In silico analysis to predict the carcinogenicity and mutagenicity of a group of triazole fungicides

Yıl 2024, Cilt: 54 Sayı: 2, 205 - 214, 26.08.2024

Mine Çağlayan

https://doi.org/10.26650/IstanbulJPharm.2024.1399961

Öz

Background and Aims: Fungicides, particularly triazoles, are of global concern for pesticide contamination because of their widespread use. This study focuses on estimating the carcinogenicity and mutagenicity of 15 commonly used triazole fungicides.

Methods: In silico prediction tools such as ProTox-II, Toxtree, Lazar, and VEGA were used to predict mutagenicity and carcino genicity.

Results: All compounds were predicted to be “non-mutagenic” by ProTox-II, Toxtree, and Lazar. However, the CONSENSUS of VEGAidentified epoxiconazole and prothioconazole as “mutagenic." Regarding carcinogenicity predictions, ProTox-II indicated non-carcinogenicity for all compounds, whereas Toxtree and VEGA (ISS) raised structural alerts for 10 compounds. In addition, Lazarpredicted carcinogenicity for tebuconazole, paclobutrazol, and penconazole. It is worth noting that the results exhibit variable reliability, emphasising the need for further investigation and validation.

Conclusion: In silico tools proved valuable for predicting the toxicity of triazole fungicides, emphasising the need for additional data. Although the study categorises compounds as non-mutagenic, some exhibit structural alerts for potential carcinogenicity. This strategic approach contributes to pesticide risk assessment by highlighting the role of computational models in advancing our understanding of the health impacts associated with pesticide exposure.

Anahtar Kelimeler

Carcinogenicity, genotoxicity, in silico, mutagenicity, triazole fungicides

Kaynakça

• Ben Othmene, Y., Hamdi, H., Annabi, E., Amara, I., Ben Salem, I., Neffati, F., Najjar, M. F., & Abid-Essefi, S. (2020). Tebucona-zole induced cardiotoxicity in male adult rat. Food and Chem-ical Toxicology : An International Journal Published for the British Industrial Biological Research Association, 137, 111134. https://doi.org/10.1016/j.fct.2020.111134 google scholar
• Benigni, R., & Bossa, C. (2006). Structure-activity models of chem-ical carcinogens: state of the art, and new directions. Annali Dell’istituto Superiore Di Sanita, 42(2), 118-126. google scholar
• Benigni, R., & Bossa, C. (2008). Structure alerts for carcinogenicity, and the Salmonella assay system: a novel insight through the chem-ical relational databases technology. Mutation Research, 659(3), 248-261. https://doi.org/10.1016/j.mrrev.2008.05.003 google scholar
• Benigni, R., & Bossa, C. (2011). Mechanisms of chemical carcino-genicity and mutagenicity: a review with implications for predic-tive toxicology. Chemical Reviews, 111(4), 2507-2536. google scholar
• Benigni, R., Bossa, C., & Tcheremenskaia, O. (2013). Nongenotoxic carcinogenicity of chemicals: mechanisms of action and early recognition through a new set of structural alerts. Chemical Re-views, 113(5), 2940-57. google scholar
• Bhat, V., & Chatterjee, J. (2021). The Use of In Silico Tools for the Toxicity Prediction of Potential Inhibitors of SARS-CoV-2. Alternatives to laboratory Animals: ATLA, 49(1-2), 22-32. https://doi.org/10.1177/02611929211008196 google scholar
• Castro, T. F. D., da Silva Souza, J. G., de Carvalho, A. F. S., de Lima Assis, I., Palmieri, M. J., Vieira, L. F. A., Mar-cussi, S., Machado, M. R. F., & Murgas, L. D. S. (2018). Anxiety-associated behavior and genotoxicity found in adult Danio rerio exposed to tebuconazole-based commercial prod-uct. Environmental Toxicology and Pharmacology, 62, 140-146. https://doi.org/10.1016/j.etap.2018.06.011. google scholar
• Chen, Y., Dong, Y., Li, L., Jiao, J., Liu, S., & Zou, X. (2022). Toxicity Rank Order (TRO) As a New Approach for Toxicity Prediction by QSAR Models. International Journal of Environmental Research and Public Health, 20(1), 701. https://doi.org/10.3390/ijerph20010701 google scholar
• de Oliveira, L. A. B., Pacheco, H. P., & Scherer, R. (2016). Flutriafol and pyraclostrobin residues in Brazil-ian green coffees. Food Chemistry, 190, 60-63. https://doi.org/10.1016/j.foodchem.2015.05.035. google scholar
• Filipov, N. M., & Lawrence, D. A. (2001). Developmental toxicity of a triazole fungicide: consideration of interorgan communication. Toxicological Sciences : An Official Journal of The Society of Tox-icology, 62(2), 185-186. https://doi.org/10.1093/toxsci/62.2.185 google scholar
• h, I. M., Ciorsac, A. A., & Isvoran, A. (2019). Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection. ADMET & DMPK, 7(3), 161-173. https://doi.org/10.5599/admet.668. google scholar
• Hamdi, H., Rjiba-Touati, K., Ayed-Boussema, I., M’nassri, A., Chaa-bani, H., Rich, S., & Abid-Essefi, S. (2022). Epoxiconazole caused oxidative stress related DNA damage and apoptosis in PC12 rat Pheochromocytoma. Neurotoxicology, 89, 184-190. https://doi.org/10.1016/j.neuro.2022.02.003 google scholar
• Holeckova, B., Sivikova, K., Dianovsky, J., & Galdıkova, M. (2013). Effect of triazole pesticide formulation on bovine culture cells. Journal of environmental science and health. Part. B, Pesticides, Food Contaminants, and Agricultural Wastes, 48(12), 1080-1088. google scholar
• Jurasekova, Z., Jutkova, A., Kozar, T., & Stanicova, J. (2022). Vibrational characterization of the pesticide molecule Tebuconazole. Spectrochimica acta. Part A, Molecular and Biomolecular Spectroscopy, 268, 120629. https://doi.org/10.1016/j.saa.2021.120629. google scholar
• Kahle, M., Buerge, I. J., Hauser, A., Müller, M. D., & Poiger, T. (2008). Azole fungicides: occurrence and fate in wastewater and surface waters. Environmental Science & Technology, 42(19), 7193-7200. https://doi.org/10.1021/es8009309 google scholar
• Kianpour, M., Mohammadinasab, E., & Isfahani, T. M. (2021). Pre-diction of Oral Acute Toxicity of Organophosphates Using QSAR Methods. Current Computer-Aided Drug Design, 17(1), 38-56. https://doi.org/10.2174/1573409916666191227093237 google scholar
• Leme, D. M., & Marin-Morales, M. A. (2009). Allium cepa test in environmental monitoring: a review on its application. Mutation Research, 682(1), 71-81. https://doi.org/10.1016/j.mrrev.2009.06.002 google scholar
• Li, Y., Nie, J., Zhang, J., Xu, G., Zhang, H., Liu, M., Gao, X., Shah, B. S. A., & Yin, N. (2022). Chiral fungicide penconazole: Absolute configuration, bioactivity, toxicity, and stereoselective degrada-tion in apples. The Science of the Total Environment, 808, 152061. https://doi.org/10.1016/j.scitotenv.2021.152061 google scholar
• Liu, N., Dong, F., Xu, J., Liu, X., & Zheng, Y. (2016). Chiral bioaccu-mulation behavior of tebuconazole in the zebrafish (Danio rerio). Ecotoxicology and Environmental Safety, 126, 78-84. google scholar
• Macar O. (2021). Multiple toxic effects of tetraconazole in Allium cepa L. meristematic cells. Environmental Science and Pollution Research International, 28(8), 10092-10099. https://doi.org/10.1007/s11356-020-11584-4 google scholar
• Mombelli, E., & Devillers, J. (2010). Evaluation of the OECD (Q)SAR Application Toolbox and Toxtree for predicting and profiling the carcinogenic potential of chemicals. SAR and QSAR in Environmental Research, 21(7-8), 731-752. https://doi.org/10.1080/1062936X.2010.528598 google scholar
• Mostafalou, S., & Abdollahi, M. (2017). Pesticides: An Update of Human Exposure and Toxicity. Archives of Toxicology, 91(2), 549-599. https://doi.org/10.1007/s00204-016-1849-x. google scholar
• Perdichizzi, S., Mascolo, M. G., Silingardi, P., Morandi, E., Ro-tondo, F., Guerrini, A., Prete, L., Vaccari, M., & Colacci, A. (2014). Cancer-related genes transcriptionally induced by the fungicide penconazole. Toxicology In Vitro : An International Journal Published in Association with BIBRA, 28(1), 125-130. https://doi.org/10.1016/j.tiv.2013.06.006 google scholar
• Protox II Software, https://tox-new.charite.de/protox_II/ (accessed November 25, 2023). google scholar
• Pubchem, “Bromuconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/3444 (accessed November 20, 2023). google scholar
• Pubchem, “Diniconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/6436605 (accessed November 20, 2023). google scholar
• Pubchem, “Enilconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/37175 (accessed November 20, 2023). google scholar
• Pubchem, “Epiconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/3317081 (accessed November 20, 2023). google scholar
• Pubchem, “Fenbuconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/86138 (accessed November 20, 2023). google scholar
• Pubchem, “Flutriafol.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/91727 (accessed November 20, 2023). google scholar
• Pubchem, “Hexaconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/66461 (accessed November 20, 2023). google scholar
• Pubchem, “Metconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/86210 (accessed November 20, 2023). google scholar
• Pubchem, “Myclobutanil.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/6336 (accessed November 20, 2023). google scholar
• Pubchem, “Paclobutrazol.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/158076 (accessed November 20, 2023). google scholar
• Pubchem, “Penconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/91693 (accessed November 20, 2023). google scholar
• Pubchem, “Prothioconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/6451142 (accessed November 20, 2023). google scholar
• Pubchem, “Tebuconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/86102 (accessed November 20, 2023). google scholar
• Pubchem, “Triticonazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/6537961 (accessed November 20, 2023). google scholar
• Pubchem, “Uniconazole.” Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/6436604 (accessed November 20, 2023). google scholar
• Rjiba-Touati, K., Ayed-Boussema, I., Hamdi, H., Azzebi, A., & Abid, S. (2022a). Bromuconazole fungicide induces cell cycle arrest and apoptotic cell death in cultured human colon carcinoma cells (HCT116) via oxidative stress pro-cess. Biomarkers : Biochemical Indicators Of Exposure, Re-sponse, and Susceptibility to Chemicals, 27(7), 659-670. https://doi.org/10.1080/1354750X.2022.2098378 google scholar
• Rjiba-Touati, K., Hamdi, H., M’nassri, A., Guedri, Y., Mokni, M., & Abid, S. (2022b). Bromuconazole Caused Genotoxicity And Hepatic and Renal Damage Via Oxidative Stress Process in Wis-tar Rats. Environmental Science and Pollution Research Inter-national, 29(10), 14111-14120. https://doi.org/10.1007/s11356-021-16091-8 google scholar
• Sharma, A., Kumar, V., Shahzad, B., Tanveer, M., Sidhu, G. P. S., Handa, N., Kohli, D. K., Yadav, P., Bali, A. S., Parihar, R. D., Dar, O. I., Singh, K., Jasroita, S., Bakshi, P., Ramakrishnan, M., Kumar, S., Bhardwaj, R., & Thukral, A. K. (2019). Worldwide pesticide usage and its impacts on ecosystem. Sn Applied Sciences, 1, 1-16. google scholar
• Sivikova, K., Holeckova, B., Schwarzbacherova, V., Galdikova, M., & Dianovsky, J. (2018). Potential chromosome damage, cell-cycle kinetics/and apoptosis induced by epoxiconazole in bovine peripheral lymphocytes in vitro. Chemosphere, 193, 82-88. https://doi.org/10.1016/j.chemosphere.2017.11.008 google scholar
• Tice, R. R., Bassan, A., Amberg, A., Anger, L. T., Beal, M. A., Bel-lion, P., Benigni, R., Birmingham, J., Brigo, A., Bringezu, F., Ceriani, L., Crooks, I., Cross, K., Elespuru, R., Faulkner, D. M., Fortin, M. C., Fowler, P., Frericks, M., Gerets, H. H. J., Jahnke, G. D., . . . Myatt, G. J. (2021). In Silico Approaches In Carcinogenicity Hazard Assessment: Current Status and Future Needs. Computational Toxicology (Amsterdam, Netherlands), 20, 100191. https://doi.org/10.1016/j.comtox.2021.100191. google scholar
• Toxtree Software, https://toxtree.sourceforge.net/ (accessed November 20, 2023). google scholar
• Varghese, J. V., Sebastian, E. M., Iqbal, T., & Tom, A. A. (2020). Pesti-cide applicators and cancer: a systematic review. Reviews On Envi-ronmental Health, 36(4), 467-476. https://doi.org/10.1515/reveh-2020-0121 google scholar
• VEGA Hub Software, Retrieved from https://www.vegahub.eu/about-vegahub/ (accessed November 20, 2023). google scholar
• Wang, Y., Ren, Y., Ning, X., Li, G., & Sang, N. (2023). Environmen-tal exposure to triazole fungicide causes left-right asymmetry de-fects and contributes to abnormal heart development in zebrafish embryos by activating PPARy-coupled Wnt/3-catenin signaling pathway. The Science of the Total Environment, 859(Pt 2), 160286. https://doi.org/10.1016/j.scitotenv.2022.160286 google scholar
• Wang, S., Zhang, X., Gui, B., Xu, X., Su, L., Zhao, Y. H., & Martyniuk, C. J. (2022). Comparison of modes of action between fish, cell and mitochondrial toxicity based on toxicity correlation, excess toxicity and QSAR for class-based compounds. Toxicology, 470, 153155. https://doi.org/10.1016/j.tox.2022.153155 google scholar
• Zhang, Z., Gao, B., He, Z., Li, L., Zhang, Q., Kaziem, A. E., & Wang, M. (2019). Stereoselective bioactivity of the chiral triazole fungicide prothioconazole and its metabo-lite. Pesticide Biochemistry and Physiology, 160, 112-118. https://doi.org/10.1016/j.pestbp.2019.07.012. google scholar