Stereoselective cardiotoxic effects of metconazole on zebrafish (Danio rerio) based on AGE-RAGE signalling pathway

Chiral pesticides; Metconazole; p38 inhibitor; Stereoselective cardiotoxicity; Zebrafish embryo; Animals; Cardiotoxicity; Embryo, Nonmammalian; Molecular Docking Simulation; Triazoles; Water Pollutants, Chemical; Zebrafish; Aquatic organisms; Binding sites; Disease control; Enantiomers; Enzyme activity; Polymerase chain reaction; Stereoselectivity; catalase; fungicide; glutathione transferase; metconazole; peroxidase; unclassified drug; triazole derivative; Chiral pesticide; Environmental risks; P38 inhibitor; Signalling pathways; Stereo-selective; Zebrafish danio rerio; Zebrafish embryos; cyprinid; disease control; environmental risk; enzyme activity; inhibitor; adult; Article; binding site; cardiotoxicity; computer model; controlled study; differential gene expression; embryo; enantiomer; fbn2b gene; female; gene; heart development; heart rate; inflammation; larva; male; molecular docking; NF kB signaling; nonhuman; oxidative stress; rbm24b gene; real time polymerase chain reaction; signal transduction; stereoselectivity; tbx20 gene; transcriptomics; zebra fish; animal; chemistry; metabolism; nonmammalian embryo; water pollutant; Transcription

Abstract :

[en] Metconazole (MEZ) is a novel chiral triazole fungicide that is widely used to prevent and control soil-borne fungal pathogens and other fungal diseases. However, it has a long half-life in aquatic environments and thus poses potential environmental risks. This study evaluates the acute and stereoselective cardiotoxicity of MEZ in zebrafish (Danio rerio) embryos. In addition, transcriptomics, real-time quantitative PCR, enzyme activity determination, and molecular docking are performed to evaluate the molecular mechanisms underlying the cardiotoxicity of MEZ in zebrafish. MEZ decreases the heart rate while increasing the pericardial oedema rate; additionally, it induces stereoselective cardiotoxicity. 1S,5S-MEZ exhibits stronger cardiotoxicity than 1R,5R-MEZ. Furthermore, MEZ increases the expression of Ahr-associated genes and the transcription factors il6st, il1b, and AP-1. Heart development-related genes, including fbn2b, rbm24b, and tbx20 are differentially expressed. MEZ administration alters the activities of catalase, peroxidase, and glutathione-S-transferase in zebrafish larvae. Molecular docking indicates that 1R,5R-MEZ binds more strongly to the inhibitor-binding sites of p38 in the AGE-RAGE signalling pathway than to other MEZ enantiomers. Studies conducted in vivo and in silico have established the enantioselective cardiotoxicity of MEZ and its underlying mechanisms, highlighting the need to evaluate the environmental risk of chiral MEZ in aquatic organisms at the enantiomeric level. © 2023 Elsevier B.V.

Disciplines :

Entomology & pest control

Author, co-author :

Li, Minmin; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Yang, Lin; National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Centre for Research and Development of Fine Chemicals, Guizhou University, Guiyang, 550025, China

Wang, Rui; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Li, Lin; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Zhang, Yifan; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Li, Long; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Jin, Nuo; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Huang, Yatao ; Université de Liège - ULiège > TERRA Research Centre ; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Kong, Zhiqiang; State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, 100193, China

Francis, Frédéric ; Université de Liège - ULiège > TERRA Research Centre > Gestion durable des bio-agresseurs

Fan, Bei; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Wang, Fengzhong; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-products Quality and Safety Control in Storage and Transport Process, Laboratory of Agro-products Quality Safety Risk Assessment, Ministry of Agriculture and Rural Affairs, Beijing, 100193, China

Language :

English

Title :

Stereoselective cardiotoxic effects of metconazole on zebrafish (Danio rerio) based on AGE-RAGE signalling pathway

Publication date :

20 February 2024

Journal title :

Science of the Total Environment

ISSN :

0048-9697

eISSN :

1879-1026

Publisher :

Elsevier

Volume :

912

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.sciencedirect.com/science/article/abs/pii/S0048969723079342

Funders :

National Key Research and Development Program of China [grant number 2022YFF1102200]
National Natural Science Foundation of China [grant number 31872006 and 32272443]
Youth Innovation of the Chinese Academy of Agricultural Sciences (Y2022QC12).

Available on ORBi :

since 25 July 2025

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Bibliography

Abu-Melha, S., Gomha, S., Abouzied, A., Edrees, M., Abo Dena, A., Muhammad, Z., Microwave-assisted one pot three-component synthesis of novel bioactive thiazolyl-pyridazinediones as potential antimicrobial agents against antibiotic-resistant bacteria. Molecules, 26(14), 2021, 4260, 10.3390/molecules26144260.
Brown, D., Samsa, L., Qian, L., Liu, J., Advances in the study of heart development and disease using zebrafish. J. Cardiovasc. Dev. Dis., 3(2), 2016, 13, 10.3390/jcdd3020013.
Chang, C., Chung, H., Su, H., Tseng, H., Tzou, W., Hu, C., Regulation of zebrafish CYP3A65 transcription by AHR2. Toxicol. Appl. Pharmacol. 270:2 (2013), 174–184, 10.1016/j.taap.2013.04.010.
Deng, Y., Zhang, W., Qin, Y., Liu, R., Zhang, L., Wang, Z., Zhou, Z., Diao, J., Stereoselective toxicity of metconazole to the antioxidant defenses and the photosynthesis system of Chlorella pyrenoidosa. Aquat. Toxicol. 210 (2019), 129–138, 10.1016/j.aquatox.2019.02.017.
Deng, Y., Liu, R., Wang, Z., Zhang, L., Yu, S., Zhou, Z., Diao, J., The stereoselectivity of metconazole on wheat grain filling and harvested seeds germination: implication for the application of triazole chiral pesticides. J. Hazard. Mater., 416, 2021, 125911, 10.1016/j.jhazmat.2021.125911.
Ding, F., Peng, W., Peng, Y.K., Liu, B.Q., Estimating the potential toxicity of chiral diclofop-methyl: mechanistic insight into the enantioselective behavior. Toxicology, 438, 2020, 152446, 10.1016/j.tox.2020.152446.
EFSA, Conclusion regarding the peer review of the pesticide risk assessment of the active substance metconazole. EFSA J., 641-71, 2006, 10.2903/j.efsa.2006.64r.
Evangelista, E.A., Lemaitre, R.N., Sotoodehnia, N., Gharib, S.A., Totah, R.A., CYP2J2 expression in adult ventricular myocytes protects against reactive oxygen species toxicity. Drug Metab. Dispos. 46:4 (2018), 380–386, 10.1124/dmd.117.078840.
Fan, Z., Yang, Y., Hu, P., Huang, Y., He, L., Hu, R., Zhao, K., Zhang, H., Liu, C., Molecular mechanism of ethylparaben on zebrafish embryo cardiotoxicity based on transcriptome analyses. Sci. Total Environ., 842, 2022, 156785, 10.1016/j.scitotenv.2022.156785.
Fu, Y., Yip, A., Seah, P.G., Blasco, F., Shi, P., Hervé, M., Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580. Antiviral Res. 110 (2014), 151–157, 10.1016/j.antiviral.2014.08.004.
Fu, H., Wang, L., Wang, J., Bennett, B.D., Li, J., Zhao, B., Hu, G., Dioxin and AHR impairs mesoderm gene expression and cardiac differentiation in human embryonic stem cells. Sci. Total Environ. 651 (2019), 1038–1046, 10.1016/j.scitotenv.2018.09.247.
Garner, L.V.T., Di Giulio, R.T., Glutathione transferase pi class 2 (GSTp2) protects against the cardiac deformities caused by exposure to PAHs but not PCB-126 in zebrafish embryos. Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol. 155:4 (2012), 573–579, 10.1016/j.cbpc.2012.01.007.
Hanna, C., Boily, M., Jumarie, C., Pesticides inhibit retinoic acid catabolism in PLHC-1 and ZFL fish hepatic cell lines. Chem. Res. Toxicol. 35:6 (2022), 1045–1058, 10.1021/acs.chemrestox.2c00050.
He, R., Guo, D., Huang, Z., Kong, Y., Ji, C., Gu, J., Zhang, Z., Diao, J., Zhou, Z., Zhao, M., Fan, J., Zhang, W., Systematic investigation of stereochemistry, stereoselective bioactivity, and antifungal mechanism of chiral triazole fungicide metconazole. Sci. Total Environ., 784, 2021, 147194, 10.1016/j.scitotenv.2021.147194.
He, R., Guo, D., Lin, C., Zhang, W., Fan, J., Enantioselective bioaccumulation, oxidative stress, and thyroid disruption assessment of cis-metconazole enantiomers in zebrafish (Danio rerio). Aquat. Toxicol., 248, 2022, 106205, 10.1016/j.aquatox.2022.106205.
Huang, C., Chen, P., Huang, C., Yu, J., Aristolochic acid induces heart failure in zebrafish embryos that is mediated by inflammation. Toxicol. Sci. 100:2 (2007), 486–494, 10.1093/toxsci/kfm235.
Huang, Y., Wang, Z., Peng, Y., Xu, R., Yan, J., Xiong, C., Ma, J., Zhong, K., Lu, H., Carboxin can induce cardiotoxicity in zebrafish embryos. Ecotoxicol. Environ. Saf., 233, 2022, 113318, 10.1016/j.ecoenv.2022.113318.
Hudson, B.I., Lippman, M.E., Targeting RAGE signaling in inflammatory disease. Annu. Rev. Med. 69:1 (2018), 349–364, 10.1146/annurev-med-041316-085215.
Kong, Z., Li, M., Chen, J., Bao, Y., Fan, B., Francis, F., Dai, X., Processing factors of triadimefon and triadimenol in barley brewing based on response surface methodology. Food Control 64 (2016), 81–86, 10.1016/j.foodcont.2015.12.021.
Kuder, R.S., Philip, G.H., Antioxidant enzymatic activities and lipid peroxidation in liver and ovary of zebrafish (Danio rerio) exposed to deltamethrin. Chem. Ecol. 33:8 (2017), 739–749, 10.1080/02757540.2017.1359263.
Kumphune, S., Chattipakorn, S., Chattipakorn, N., Role of p38 inhibition in cardiac ischemia/reperfusion injury. Eur. J. Clin. Pharmacol. 68:5 (2012), 513–524, 10.1007/s00228-011-1193-2.
Lee, J.C., Laydon, J.T., Mcdonnell, P.C., Gallagher, T.F., Kumar, S., Green, D., Mcnulty, D., Blumenthal, M.J., Heys, J.R., Landvatter, S.W., Strickler, J.E., Mclaughlin, M.M., Siemens, I.R., Fisher, S.M., Livi, G.P., White, J.R., Adams, J.L., Young, P.R., A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372 (1994), 739–746, 10.1038/372739a0.
Li, Y., Canário, A.V.M., Power, D.M., Campinho, M.A., Ioxynil and diethylstilbestrol disrupt vascular and heart development in zebrafish. Environ. Int. 124 (2019), 511–520, 10.1016/j.envint.2019.01.009.
Li, L., Huang, P., Li, J., Enantioselective effects of the fungicide metconazole on photosynthetic activity in Microcystis flos-aquae. Ecotoxicol. Environ. Saf., 211, 2021, 111894, 10.1016/j.ecoenv.2021.111894.
Li, C., Fan, S., Zhang, Y., Zhang, X., Luo, J., Liu, C., Toxicity, bioactivity of triazole fungicide metconazole and its effect on mycotoxin production by fusarium verticillioides: new perspective from an enantiomeric level. Sci. Total Environ., 828, 2022, 154432, 10.1016/j.scitotenv.2022.154432.
Li, W., Guo, S., Miao, N., Transcriptional responses of fluxapyroxad-induced dysfunctional heart in zebrafish (Danio rerio) embryos. Environ. Sci. Pollut. Res. 29:60 (2022), 90034–90045, 10.1007/s11356-022-21981-6.
OECD, OECD guidelines for the testing of chemicals. Section 2: Effects on Biotic Systems Test No. 236: Fish Embryo Acute Toxicity (FET) Test, 2013, OECD Publishing, Paris, 10.1007/978-1-62703-131-8_4.
Park, H., Song, G., Hong, T., An, G., Park, S., Lim, W., Exposure to the herbicide fluridone induces cardiovascular toxicity in early developmental stages of zebrafish. Sci. Total Environ., 867, 2023, 161535, 10.1016/j.scitotenv.2023.161535.
Peterson, R.T., Macrae, C.A., Systematic approaches to toxicology in the zebrafish. Annu. Rev. Pharmacol. Toxicol. 52 (2012), 433–453, 10.1146/annurev-pharmtox-010611-134751.
Redaelli, C., Gaffarogullari, E.C., Brune, M., Pilz, C., Becker, S., Sonner, J., Jäschke, A., Gröne, H., Wick, W., Platten, M., Lanz, T.V., Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice. Biochem. Pharmacol. 98:3 (2015), 484–492, 10.1016/j.bcp.2015.08.111.
Schieven, G.L., The biology of p38 kinase: a central role in inflammation. Curr. Top. Med. Chem. 5:10 (2005), 921–928, 10.2174/1568026054985902.
Shin, S., Park, J., Lee, Y.E., Ko, H., Youn, H.S., Isobavachalcone suppresses the TRIF-dependent signaling pathway of toll-like receptors. Arch. Pharm., 355(3), 2022, 2100404, 10.1002/ardp.202100404.
Simard, J.R., Getlik, M., Grütter, C., Pawar, V., Wulfert, S., Rabiller, M., Rauh, D., Development of a fluorescent-tagged kinase assay system for the detection and characterization of allosteric kinase inhibitors. J. Am. Chem. Soc. 131:37 (2009), 13286–13296, 10.1021/ja902010p.
Sun, Y., Cao, Y., Tong, L., Tao, F., Wang, X., Wu, H., Wang, M., Exposure to prothioconazole induces developmental toxicity and cardiovascular effects on zebrafish embryo. Chemosphere, 251, 2020, 126418, 10.1016/j.chemosphere.2020.126418.
USEPA, Pesticide Fact Sheet: Metconazole. 2007, USEPA Publishing, Washington, D.C.
Van Tiem, L.A., Di Giulio, R.T., AHR2 knockdown prevents PAH-mediated cardiac toxicity and XRE- and ARE-associated gene induction in zebrafish (Danio rerio). Toxicol. Appl. Pharmacol. 254:3 (2011), 280–287, 10.1016/j.taap.2011.05.002.
Waghela, B.N., Vaidya, F.U., Ranjan, K., Chhipa, A.S., Tiwari, B.S., Pathak, C., AGE-RAGE synergy influences programmed cell death signaling to promote cancer. Mol. Cell. Biochem. 476 (2021), 585–598, 10.1007/s11010-020-03928-y.
Wang, Y., Zhang, Y., Sun, B., Tong, Q., Ren, L., Rutin protects against pirarubicin-induced cardiotoxicity through TGF-β1-p38 MAPK signaling pathway. Evid.-based Complement Altern. Med. 2017 (2017), 1–10, 10.1155/2017/1759385.
Wang, J., Li, Y., Lu, L., Zheng, M., Zhang, X., Tian, H., Wang, W., Ru, S., Polystyrene microplastics cause tissue damages, sex-specific reproductive disruption and transgenerational effects in marine medaka (Oryzias melastigma). Environ. Pollut., 254, 2019, 113024, 10.1016/j.envpol.2019.113024.
Wasim, R., Mahmood, T., Siddiqui, M.H., Ahsan, F., Shamim, A., Singh, A., Shariq, M., Parveen, S., Aftermath of AGE-RAGE Cascade in the pathophysiology of cardiovascular ailments. Life Sci., 307, 2022, 120860, 10.1016/j.lfs.2022.120860.
Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F.T., de Beer, T.A.P., Rempfer, C., Bordoli, L., Lepore, R., Schwede, T., SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46:W1 (2018), W296–W303, 10.1093/nar/gky427.
Xu, C., Sun, X., Niu, L., Yang, W., Tu, W., Lu, L., Song, S., Liu, W., Enantioselective thyroid disruption in zebrafish embryo-larvae via exposure to environmental concentrations of the chloroacetamide herbicide acetochlor. Sci. Total Environ. 653 (2019), 1140–1148, 10.1016/j.scitotenv.2018.11.037.
Yalcin, H.C., Amindari, A., Butcher, J.T., Althani, A., Yacoub, M., Heart function and hemodynamic analysis for zebrafish embryos. Dev. Dyn. 246:11 (2017), 868–880, 10.1002/dvdy.24497.
Yang, Y., Tao, Y., Li, Z., Cui, Y., Zhang, J., Zhang, Y., Agrochemical-mediated cardiotoxicity in zebrafish embryos/larvae: what we do and where we go. Crit. Rev. Environ. Sci. Technol. 53:18 (2023), 1662–1683, 10.1080/10643389.2023.2174771.
Yurtsever, Z., Scheaffer, S.M., Romero, A.G., Holtzman, M.J., Brett, T.J., The crystal structure of phosphorylated MAPK13 reveals common structural features and differences in p38 MAPK family activation. Acta Crystallogr. D Biol. Crystallogr. 71:4 (2015), 790–799, 10.1107/S1399004715001212.
Zhu, L., Wang, C., Jiang, H., Zhang, L., Mao, L., Zhang, Y., Qi, S., Liu, X., Quizalofop-P-ethyl induced developmental toxicity and cardiotoxicity in early life stage of zebrafish (Danio rerio). Ecotoxicol. Environ. Saf., 238, 2022, 113596, 10.1016/j.ecoenv.2022.113596.
Zhuang, S., Zhang, Z., Zhang, W., Bao, L., Xu, C., Zhang, H., Enantioselective developmental toxicity and immunotoxicity of pyraclofos toward zebrafish (Danio rerio). Aquat. Toxicol. 159 (2015), 119–126, 10.1016/j.aquatox.2014.12.006.