Potential Impacts of FB1 Exposure on Global DNA Methylation in Pancreatic Cells

Abstract

Background and Aims: Fumonisin B1 (FB1), which emerges from the contamination of corn and similar products by Fusarium species, causes a high risk for human and animal health. There are studies showing that FB1 causes carcinogenesis in the kidney and liver, but there is no study yet on the toxic effects of this molecule, which has an effect on lipid metabolism, on the pancreas. Because FB1 shows its toxic effects through nongenotoxic mechanisms, this study aimed to investigate the effects of FB1 on DNA methylation, an important epigenetic biomarker, in human pancreatic epithelial carcinoma cells (PANC-1). Methods: PANC-1 cells treated with FB1 at concentrations of 10, 50, and 100 µM for 24 h were evaluated for global DNA methylation and expression of DNMT1, DNMT3a, and DNMT3b genes. Results: It was found that exposure to 100 µM of FB1 increased global DNA methylation by 2.15-fold, however this phenomenon was not found to be associated with the changes in the gene expression of DNMTs. Conclusion: The findings of this study indicate that high doses (100 µM) of FB1 resulted in global DNA methylation in PANC-1 cells. However, this increase was not associated with a change in the gene expression of DNMT enzymes. Consequently, further research is required to gain a deeper understanding of the epigenetic effects of FB1.

Keywords

• DNMTs
• Fumonisin B1
• Global DNA Methylation
• PANC-1 Cell Line

References

1. Abado-Becognee, K., Mobio, T. A., Ennamany, R., Fleurat-Lessard, F., Shier, W. T., Badria, F., & Creppy, E. E. (1998). Cytotoxicity of fumonisin B1: Implication of lipid peroxidation and inhibition of protein and DNA syntheses. Archives of Toxicology, 72(4), 233–236. https://doi.org/10. 1007/s002040050494 google scholar
2. Abel S., & Gelderblom, W. C. (1998). Oxidative damage and fumonisin B1- induced toxicity in primary rat hepatocytes and rat liver in vivo. Toxicology, 131(2-3), 121–31. https://doi.org/10.1016/S0300-483X(98)00123-1 google scholar
3. Abudayyak, M., Karaman, E. F., Guler, Z. R., & Ozden, S. (2023). Effects of perfluorooctanoic acid on endoplasmic reticulum stress and lipid metabolism-related genes in human pancreatic cells. Environmental Toxicology and Pharmacology, 98, 104083. https://doi.org/10.1016/j.etap.2023.104083 google scholar
4. Ahmadnejad, M., Amirizadeh, N., Mehrasa, R., Karkhah, A., Nikougoftar, M., & Oodi, A. (2017). Elevated expression of DNMT1 is associated with increased expansion and proliferation of hematopoietic stem cells co-cultured with human MSCs. Blood Research, 52(1), 25–30. https://doi.org/10.5045/br.2017.52.1.25 google scholar
5. Alley, M. C., Scudiere, D. A., Monks, A., Hursey, M. L., Czerwinski, M. J., Fine, D. L., Abbott, B. J., Mayo, J. G., Shoemaker, R. H., & Boyd, M. R. (1988). Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Research, 48(3), 589–60. https://pubmed.ncbi.nlm.nih.gov/3335022/ google scholar
6. 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. https://doi.org/10.3390/toxins12100625 google scholar
7. Chuturgoon, A. A., Phulukdaree, A., & Moodley, D. (2014). Fumonisin B1 induces global DNA hypomethylation in HepG2 cells - An alternative mechanism of action. Toxicology, 315, 65–69. https://doi.org/10.1016/j.tox.2013.11.004 google scholar
8. Chuturgoon, A. A., Phulukdaree, A., & Moodley, D. (2015). Fumonisin B1 inhibits apoptosis in HepG2 cells by inducing Birc-8/ILP-2. Toxicology Letters, 235(2), 67–74. https://doi.org/10.1016/j.toxlet.2015.03.006 google scholar

9. Cetin, Y., & Bullerman, L. B. (2005). Cytotoxicity of Fusarium mycotoxins to mammalian cell cultures as determined by the MTT bioassay. Food and Chemical Toxicology, 43(5), 755–764. https://doi.org/10.1016/0278-6915(92)90038-M google scholar
10. 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. https://doi.org/10.3109/13880209.2014.976714 google scholar
11. Domijan, A. M., & Abramov, A. Y. (2011). Fumonisin B1 inhibits mitochondrial respiration and deregulates calcium homeostasis—implication to mechanism of cell google scholar
12. toxicity. The International Journal of Biochemistry & Cell Biology, 43(6), 897– 904. https://doi.org/10.1016/j.biocel.2011.03.003 google scholar
13. Dutton, M. (2009). The African Fusarium/maize disease. Mycotoxin Research, 25, 29– 39. https://doi.org/10.1007/s12550-008-0005-8 google scholar
14. Galvano, F., Russo, A., Cardile, V., Galvano, G., Vanella, A., & Renis, M. (2002). DNA damage in human fibroblasts exposed to fumonisin B1. Food and Chemical Toxicology, 40(1), 25–31. https://doi.org/10.1016/S0278-6915(01)00083-7 google scholar
15. Gavino, V. C., Miller, J. S., Ikharebha, S. O., Milo, G. E., & Cornwell, D. G. (1981). Effect of polyunsaturated fatty acids and antioxidants on lipid peroxidation in tissue cultures. Journal of Lipid Research, 22(5), 763 – 9. https://pubmed.ncbi.nlm.nih. gov/7288284/ google scholar
16. Gelderblom, W. C. A., Marasas, W., Thiel, P., Semple, E. & Farber, E. (1989). Possible nongenotoxic nature of active carcinogenic components produced by Fusarium moniliforme. The American Association for Cancer Research, 30, 144 – 147. google scholar
17. Gelderblom, W. C., Kriek, N. P., Marasas, W. F., & Thiel, P. G. (1991a). Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1, in rats. Carcinogenesis, 12(7), 1247–1251. https://doi.org/10.1093/carcin/12.7.1247 google scholar
18. Gelderblom, W. C., & Synman, L. (1991b). Mutagenicity of potentially carcinogenic mycotoxins produced by Fusarium moniliforme. Mycotoxin Research, 7(2), 46– 52. https://doi.org/10.1007/BF03192165 google scholar
19. Gelderblom, W. C., Semple, E., Marasas, W. F., & Farber, E. (1992). The cancer-initiating potential of the fumonisin B mycotoxins. Carcinogenesis, 13(3), 433–437. https://doi.org/10.1093/carcin/13.3.433 google scholar
20. Gelderblom, W. C., Snyman, L., Van der Westhuizen, L., & Marasas, W. F. (1995). Mitoinhibitory effect of fumonisin B1 on rat hepatocytes in primary culture. Carcinogenesis, 16(3), 625–631. https://doi.org/10.1093/carcin/16.3.625 google scholar
21. Gelderblom, W. C., Smuts, C. M., Abel, S., Snyman, S. D., Cawood, M. E., Van der West-huizen, L., Swanevelder, S. (1996a). Effect of fumonisin B₁ on protein and lipid synthesis in primary rat hepatocytes. Food and Chemical Toxicology, 34(4), 361–369. https://doi.org/10.1016/0278-6915(96)00107-X google scholar
22. Gelderblom, W. C., Snyman, S., Abel, S., Lebepe-Mazur, S., Smuts, C. M., Van der Westhuizen, L., Marasas, W. F., Victor, T. C., Knasmüller, S., & Huber, W. (1996b). Hepatotoxicity and carcinogenicity of the fumonisins in rats: A review regarding mechanistic implications for establishing risk in humans. Advances in Experimental Medicine and Biology, 392, 279–96. https://pubmed.ncbi.nlm.nih. gov/8850624/ google scholar
23. Gelderblom, W. C. A., Abel, S., Smuts, C. M., Marnewick, J., Marasas, W. F. O., & Lemmer, E. R. (2001). Fumonisin induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion. Environmental Health Perspectives, 109(Suppl 2), 291–300. https://doi.org/10.1289/ehp.01109s2291 google scholar
24. Gelderblom, W. C. A., & Marasas, W. F. A. (2012). Controversies in fumonisin mycotox-icology and risk assessment. Human & Experimental Toxicology, 31(3), 215-35. https://doi.org/10.1177/0960327110395338 google scholar
25. Gu, H., Gao, J., Guo, W., Zhou, Y., & Kong, Q. (2017). The expression of DNA methyltransferases 3A is specifcally downregulated in chorionic villi of early embryo growth arrest cases. Molecular Medicine Reports, 16(1), 591–596. https://doi. org/10.3892/mmr.2017.6650 google scholar
26. Joshi, K., Liu, S., Breslin, S. J. P., & Zhang, J. (2022). Mechanisms that regulate the activities of TET proteins. Cellular and Molecular Life Sciences, 79(7), 363. https:// doi.org/10.1007/s00018-022-04396-x google scholar
27. Kang, Y. J., & Alexander, J. M. (1996). Alterations of the glutathione redox cycle status in fumonisin B1-treated pig kidney cells. Journal of Biochemical Toxicology, 11(3), 121–6. https://doi.org/10.1002/(SICI)1522-7146(1996)11:3<121::AID-JBT3>3.0.CO;2-M google scholar
28. 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. https://doi.org/10.1007/s12550-019-00358-8 google scholar
29. Karaman, E. F., Zeybel, M., & Ozden, S. (2020) Evaluation of the epigenetic alterations and gene expression levels of HepG2 cells exposed to zearalenone and alphazearalenol. Toxicology Letters, 326, 52–60. https://doi.org/10.1016/j.toxlet.2020. 02.015 google scholar
30. Karaman, E. F., Abudayyak, M., & Ozden, S. (2023). The role of chromatin‑modifying enzymes and histone modifications in the modulation of p16 gene in fumon- google scholar
31. isin B1‑induced toxicity in human kidney cells. Mycotoxin Research, 39(3), 271– 283. https://doi.org/10.1007/s12550-023-00494-2 google scholar
32. Kellerman, T. S., Marasas, W. F., Pienaar, J. G., & Naudé, T. W. (1972). A mycotoxicosis of equidae caused by Fusarium moniliforme sheldon. A preliminary communication. Onderstepoort Journal of Veterinary Research, 39(4), 205-8. https:// pubmed.ncbi.nlm.nih.gov/4664322/ google scholar
33. Kouadio, J. H., Mobio, T. A., Baudrimont, I., Moukha, S., Dano, S. D., Creppy, E. E. (2005). Comparative study of cytotoxicity and oxidative stress induced by deoxyni-valenol, zearalenone or fumonisin B1 in human intestinalcell line Caco-2. Toxicology, 213: 56–65. https://doi.org/10.1016/j.tox.2005.05.010 google scholar
34. 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. https://doi.org/10.1016/j. toxicon.2006.09.029 google scholar
35. 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(1), 34– 41. https://doi.org/10.1002/19960401NT5 google scholar
36. Marasas, W. F., Kellerman, T. S., Gelderblom, W. C., Coetzer, J. A., Thiel, P. G., & Van der Lugt, J. J. (1988). Leukoencephalomalacia in a horse induced by fumonisin B1 isolated from Fusarium moniliforme. Onderstepoort Journal of Veterinary Research, 55(4), 197-203. https://pubmed.ncbi.nlm.nih.gov/3217091/ google scholar
37. Marasas, W. F. (2001). Discovery and occurrence of the fumonisins: a historical perspective. Environmental Health Perspective, 109(2): 239–243. https://doi.org/10. 1289/ehp.01109s2239 google scholar
38. Matthaios, D., Hountis, P., Karakitsos, P., Bouros, D., & Kakolyris, S. (2013). H2AX a promising biomarker for lung cancer: a review. Cancer Investigation, 31(9), 582– 99. https://doi.org/10.3109/07357907.2013.849721 google scholar
39. McKean, C., Tang, L., Tang, M., Billam, M., Wang, Z., Theodorakis, C. W., Kendall, R. J., & Wang, J. S. (2006). Comparative acute and combinative toxicity of aflatoxin B1 and fumonisin B1 in animals and human cells. Food and Chemical Toxicology, 44(6), 868–876. https://doi.org/10.1016/j.fct.2005.11.011 google scholar
40. Mobio, T. A., Anane, R., Baudrimont, I., Carratú, M. R., Shier, T. W., Dano, S. D., Ueno, Y., & Creppy, E. E. (2000). Epigenetic properties of fumonisin B1: cell cycle arrest and DNA base modifcation in C6 glioma cells. Toxicology and Applied Pharmacology, 164(1), 91–96. https://doi.org/10.1006/taap.2000.8893 google scholar
41. Mobio, T. A., Tavan, E., Baudrimont, I., Anane, R., Carratú, M. R., Sanni, A., et al. (2003). Comparative study of the toxic effects of fumonisin B1 in rat C6 gliomacells and p53-null mouse embryo fibroblasts. Toxicology, 183, 65–75. https://doi.org/10. 1016/S0300-483X(02)00441-9 google scholar
42. Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1-2), 55-63. https://doi.org/10.1016/0022-1759(83)90303-4 google scholar
43. 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). National Toxicology Program technical report series, 496, 1–352. https://pubmed.ncbi.nlm.nih.gov/11852482/ google scholar
44. Norred, W. P., Plattner, R. D., Vesonder, R. F., Bacon, C. W. & Voss, K. A. (1992). Effects of selected secondary metabolites of Fusarium moniliforme on unscheduled synthesis of DNA by rat primary hepatocytes. Food and Chemical Toxicology, 30(3), 233 – 237. https://doi.org/10.1016/0278-6915(92)90038-M google scholar
45. Park, D. L., Rua, S. M., Mirocha, C. J., Abd-Alla, E. S., & Wenig, C.Y. (1992). Mutagenic potentials of fumonisin contaminated corn following ammonia decontamination procedure. Mycopathologia, 117, 105–108. https://doi.org/10.1007/BF00497285 google scholar
46. Qiu, M., & Liu, X. (2001). Determination of sphinganine, sphingosine and Sa/So ratio in urine of humans exposed to dietary fumonisin B1. Food Additives & Contaminants, 18, 263–269. https://doi.org/10.1080/02652030117470 google scholar
47. Rheeder, J. P., Marasas, W. F., & Vismer, H. F. (2002). Production of fumonisin analogs by Fusarium species. Applied and Environmental Microbiology, 68(5), 2101– 2105. https://doi.org/10.1128/AEM.68.5.2101-2105.2002 google scholar
48. Riley, R. T., Hinton, D. M., Chamberlain, W. J., Bacon, C. W., Wang, E., Merrill, A. H. Jr., & Voss K. A. (1994). Dietary fumonisin B1 induces disruption of sphingolipid metabolism in Sprague-Dawley rats: a new mechanism of nephrotoxicity. The Journal of Nutrition, 124(4), 594–603. https://doi.org/10.1093/jn/124.4.594 google scholar
49. Riley, R. T., Enongene, E., Voss, K. A., Norred, W. P., Meredith, F. I., Sharma, R. P., Spitsbergen, J., Williams, D. E., Carlson, D. B., & Merrill, A. H. Jr. (2001). Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environmental Health Perspectives, 109(2), 301–308. https://doi.org/10.1289/ehp.01109s2301 google scholar
50. Rosa, S. C., Rufno, A. T., Judas, F., Tenreiro, C., Lopes, M. C., & Mendes, A. F. (2011). Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin. Osteoarthritis and Cartilage, 19(6), 719–727. https://doi.org/10.1016/j.joca.2011.02.004 google scholar
51. Senyildiz, M., Ozden, S. (2015). Alteration in global DNA methylation after bisphenol a exposure in MCF-7 cells. Istanbul Journal of Pharmacy, 45(2), 153–164. google scholar
52. Senyildiz, M., Karaman, E. F., Bas, S. S., Pirincci, P. A., & Ozden, S. (2016). Alteration on global and gene-spesific DNA methylation and global histone modifications in HepG2 cells in response to BPA. Istanbul Journal of Pharmacy, 46(2), 97–114. https://dergipark.org.tr/en/pub/iujfp/issue/27053/284679 google scholar
53. Sancak, D., & Ozden, S. (2015). Global histone modifcations in Fumonisin B1 exposure in rat kidney epithelial cells. Toxicology In Vitro, 29(7), 1809–1815. https://doi. org/10.1016/j.tiv.2015.07.019 google scholar
54. Soriano, J. M., Gonzalez, L., & Catala, A. I. (2005). Mechanism of action of sphingolipids and their metabolites in the toxicity of fumonisin B1. Progress in Lipid Research, 44(6), 345–356. https://doi.org/10.1016/j.plipres.2005.09.001 google scholar
55. 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), 295–30. https://doi.org/10.1093/mutage/geab019 google scholar
56. Sun, G., Wang, S., Hu, X., Su, J., Zhang, Y., Xie, Y., Zhang, H., Tang, L., & Wang, J. S. (2011). Co-contamination of aflatoxin B1 and fumonisin B1 in food and human dietary exposure in three areas of China. Food Additives & Contaminants: Part A Chem Anal Control Expo Risk Assess., 28(4), 461–470. https://doi.org/10.1080/ 19440049.2010.544678 google scholar
57. Stockmann-Juvala, H., Mikkola, J., Naarala, J., Loikkanen, J., Elovaara, E., Savolainen, K. (2004). Oxidative stress induced by fumonisin B1 in continuous human and rodent neural cell cultures. Free Radical Research, 38, 933–942. https://doi.org/ 10.1080/10715760412331273205 google scholar
58. 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. https://doi.org/10.1177/0960327108099525 google scholar
59. Voss, K. A., Chamberlain, W. J., Bacon, C. W., Herbert, R. A., Walters, D. B., & Norred, W. P. (1995). Subchronic feeding study of the mycotoxin fumonisin B1 in B6C3F1 mice and Fischer 344 rats. Toxicological Sciences, 24(1), 102–110. https://doi. org/10.1093/toxsci/24.1.102 google scholar
60. Voss, K. A., Gelineau-van Waes, J. B., & Riley, R.T. (2006). Fumonisins: current research trends in developmental toxicology. Mycotoxin Research, 22(1), 61–69. https:// doi.org/10.1007/BF02954559 google scholar
61. Wang, E., Norred, W. P., Bacon, C. W., Riley, R. T., & Merrill, A. H. Jr. (1991). Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme. Journal of Biological Chemistry, 266(2), 14486– 14490. https://pubmed.ncbi.nlm.nih.gov/1860857/ google scholar