Updated Review of the Toxicity of Selected Fusarium Toxins and Their Modified Forms
Abstract
:1. Introduction
2. Metabolism
2.1. DON
2.2. T-2 and HT-2 Toxins
2.3. ZEN
3. Modified Forms of DON
3.1. In Vitro Cytotoxicity
3.2. Cytotoxicity in In Vivo Systems
3.3. Immunotoxicity
3.4. Interactions
4. Modified Forms of T-2 and HT-2
4.1. Cytotoxicity
4.2. Studies in In Vivo Systems
4.3. Immunotoxicity
4.4. Interactions
4.5. Bioinformatic Evaluation of Toxicity
4.6. Metabolism vs. Toxicity
5. Modified Forms of ZEN
5.1. Cytotoxicity
5.2. Studies in the In Vivo Systems
5.3. Immunotoxicity
5.4. Interactions
5.5. Estrogenic Activity
5.6. Oxidative Activity
5.7. Induction of Epigenetic Alteration and Modulation of Gene Expression
5.8. Bioinformatic Evaluation of Toxicity
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Unprocessed Cereals | Maximum Levels (μg/kg) | Source |
---|---|---|
DON | ||
Cereals other than durum wheat, oat, maize | 1250 | [7,8] |
Oat, maize, durum wheat | 1750 | |
ZEN | ||
Cereals other than maize | 100 | [7,8] |
Maize | 350 | |
Sum of T-2 and HT-2 | ||
Oat | 1000 | [9] |
Barley, maize | 200 | |
Wheat, rye and other cereals | 100 |
Tested Animals | Tested Toxins | Exposure Type | Dose | Main Observations | Source |
---|---|---|---|---|---|
Pigs | DON DOM-1 | Orally | 0.5 nmol/kg BW for 21 days 1 mol/kg BW for 14 days | DOM-1 does not cause vomiting, body weight changes, or pathological changes in intestines and liver | [37] |
DON DOM-1 3-epi-DON | Orally | Unrestricted access to feed with toxin content of 3 mg/kg | DON and DOM-1, 3-epi-DON do not cause vomiting, body weight changes, or pathological changes in intestines and liver | [38] | |
DON DON-3G | Orally and intravenously | 55.7 µg/kg BW for DON-3G 36 µg/kg BW for DON | DON-3G does not undergo hydrolysis within the circulatory system and is not absorbed when administered orally | [89,90] | |
Chickens Broilers | DON DON-3G | Orally and intravenously | 500 µg/kg BW for DON 774 µg/kg BW for DON-3G | DON-3G does not undergo hydrolysis within the circulatory system and gastrointestinal tract | [90] |
Cell Line | Tested Toxins | Concentration Range and Exposure Time | Methodology | Main Conclusions | Source |
---|---|---|---|---|---|
HEPG2 | DON 3-AcDON 15-AcDON | 0–12.5 (µM) for 24 h | MTT | IC50 values (µM) were 4.3, 6.2, and 8.1 for DON, 3-AcDON, and 15-AcDON, respectively | [30] |
H2-DCFDA applied and fluorescence measured, TBARS applied and absorbance measured | Increase in ROS level was observed upon exposure to 15-AcDON. Lipid peroxidation was observed upon exposure to DON, 3-AcDON, and 15-AcDON | ||||
0–7.5 (µM) 3-AcDON, 15-AcDON 0–15 (µM) DON for 24 h | Neutral red assay | IC50 values (µM) were 3.90, 6.00, and 10.15 for 3-AcDON, 15-AcDON, and DON, respectively | [39] | ||
0–4.8 (µM) DON 0–3 (µM) 3-AcDON, 15-AcDON for 48 h | Flow cytometry | Toxins have the ability to disturb the cell cycle and induce micronucleus formation | |||
GES-1 | DON 3-AcDON 15-AcDON DON-3G | 0–3 (ppm) DON, 15-AcDON 0–12 (ppm) 3-AcDON, DON-3G for 24 h | Cell counting kit-8 (DOJINDO, Kumamoto, Japan) | The following toxicity ranking was proposed: DON >15-AcDON >>3-AcDON >DON-3G | [31] |
DON 15-AcDON | 0–5 (μM) for 8 h | High-performance liquid chromatography-tandem high-resolution mass | Proving metabolic balance disturbances upon exposure to DON, 15-AcDON | [41] | |
Western blot | Induction of apoptosis by DON and 15-AcDON was observed as a result of the activation of mitogene-activated kinases (MAPK) p38 and JNK and ERK1/2 kinases inhibition | ||||
5 (μM) for 30 min for the ROS assay 5 (μM) for 24 h for ATP and NAD+/NADH measurements | DCF-DA applied and fluorescence measured ATP Assay Kit NAD+/NADH Assay Kit | Increase in ROS level Decrease in ATP level and NAD+/NADH balance disturbances upon exposure to DON and 15-AcDON. | |||
IPEC-J2 | DON 3-AcDON 15-AcDON DON-3G | 0–20 µg/ml for 72 h | Flow cytometry | Following toxicity ranking: 15-AcDON ≈DON >3-AcDON >>DON-3G was drawn | [25] |
DON DOM-1 | 0–100 (µM) for 24, 48, and 72 h | NR, SRB, LDH, WST-1, MTT, CTG | DOM-1 showed no cytotoxicity | [88] | |
CACO-2 | DON DON-3G | 0–10 (µM) for 48 h | CellTiter-Glo Luminescent Cell Viability Assay (Promega, Madison, USA) | DON-3G showed no cytotoxicity | [87] |
DON 3-AcDON 15-AcDON DON-3G DOM-1 | 0–8.4 (µM) for 24 h for LDH assay for 4, 8, 12, and 24 h for TEER assays | LDH, TEER assay | Lower 3-AcDON cytotoxicity compared with that of 15-AcDON and DON DON-3G and DOM-1 showed no cytotoxicity | [82] | |
DON 3-AcDON 15-AcDON | 0–0.5 (µM) for 24 h | RT-PCR | Inhibition of cell cycle by DON, 3-AcDON, and 15-AcDON as a result of ATM kinase activation | [43] | |
0–10 (µM) for 24, 48, and 72 h | Cell-counting kit-8 (Shanghai, China) | Toxicity ranking below reported: 15-AcDON ≈DON >3-AcDON | |||
PBMC from bovine, pig and chicken sources | DON DOM-1 | 0–3.37 (µM) for 28 h DON 0–357 (µM) for 72 h DOM-1 | Bromodeoxyuridine assay (BrdU) | DOM-1 at a concentration of 357 (µM) inhibits proliferation of PBMC obtained from bovine, pig and chicken sources | [97] |
Tested Animals | Tested Toxins | Exposure Type | DOSE | Main Observations | Source |
---|---|---|---|---|---|
Pigs | ZEN-14G ZEN-14S | Intravenously/orally | 500 μg/kg BW for ZEN-14G 415 μg/kg BW for ZEN-14S | ZEN-14G may hydrolyse in the circulatory system. ZEN-14G and ZEN-14S are fully hydrolysed within the GI tract | [132] |
ZEN-14G ZEN-14S | Orally | 15.1 µg/kg BW for ZEN-14G 12.5 µg/kg BW for ZEN-14S | No detectable quantities of tested toxins were found in urine or faeces | [135] | |
Rats | α-ZOL α-ZOL-14G | Intravenously/orally | 0.5 mg/kg BW for α-ZOL 0.75 mg/kg BW for α-ZOL-14G | Efficient conversion of α-ZOL-14G into ZEN. Low bioavailability of oral α-ZOL and α-ZOL-14G after oral administration | [133] |
Caenorhabditis elegans (nematodes) | ZEN ZEN-14S | Medium culture containing mycotoxins | ZEN: 24; 228 (µM) ZEN-14S: 19; 95 (µM) | Comparable reduction in the offspring number of nematodes by ZEN and ZEN-14S | [136] |
Cell Line | Tested Toxins | Applied Concentrations | Methodology | Main Conclusions | Source |
---|---|---|---|---|---|
HEPG2 | ZEN α-ZOL β-ZOL | 0–100 (µM) for 72 h | Neutral red assay | Established IC50 values(μM): 13.1 for β-ZOL 39.7 forZEN 119 for α-ZOL | [35] |
Qiagen RNeasy midi kit (QIAGEN GmbH, Germany) | IL-1β, IL-8, and TNF-α expression were inhibited by ZEN, α-ZOL, and β-ZOL | ||||
ZEN α-ZOL | 0–250 (μM) for 24 h | MTT | Established IC50 values (µM): 131.40 for α-ZOL 143.35 forZEN | [36] | |
ZEN α-ZOL β-ZOL | 0–100 (μM) for: 24, 48, and 72 h | MTT | Toxicity ranking: α-ZOL >β-ZOL >ZEN | [124] | |
ZEN α-ZOL β-ZOL | 0–25 (μM) for 2 h | Fluorescence measured using dichlorofluorescein | Induction of ROS formation by ZEN, α-ZOL, and β-ZOL at all concentrations used | [119] | |
Comet assay | Dose-dependent induction of DNA damage by ZEN, α-ZOL, and β-ZOL | ||||
Spectrophotometry, Ransod (Randox Laboratories, UK) | Increase in the activities of SOD and GPx, decrease in CAT activity upon exposure to ZEN, α-ZOL, and β-ZOL | ||||
ZEN α-ZOL | 0–50 (μM) for 24 h | Western blot | Increased activities of methyltransferase and acetyltransferase. Increased expression of genes coding components of metabolic pathways and nuclear receptors. | [36] | |
CACO-2 | ZEN α-ZOL β-ZOL | 0–100 (μM) for 48 h | MTT | Established IC50 values (µM): 20 for ZEN 60 forβ-ZOL 80 forα-ZOL | [122] |
ZEN-14G | 0–40 (μM) for 6 h | Resazurin dyeing | No ZEN-14G cytotoxicity found | [131] | |
SH-SY5Y | α-ZOL β-ZOL | 0–100 (μM) for 72 h | MTT | Established IC50 values (μM): 7.5 for β-ZOL 14 for α-ZOL | [48] |
0–12.5 (μM) for: 24, 48, and 72 h | Synergy in the induction of toxic effect found for the mixture of α-ZOL and β-ZOL | ||||
Neutrophils isolated from porcine peripheral blood | ZEN α-ZOL β-ZOL ZAN | 0–50 (μM) for 1 h | MTT | Established IC50 values (μM): 53.1 for ZAN 56.8 for β-ZOL 59.0 for α-ZOL 73.4 for ZEN | [138] |
0–10 (μM) for 3 h | ELISA | IL8 expression in neutrophils reduction caused by ZEN, α-ZOL, β-ZOL, and ZAN | |||
PBMC isolated from porcine peripheral blood | ZEN α-ZOL β-ZOL ZAN | 0–100 (μM) for 48 h | MTT | Established IC50 values (μM): 17.3 for β-ZOL 22.7 for ZEN 26.3 for ZAN 29.1 for α-ZOL | [139] |
0–10 (μM) for 7 days | ELISA | ZEN, α-ZOL, β-ZOL, and ZAN show the ability to decrease production of antibodies in classes: IgG, IgA, and IgM | |||
RAW264.7 | α-ZOL β-ZOL | 0–50 (μM) for 24 h | WST-8 | Higher cytotoxicity of β-ZOL, compared with that of α-ZOL. | [123] |
Flow cytometry | α-ZOL and β-ZOL induce cell death to a greater extent by apoptosis than by necrosis | ||||
Flow cytometry Western blot | α-ZOL and β-ZOL induce apoptosis independently of caspases through mitochondrial stress | ||||
MCF-7 | ZEN-14G | 0–1 (μM) for 6 h | MTS | ZEN-14G shows no cytotoxicity | [130] |
ZEN α-ZOL β-ZOL | 0–25 (µM) for 6 days | E-Screen | Oestrogen activity displayed by ZEN, α-ZOL, and β-ZOL | [141] | |
CHO-K1 | ZEN α-ZOL β-ZOL | 0–25 (μM) for 2 h | Fluorescence measured using dichlorofluorescin | Induction of ROS formation by ZEN, α-ZOL, and β-ZOL at all concentrations tested | [149] |
Comet assay | Dose-dependent induction of DNA damage by ZEN, α-ZOL, and β-ZOL | ||||
Spectrophotometry, Ransod (Randox Laboratories, UK) | SOD and GPx activity increase, CAT activity decreases upon exposure to ZEN, α-ZOL, and β-ZOL | ||||
Jurkat T Cells | α-ZOL | 0–80 (μM) for 24 h | RT–PCR | α-ZOL inhibits expression of IL-2 and IFNγ in a T cell culture | [137] |
3H-thymidine incorporation measurement | T cell proliferation inhibited by α-ZOL | ||||
HCT116 | α-ZOL β-ZOL | 180 (mM) α-ZOL 300 (mM) β-ZOL for 24 h | qRT-PCR | Presence of endoplasmic reticulum stress markers identified upon cell exposure to α-ZOL or β-ZOL | [129] |
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Pierzgalski, A.; Bryła, M.; Kanabus, J.; Modrzewska, M.; Podolska, G. Updated Review of the Toxicity of Selected Fusarium Toxins and Their Modified Forms. Toxins 2021, 13, 768. https://doi.org/10.3390/toxins13110768
Pierzgalski A, Bryła M, Kanabus J, Modrzewska M, Podolska G. Updated Review of the Toxicity of Selected Fusarium Toxins and Their Modified Forms. Toxins. 2021; 13(11):768. https://doi.org/10.3390/toxins13110768
Chicago/Turabian StylePierzgalski, Adam, Marcin Bryła, Joanna Kanabus, Marta Modrzewska, and Grażyna Podolska. 2021. "Updated Review of the Toxicity of Selected Fusarium Toxins and Their Modified Forms" Toxins 13, no. 11: 768. https://doi.org/10.3390/toxins13110768