its presence is highly regulated.

Mycotoxicology is the branch of mycology that focuses on analyzing and studying the toxins produced by fungi, known as mycotoxins. In the food industry it is important to adopt measures that keep mycotoxin levels as low as practicable, especially those that are heat-stable. These chemical compounds are the result of secondary metabolism initiated in response to specific developmental or environmental signals. This includes biological stress from the environment, such as lower nutrients or competition for those available. Under this secondary path the fungus produces a wide array of compounds in order to gain some level of advantage, such as incrementing the efficiency of metabolic processes to gain more energy from less food, or attacking other microorganisms and being able to use their remains as a food source.

<span class="mw-page-title-main">Sterigmatocystin</span> Chemical compound

Sterigmatocystin is a polyketide mycotoxin produced by certain species of Aspergillus. The toxin is naturally found in some cheeses.

<i>Gibberella zeae</i> Species of fungus

Gibberella zeae, also known by the name of its anamorph Fusarium graminearum, is a fungal plant pathogen which causes fusarium head blight (FHB), a devastating disease on wheat and barley. The pathogen is responsible for billions of dollars in economic losses worldwide each year. Infection causes shifts in the amino acid composition of wheat, resulting in shriveled kernels and contaminating the remaining grain with mycotoxins, mainly deoxynivalenol (DON), which inhibits protein biosynthesis; and zearalenone, an estrogenic mycotoxin. These toxins cause vomiting, liver damage, and reproductive defects in livestock, and are harmful to humans through contaminated food. Despite great efforts to find resistance genes against F. graminearum, no completely resistant variety is currently available. Research on the biology of F. graminearum is directed towards gaining insight into more details about the infection process and reveal weak spots in the life cycle of this pathogen to develop fungicides that can protect wheat from scab infection.

<span class="mw-page-title-main">Vomitoxin</span> Fungal toxic chemical in grains

Vomitoxin, also known as deoxynivalenol (DON), is a type B trichothecene, an epoxy-sesquiterpenoid. This mycotoxin occurs predominantly in grains such as wheat, barley, oats, rye, and corn, and less often in rice, sorghum, and triticale. The occurrence of deoxynivalenol is associated primarily with Fusarium graminearum and F. culmorum, both of which are important plant pathogens which cause fusarium head blight in wheat and gibberella or fusarium ear blight in corn. The incidence of fusarium head blight is strongly associated with moisture at the time of flowering (anthesis), and the timing of rainfall, rather than the amount, is the most critical factor. However, increased amount of moisture towards harvest time has been associated with lower amount of vomitoxin in wheat grain due to leaching of toxins. Furthermore, deoxynivalenol contents are significantly affected by the susceptibility of cultivars towards Fusarium species, previous crop, tillage practices, and fungicide use. It occurs abundantly in grains in Norway due to heavy rainfall.

Mycoestrogens are xenoestrogens produced by fungi. They are sometimes referred to as mycotoxins. Among important mycoestrogens are zearalenone, zearalenol and zearalanol. Although all of these can be produced by various Fusarium species, zearalenol and zearalanol may also be produced endogenously in ruminants that have ingested zearalenone. Alpha-zearalanol is also produced semisynthetically, for veterinary use; such use is prohibited in the European Union.

<span class="mw-page-title-main">Zeranol</span> Chemical compound

Zeranol, or zearanol, also known as α-zearalanol or simply zearalanol, is a synthetic nonsteroidal estrogen of the resorcylic acid lactone group related to mycoestrogens found in fungi in the Fusarium genus and is used mainly as an anabolic agent in veterinary medicine.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxins. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.

<span class="mw-page-title-main">Zearalanone</span> Chemical compound

Zearalanone (ZAN) is a mycoestrogen that is a derivative of zearalenone (ZEN). Zearalanone can be extracted from medical herbs and edible herbs along with aflatoxins in the same time by a specific immunoaffinity column.

<span class="mw-page-title-main">Nonsteroidal estrogen</span> Class of drugs

A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.

β-Zearalenol Chemical compound

β-Zearalenol is a nonsteroidal estrogen of the resorcylic acid lactone group related to mycoestrogens found in Fusarium spp. It is the β epimer of α-zearalenol and along with α-zearalenol is a major metabolite of zearalenone formed mainly in the liver but also to a lesser extent in the intestines during first-pass metabolism. A relatively high proportion of α-zearalenol is formed from zearalenone compared to β-zearalenol in humans. β-Zearalenol is about the same or slightly less potent as an estrogen relative to zearalenone.

α-Zearalenol Chemical compound

α-Zearalenol is a nonsteroidal estrogen of the resorcylic acid lactone group related to mycoestrogens found in Fusarium spp. It is the α-epimer of β-zearalenol. Along with β-zearalenol, it is a major metabolite of zearalenone formed mainly in the liver but also to a lesser extent in the intestines during first-pass metabolism. A relatively low proportion of β-zearalenol is metabolized from zearalenone compared to α-zearalenol in humans. α-Zearalenol is about three to four times more potent as an estrogen relative to zearalenone.

<span class="mw-page-title-main">Nivalenol</span> Type of mycotoxin

Nivalenol (NIV) is a mycotoxin of the trichothecene group. In nature it is mainly found in fungi of the Fusarium species. The Fusarium species belongs to the most prevalent mycotoxin producing fungi in the temperate regions of the northern hemisphere, therefore making them a considerable risk for the food crop production industry.

References

  1. 1 2 "Zearalenone". Fermentek. January 2002.
  2. ↑ Liu J, Applegate T (June 2020). "Zearalenone (ZEN) in Livestock and Poultry: Dose, Toxicokinetics, Toxicity and Estrogenicity". Toxins. 12 (6): 377. doi: 10.3390/toxins12060377 . PMC   7354539 . PMID   32517357.
  3. 1 2 Bulgaru CV, Marin DE, Pistol GC, Taranu I (March 2021). "Zearalenone and the Immune Response". Toxins. 13 (4): 248. doi: 10.3390/toxins13040248 . PMC   8066068 . PMID   33807171.
  4. 1 2 3 4 5 6 7 Ropejko K, Twarużek M (January 2021). "Zearalenone and Its Metabolites-General Overview, Occurrence, and Toxicity". Toxins. 13 (1): 35. doi: 10.3390/toxins13010035 . PMC   7825134 . PMID   33418872.
  5. ↑ Peillod C, Laborde M, Travel A, Mika A, Bailly JD, Cleva D, et al. (February 2021). "Toxic Effects of Fumonisins, Deoxynivalenol and Zearalenone Alone and in Combination in Ducks Fed the Maximum EUTolerated Level". Toxins. 13 (2): 152. doi: 10.3390/toxins13020152 . PMC   7920068 . PMID   33669302.
  6. ↑ Kuiper-Goodman T, Scott PM, Watanabe H (September 1987). "Risk assessment of the mycotoxin zearalenone". Regulatory Toxicology and Pharmacology. 7 (3): 253–306. doi:10.1016/0273-2300(87)90037-7. PMID   2961013.
  7. ↑ Tanaka T, Hasegawa A, Yamamoto S, Lee US, Sugiura Y, Ueno Y (1988). "Worldwide Contamination of Cereals by the Fusarium Mycotoxins Nivalenol, Deoxynivalenol, and Zearalenone. 1. Survey of 19 Countries". Journal of Agricultural and Food Chemistry. 36 (5). American Chemical Society: 979–983. Bibcode:1988JAFC...36..979T. doi:10.1021/jf00083a019.
  8. 1 2 Prossnitz ER, Barton M (May 2014). "Estrogen biology: new insights into GPER function and clinical opportunities". Molecular and Cellular Endocrinology. 389 (1–2): 71–83. doi:10.1016/j.mce.2014.02.002. PMC   4040308 . PMID   24530924.
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  10. ↑ Brezina U, Kersten S, Valenta H, Sperfeld P, Riedel J, Dänicke S (November 2013). "UV-induced cis-trans isomerization of zearalenone in contaminated maize". Mycotoxin Research. 29 (4): 221–227. doi:10.1007/s12550-013-0178-7. PMID   24018604. S2CID   17466231.
  11. 1 2 Yang D, Jiang X, Sun J, Li X, Li X, Jiao R, et al. (September 2018). "Toxic effects of zearalenone on gametogenesis and embryonic development: A molecular point of review". Food and Chemical Toxicology. 119: 24–30. doi:10.1016/j.fct.2018.06.003. PMID   29864477. S2CID   46927149.
  12. ↑ Peillod C, Laborde M, Travel A, Mika A, Bailly JD, Cleva D, et al. (February 2021). "Toxic Effects of Fumonisins, Deoxynivalenol and Zearalenone Alone and in Combination in Ducks Fed the Maximum EUTolerated Level". Toxins. 13 (2): 152. doi: 10.3390/toxins13020152 . PMC   7920068 . PMID   33669302.
  13. ↑ Gruber-Dorninger C, Faas J, Doupovec B, Aleschko M, Stoiber C, Höbartner-Gußl A, et al. (January 2021). "Metabolism of Zearalenone in the Rumen of Dairy Cows with and without Application of a Zearalenone-Degrading Enzyme". Toxins. 13 (2): 84. doi: 10.3390/toxins13020084 . PMC   7911295 . PMID   33499402.
  14. ↑ Al-Jaal B, Latiff A, Salama S, Hussain HM, Al-Thani NA, Al-Naimi N, et al. (April 2021). "Analysis of Multiple Mycotoxins in the Qatari Population and Their Relation to Markers of Oxidative Stress". Toxins. 13 (4): 267. doi: 10.3390/toxins13040267 . PMC   8068385 . PMID   33917988.
  15. 1 2 Yan Z, Wang L, Wang J, Tan Y, Yu D, Chang X, et al. (March 2018). "A QuEChERS-Based Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Determination of Nine Zearalenone-Like Mycotoxins in Pigs". Toxins. 10 (3): 129. doi: 10.3390/toxins10030129 . PMC   5869417 . PMID   29558416.
  16. ↑ Boonen J, Malysheva SV, Taevernier L, Diana Di Mavungu J, De Saeger S, De Spiegeleer B (November 2012). "Human skin penetration of selected model mycotoxins". Toxicology. 301 (1–3): 21–32. Bibcode:2012Toxgy.301...21B. doi:10.1016/j.tox.2012.06.012. PMID   22749975.
  17. ↑ Massart F, Saggese G (April 2010). "Oestrogenic mycotoxin exposures and precocious pubertal development". International Journal of Andrology. 33 (2): 369–376. doi: 10.1111/j.1365-2605.2009.01009.x . PMID   20002219.
  18. ↑ Schoevers EJ, Santos RR, Colenbrander B, Fink-Gremmels J, Roelen BA (August 2012). "Transgenerational toxicity of Zearalenone in pigs". Reproductive Toxicology. 34 (1): 110–119. Bibcode:2012RepTx..34..110S. doi:10.1016/j.reprotox.2012.03.004. PMID   22484360.
  19. ↑ Hueza IM, Raspantini PC, Raspantini LE, Latorre AO, Górniak SL (March 2014). "Zearalenone, an estrogenic mycotoxin, is an immunotoxic compound". Toxins. 6 (3): 1080–1095. doi: 10.3390/toxins6031080 . PMC   3968378 . PMID   24632555.
  20. ↑ Peltomaa R, Fikacek S, Benito-Peña E, Barderas R, Head T, Deo S, et al. (September 2020). "Bioluminescent detection of zearalenone using recombinant peptidomimetic Gaussia luciferase fusion protein". Mikrochimica Acta. 187 (10): 547. doi:10.1007/s00604-020-04538-7. PMC   7938698 . PMID   32886242.
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