THE EFFECTS OF FUSARIUM TOXINS ON EPIGENETIC MECHANISMS: FUMONISIN B1 AND ZEARALENONE

Öz

Objective: Fumonisin B1 (FB1) and zearalenone (ZEA) have been the most widely studied Fusarium mycotoxins. It is demonstrated that FB1 and ZEA affect different molecular mechanisms and cause many toxic effects. In this review, it has been aimed to summarize the effects of FB1 and ZEA on epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA (miRNA) levels, as well as their toxic effects at the molecular level. Result and Discussion: It is shown in various studies that FB1 and ZEA change DNA methylation, histone modification and miRNA levels with dose and application time dependent. Additionally, it is identified that epigenetic studies are important in the molecular mechanisms of these mycotoxins.

Anahtar Kelimeler

• Epigenetic mechanisms
• fumonisin B1
• fusarium toxins
• zearalenone

FUSARİUM TOKSİNLERİNİN EPİGENETİK MEKANİZMALAR ÜZERİNE ETKİLERİ: FUMONİSİN B1 VE ZEARALENON

Öz

Amaç: Günümüzde en çok çalışılan Fusarium mikotoksin türleri arasında fumonisin B1 (FB1) ve zearalenon (ZEA) bulunmaktadır. FB1 ve ZEA farklı moleküler mekanizmaları etkilemekte olup birçok toksik etkiye sebep olmaktadır. Bu derlemede FB1 ve ZEA’nın DNA metilasyonu, histon modifikasyonları ve mikroRNA (miRNA) seviyeleri gibi epigenetik mekanizmalar üzerine etkileri ve moleküler düzeyde gözlenen toksik etkilerinin özetlenmesi amaçlanmıştır. Sonuç ve Tartışma: FB1 ve ZEA’nın DNA metilasyonunu, histon modifikasyonunu ve miRNA seviyelerini uygulama süresi ve doza bağlı olarak değiştirdiği çeşitli çalışmalarda gösterilmiş olup bu mikotoksinlerin moleküler mekanizmalarında epigenetik çalışmaların önemi vurgulanmıştır.

Anahtar Kelimeler

• Epigenetik mekanizmalar
• fumonisin B1
• fusarium toksinleri
• zearalenon

Kaynakça

1. 1. Bennett, J.W., Klich, M. (2003). Mycotoxins. Clinical Microbiological Reviews, 16, 497-516. [CrossRef]
2. 2. Creppy, E.E. (2002). Update of survey, regulation and toxic effects of mycotoxins in Europe. Toxicology Letters, 127(1-3), 19-28. [CrossRef]
3. 3. Omurtag, G.Z. (2002). Mikotoksinli besinlerin oluşturacağı tehlikeler. Clinic, 1, 34-37.
4. 4. Alshannaq, A., Yu, J.H. (2017). Occurrence, toxicity, and analysis of major mycotoxins in food. International Journal of Environmental Research and Public Health, 14(6), 632. [CrossRef]
5. 5. Gelderblom, W.C.A., Kriek, N.P.J., Marasas, W.F.O., Thiel, P.G. (1991). Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1 in rats. Carcinogenesis, 12, 1247-1251. [CrossRef]
6. 6. Smith, J.S., Thakur, R.A. (1996). Occurrence and fate of fumonisins in beef. Advances in Experimental Medicine and Biology, 39-55. [CrossRef]
7. 7. Liu, X., Fan, L., Yin, S., Chen, H., Hu, H. (2019). Molecular mechanisms of fumonisin B1-induced toxicities and its applications in the mechanism-based interventions. Toxicon, 167, 1-5. [CrossRef]
8. 8. Dutton, M.F. (1996). Fumonisins, mycotoxins of increasing importance: Their nature and their effects. Pharmacology & Therapeutics, 70(2), 137-161. [CrossRef]

9. 9. National Toxicology Program (NTP). (2001). Toxicology and carcinogenesis studies of fumonisin B1 (CAS No. 116355-83-0) in F344/N rats and B6C3F1 mice (Feed Studies). Nationall Toxicol Program Technical Report, 496, 1-352.
10. 10. Shephard, G.S., Thiel, P.G., Sydenham, E.W., Vleggaar, R., Alberts, J.F. (1994). Determination of the mycotoxin fumonisin B1 and identification of its partially hydrolysed metabolites in the faeces of non-human primates. Food and Chemical Toxicology, 32(1), 23-29. [CrossRef]
11. 11. Voss, K.A., Bacon, C.W., Norred, W.P., Chapin, R.E., Chamberlain, W.J., Plattner, R D., Meredith, F.I. (1996). Studies on the reproductive effects of Fusarium moniliforme culture material in rats and the biodistribution of [14C] fumonisin B1 in pregnant rats. Natural Toxins, 4(1), 24-33. [CrossRef]
12. 12. Dragan, Y.P., Bidlack, W.R., Cohen, S.M., Goldsworthy, T.L., Hard, G.C., Howard, P.C., Voss, K.A. (2001). Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: Fumonisin B1 as an example. Toxicological Sciences, 61(1), 6-17. [CrossRef]
13. 13. EHC. (2000). Fumonisin B1. Environmental health criteria international programme on chemical safety. World Health Organization, Geneva, 219, 1-150.
14. 14. Stockmann-Juvala, H., Savolainen, K. (2008). A review of the toxic effects and mechanisms of action of fumonisin B1. Human & Experimental Toxicology, 27(11), 799-809. [CrossRef]
15. 15. Marasas, W.F.O., Kellerman, T.S., Gelderblom, W.C., Thiel, P.G., Van der Lugt, J.J., Coetzer, J.A. (1988). Leukoencephalomalacia in a horse induced by fumonisin B₁isolated from Fusarium moniliforme. The Onderstepoort Journal of Veterinary Research, 55(4), 197-203.
16. 16. Haschek, W.M., Gumprecht, L.A., Smith, G., Tumbleson, M.E., Constable, P.D. (2001). Fumonisin toxicosis in swine: An overview of porcine pulmonary edema and current perspectives. Environmental Health Perspectives, 109(suppl 2), 251-257. [CrossRef]
17. 17. Chu, F.S., Li, G.Y. (1994). Simultaneous occurrence of fumonisin B1 and other mycotoxins in moldy corn collected from the People's Republic of China in regions with high incidences of esophageal cancer. Applied And Environmental Microbiology, 60(3), 847-852. [CrossRef]
18. 18. Liu, X., Fan, L., Yin, S., Chen, H., Hu, H. (2019). Molecular mechanisms of fumonisin B1-induced toxicities and its applications in the mechanism-based interventions. Toxicon, 167, 1-5. [CrossRef]
19. 19. Wang, E., Norred, W.P., Bacon, C.W., Riley, R.T., Merrill Jr, A.H. (1991). Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme. Journal of Biological Chemistry, 266(22), 14486-14490. [CrossRef]
20. 20. Yoo, H.S., Norred, W.P., Wang, E., Merrill Jr, A.H., Riley, R.T. (1992). Fumonisin inhibition of de novo sphingolipid biosynthesis and cytotoxicity are correlated in LLC-PK1 cells. Toxicology And Applied Pharmacology, 114(1), 9-15. [CrossRef]
21. 21. Turner, P.C., Nikiema, P. ve Wi1d, C.R. (1999). Fumonisin contamination of food: progess in development of biomarkers to better assess human health risks. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 443, 81-93. [CrossRef]
22. 22. He, Q., Riley, R.T., Sharma, R.P. (2002). Pharmacological antagonism of fumonisin B1 cytotoxicity in porcine renal epithelial cells (LLC‐PK1): A model for reducing fumonisin‐induced nephrotoxicity in vivo. Pharmacology & Toxicology, 90(5), 268-277. [CrossRef]
23. 23. Yoo, H.S., Norred, W.P., Showker, J., Riley, R.T. (1996). Elevated sphingoid bases and complex sphingolipid depletion as contributing factors in fumonisin-induced cytotoxicity. Toxicology And Applied Pharmacology, 138(2), 211-218. [CrossRef]
24. 24. Yin, S., Guo, X., Li, J., Fan, L., Hu, H. (2016). Fumonisin B1 induces autophagic cell death via activation of ERN1-MAPK8/9/10 pathway in monkey kidney MARC-145 cells. Archives of Toxicology, 90(4), 985-996. [CrossRef]
25. 25. Singh, M.P., Kang, S.C. (2017). Endoplasmic reticulum stress-mediated autophagy activation attenuates fumonisin B1 induced hepatotoxicity in vitro and in vivo. Food And Chemical Toxicology, 110, 371-382. [CrossRef]
26. 26. Domijan, A.M., Abramov, A.Y. (2011). Fumonisin B1 inhibits mitochondrial respiration and deregulates calcium homeostasis-implication to mechanism of cell toxicity. The International Journal of Biochemistry & Cell Biology, 43(6), 897-904. [CrossRef]
27. 27. Galvano, F., Russo, A., Cardile, V., Galvano, G., Vanella, A., Renis, M. (2002). DNA damage in human fibroblasts exposed to fumonisin B(1). Food Chem Toxicology, 40(1), 25-31. [CrossRef]
28. 28. Stockmann-Juvala, H., Mikkola, J., Naarala, J., Loikkanen, J., Elovaara, E., Savolainen, K. (2004). Fumonisin B1-induced toxicity and oxidative damage in U-118MG glioblastoma cells. Toxicology, 202(3), 73–183. [CrossRef]
29. 29. Arumugam, T., Pillay,Y., Ghazi, T., Nagiah, S., Abdul, N.S., Chuturgoon, A.A. (2019). Fumonisin B1-induced oxidative stress triggers Nrf2-mediated antioxidant response in human hepatocellular carcinoma (HepG2) cells Mycotoxin Research, 35(1), 99-109. [CrossRef]
30. 30. Lim, C.W., Parker, H.M., Vesonder, R.F., Haschek, W.M. (1996). Intravenous fumonisin B1 induces cell proliferation and apoptosis in the rat. Natural Toxins, 4, 34-41. [CrossRef]
31. 31. Yu, S., Jia, B., Liu, N., Yu, D., Zhang, S., Wu, A. (2021). Fumonisin B1 triggers carcinogenesis via HDAC/PI3K/Akt signalling pathway in human esophageal epithelial cells. Science of The Total Environment, 787, 147405. [CrossRef]
32. 32. Zinedine, A., Soriano, J.M., Moltó, J. C., Mañes, J. (2007). Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: An oestrogenic mycotoxin. Food and Chemical Toxicology, 45(1), 1-18.[CrossRef]
33. 33. Kunishige, K., Kawate, N., Inaba, T., Tamada, H. (2017). Exposure to zearalenone during early pregnancy causes estrogenic multitoxic effects in mice. Reproductive Sciences, 24(3), 421-427. [CrossRef]
34. 34. Zheng, W., Wang, B., Li, X., Wang, T., Zou, H., Gu, J., Yuan, Y., Liu, X., Bai, J., Bian, J., Liu, Z. (2018). Zearalenone Promotes Cell Proliferation or Causes Cell Death? Toxins, 10(5), 184. [CrossRef]
35. 35. Abid-Essefi, S., Baudrimont, I., Hassen, W., Ouanes, Z., Mobio, T.A., Anane, R., Bacha, H. (2003). DNA fragmentation, apoptosis and cell cycle arrest induced by zearalenone in cultured DOK, Vero and Caco-2 cells: Prevention by Vitamin E. Toxicology, 192(2-3), 237-248. [CrossRef]
36. 36. Zheng, W., Pan, S., Wang, G., Wang, Y.J., Liu, Q., Gu, J., Bian, J.C. (2016). Zearalenone impairs the male reproductive system functions via inducing structural and functional alterations of sertoli cells. Environmental Toxicology And Pharmacology, 42, 146-155. [CrossRef]
37. 37. Dolinoy, D.C., Weidman, J.R., Jirtle, R.L. (2007). Epigenetic gene regulation: Linking early developmental environment to adult disease. Reproductive Toxicology, 23(3), 297- 307. [CrossRef]
38. 38. Waddington, C. H. (1940). Organisers and genes, The University Press, Cambridge, p160.
39. 39. Portela, A., Esteller, M. (2010). Epigenetic modifications and human disease. Nature Biotechnology, 28, 1057–1068. [CrossRef]
40. 40. Ostry, V., Malir, F., Toman, J., Grosse, Y. (2017). Mycotoxins As human carcinogens-the IARC Monographs classification. Mycotoxin Research, 33, 65–73. [CrossRef]
41. 41. Yan, M.S., Matouk, C.C., Marsden, P.A. (2010). Epigenetics of the vascular endothelium. Journal of Applied Physiology, 109, 916-926. [CrossRef]
42. 42. Herman, J.G., Baylin, S.B. (2003). Gene silencing in cancer in association with promoter hypermethylation. New England Journal of Medicine, 349(21), 2042-2054. [CrossRef]
43. 43. Jones, P.A., Takai, D. (2001). The role of DNA methylation in mammalian epigenetics. Science, 293(5532), 1068-1070. [CrossRef]
44. 44. Yokochi, T., Robertson, K.D. (2002). Preferential methylation of unmethylated DNA by mammalian de novo DNA methyltransferase Dnmt3a. Journal of Biological Chemistry, 277(14), 11735-11745. [CrossRef]
45. 45. Caudill, M.A., Wang, J.C., Melnyk, S., Pogribny, I.P., Jernigan, S., Collins, M.D., James, S.J. (2001). Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine β-synthase heterozygous mice. The Journal of Nutrition, 131(11), 2811-2818. [CrossRef]
46. 46. Choumenkovitch, S.F., Selhub, J., Bagley, P.J., Maeda, N., Nadeau, M.R., Smith, D.E., Choi, S.W. (2002). In the cystathionine β-synthase knockout mouse, elevations in total plasma homocysteine increase tissue S-adenosylhomocysteine, but responses of S-adenosylmethionine and DNA methylation are tissue specific. The Journal of Nutrition, 132(8), 2157-2160. [CrossRef]
47. 47. Das, P.M., Singal, R. (2004). DNA methylation and cancer. Journal of Clinical Oncology, 22(22), 4632-4642. [CrossRef]
48. 48. Esteller, M., Herman, J.G. (2002). Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland, 196(1), 1-7. [CrossRef]
49. 49. Gonzalgo, M.L., Jones, P.A. (1997). Rapid quantitation of methylation differences at specific sites using methylation-sensitive single nucleotide primer extension (Ms-SNuPE). Nucleic Acids Research, 25(12), 2529-2531. [CrossRef]
50. 50. Sayın, D.B. (2008). Metilasyon ve Kanser. Türkiye Klinikleri Tıp Dergisi, 28(4), 513-524.
51. 51. Tsankova, N., Renthal, W., Kumar, A., Nestler, E.J. (2007). Epigenetic regulation in psychiatric disorders. Nature Reviews Neuroscience, 8(5), 355-367. [CrossRef]
52. 52. Strahl, B.D., Allis, C.D. (2000). The language of covalent histone modifications. Nature, 403(6765), 41-45. [CrossRef]
53. 53. Grant, A.P. (2001). A tale of histone modifications. Genome Biology, 2, 1-6. [CrossRef]
54. 54. Peterson, C.L., Laniel, M.A. (2004). Histones and histone modifications. Current Biology, 14(14), R546-R551. [CrossRef]
55. 55. Lizuka, M., Smith, M.M. (2003). Functional consequences of histone modifications. Current Opinion in Genetics & Development, 13, 154-160. [CrossRef]
56. 56. Yao, Q., Chen, Y., Zhou, X. (2019). The roles of microRNAs in epigenetic regulation. Current Opinion in Chemical Biology, 51, 11-17. [CrossRef]
57. 57. Chuturgoon, A., Phulukdaree, A., Moodley, D. (2014). Fumonisin B1 induces global DNA hypomethylation in Hepg2 cells-An alternative mechanism of action. Toxicology, 315, 65-69. [CrossRef]
58. 58. Kouadio, J.H., Dano, S.D., Moukha, S., Mobio, T.A., Creppy, E.E. (2007). Effects of combinations of Fusarium mycotoxins on the inhibition of macromolecular synthesis, malondialdehyde levels, DNA methylation and fragmentation, and viability in Caco-2 cells. Toxicon, 49(3), 306-317. [CrossRef]
59. 59. Demirel, G., Alpertunga, B., Ozden, S. (2015). Role of fumonisin B1 on DNA methylation changes in rat kidney and liver cells. Pharmaceutical Biology, 53(9), 1302-1310. [CrossRef]
60. 60. Sugiyama, K.I., Kinoshita, M., Furusawa, H., Sato, K., Honma, M. (2021). Epigenetic effect of the mycotoxin fumonisin B1 on DNA methylation. Mutagenesis, 36(4), 295-301. [CrossRef]
61. 61. Karaman, E.F., Abudayyak, M., Ozden, S. (2023). The role of chromatin-modifying enzymes and histone modifications in the modulation of p16 gene in fumonisin B1-induced toxicity in human kidney cells. Mycotoxin Research, 1-13. [CrossRef]
62. 62. Karaman, E.F., Ozden, S. (2019). Alterations in global DNA methylation and metabolism-related genes caused by zearalenone in MCF7 and MCF10F cells. Mycotoxin Research, 35(3), 309-320. [CrossRef]
63. 63. Karaman, E.F., Zeybel, M., Ozden, S. (2020). Evaluation of the epigenetic alterations and gene expression levels of HepG2 cells exposed to zearalenone and α-zearalenol. Toxicology Letters, 326, 52-60. [CrossRef]
64. 64. So, M.Y., Tian, Z., Phoon, Y.S., Sha, S., Antoniou, M.N., Zhang, J., Tan-Un, K. C. (2014). Gene expression profile and toxic effects in human bronchial epithelial cells exposed to zearalenone. PloS One, 9(5), e96404. [CrossRef]
65. 65. Zhu, C.C., Hou, YJ., Han, J., Cui, X. S., Kim, N.H., Sun, S.C. (2014). Zearalenone exposure affects epigenetic modifications of mouse eggs. Mutagenesis, 29(6), 489-495. [CrossRef]
66. 66. Pellanda, H., Forges, T., Bressenot, A., Chango, A., Bronowicki, J.P., Guéant, J.L., Namour, F. (2012). Fumonisin FB 1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H 3‐and H 4‐histone methylation patterns in fetuses. Molecular Nutrition & Food Research, 56(6), 976-985. [CrossRef]
67. 67. Sancak, D., Ozden, S. (2015). Global histone modifications in fumonisin B1 exposure in rat kidney epithelial cells. Toxicology in Vitro, 29(7), 1809-1815. [CrossRef]
68. 68. Gardner, N.M., Riley, R.T., Showker, J.L., Voss, K.A., Sachs, A.J., Maddox, J.R., Gelineau-van Waes, J. B. (2016). Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts. Toxicology and Applied Pharmacology, 298, 56-65. [CrossRef]
69. 69. Gao, Y., Zhao, Y., Zhang, H., Zhang, P., Liu, J., Feng, Y., Min, L. (2019). Pubertal exposure to low doses of zearalenone disrupting spermatogenesis through ERα related genetic and epigenetic pathways. Toxicology Letters, 315, 31-38. [CrossRef]
70. 70. Men, Y., Zhao, Y., Zhang, P., Zhang, H., Gao, Y., Liu, J., Min, L. (2019). Gestational exposure to low‐dose zearalenone disrupting offspring spermatogenesis might be through epigenetic modifications. Basic & Clinical Pharmacology & Toxicology, 125(4), 382-393. [CrossRef]
71. 71. Chuturgoon, A.A., Phulukdaree, A., Moodley, D. (2014). Fumonisin B1 modulates expression of human cytochrome P450 1b1 in human hepatoma (Hepg2) cells by repressing Mir-27b. Toxicology Letters, 227(1), 50-55. [CrossRef]
72. 72. Arumugam, T., Ghazi, T., Chuturgoon, A. (2020). Fumonisin B1 epigenetically regulates PTEN expression and modulates DNA damage checkpoint regulation in HepG2 liver cells. Toxins, 12(10), 625. [CrossRef]
73. 73. Cao, C., Ding, Y., Kong, X., Feng, G., Xiang, W., Chen, L., Zhang, B. (2018). Reproductive role of miRNA in the hypothalamic-pituitary axis. Molecular and Cellular Neuroscience, 88, 130-137. [CrossRef]
74. 74. Das, N., Kumar, T.R. (2018). Molecular regulation of follicle-stimulating hormone synthesis, secretion and action. Journal of Molecular Endocrinology, 60(3), R131-R155. [CrossRef]
75. 75. He, J., Zhang, J., Wang, Y., Liu, W., Gou, K., Liu, Z., Cui, S. (2018). MiR-7 mediates the zearalenone signaling pathway regulating FSH synthesis and secretion by targeting FOS in female pigs. Endocrinology, 159(8), 2993-3006. [CrossRef]
76. 76. Grenier, B., Hackl, M., Skalicky, S., Thamhesl, M., Moll, W.D., Berrios, R., Nagl, V. (2019). MicroRNAs in porcine uterus and serum are affected by zearalenone and represent a new target for mycotoxin biomarker discovery. Scientific Reports, 9(1), 1-14. [CrossRef]
77. 77. Wang, M., Wu, W., Li, L., He, J., Huang, S., Chen, S., Li, P. (2019). Analysis of the miRNA expression profiles in the zearalenone-exposed TM3 Leydig cell line. International Journal of Molecular Sciences, 20(3), 635. [CrossRef]
78. 78. Zheng, W., Fan, W., Feng, N., Lu, N., Zou, H., Gu, J., Liu, Z. (2019). The role of miRNAs in zearalenone-promotion of TM3 cell proliferation. International Journal of Environmental Research and Public Health, 16(9), 1517. [CrossRef]
79. 79. Brzuzan, P., Woźny, M., Wolinska-Nizioł, L., Piasecka, A., Florczyk, M., Jakimiuk, E., Gajęcki, M. (2015). MicroRNA expression profiles in liver and colon of sexually immature gilts after exposure to Fusarium mycotoxins. Polish Journal of Veterinary Sciences, 18(1), 29-38. [CrossRef]
80. 80. Tian, Y., Zhang, M.Y., Li, N., Wang, J.J., Ge, W., Tan, S.J., Li, L. (2020). Zearalenone exposure triggered porcine granulosa cells apoptosis via microRNAs-mediated focal adhesion pathway. Toxicology Letters, 330, 80-89. [CrossRef]