Alternaria toxins-Still emerging?
black mold
food safety
genotoxicity
mycotoxins
natural toxins
synergism
Journal
Comprehensive reviews in food science and food safety
ISSN: 1541-4337
Titre abrégé: Compr Rev Food Sci Food Saf
Pays: United States
ID NLM: 101305205
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
18
06
2021
received:
11
12
2020
accepted:
19
06
2021
pubmed:
30
7
2021
medline:
26
10
2021
entrez:
29
7
2021
Statut:
ppublish
Résumé
Alternaria molds are known to cause the contamination of food with their secondary metabolites, a chemically very heterogeneous group of compounds. Yet, after decades of research on the occurrence and the toxicity of Alternaria toxins in academia, no regulation has been implemented yet, thus leaving these potential food contaminants in the status of so-called "emerging mycotoxins". However, research on this topic has been far from static, leading to the European Food Safety Authority repeatedly calling for more data on the occurrence and toxicity of genotoxic metabolites such as alternariol (AOH) and its monomethyl ether (AME). To give an overview on recent developments in the field, this comprehensive review summarizes published data and addresses current challenges arising from the chemical complexity of Alternaria's metabolome, mixture effects and the emergence of novel biological targets like cell membranes or the interaction with different receptors. Besides toxicodynamics, we review recent research on toxicokinetics, including the first in vivo studies which incorporated the rarely investigated-but highly genotoxic-perylene quinones. Furthermore, a particular focus lies on the advances of liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based analytical tools for determining a broader spectrum of Alternaria toxins including modified/masked forms and assessing exposure via human biomonitoring (HBM).
Identifiants
pubmed: 34323368
doi: 10.1111/1541-4337.12803
doi:
Substances chimiques
Mycotoxins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
4390-4406Informations de copyright
© 2021 The Authors. Comprehensive Reviews in Food Science and Food Safety published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.
Références
Aichinger, G., Beisl, J., & Marko, D. (2017). Genistein and delphinidin antagonize the genotoxic effects of the mycotoxin alternariol in human colon carcinoma cells. Molecular Nutrition & Food Research, 61(2). 1600462. https://doi.org/10.1002/mnfr.201600462
Aichinger, G., Dellafiora, L., Pantazi, F., Del Favero, G., Galaverna, G., Dall'Asta, C., & Marko, D. (2020a). Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: A hybrid in silico/in vitro study. Archives of Toxicology. 94, 2225-2237. https://doi.org/10.1007/s00204-020-02746-x
Aichinger, G., Kruger, F., Puntscher, H., Preindl, K., Warth, B., & Marko, D. (2019). Naturally occurring mixtures of Alternaria toxins: Anti-estrogenic and genotoxic effects in vitro. Archives of Toxicology. 93, 3021-3031. https://doi.org/10.1007/s00204-019-02545-z
Aichinger, G., Pantazi, F., & Marko, D. (2020b). Combinatory estrogenic effects of bisphenol A in mixtures with alternariol and zearalenone in human endometrial cells. Toxicology Letters, 319, 242-249. https://doi.org/10.1016/j.toxlet.2019.10.025
Aichinger, G., Puntscher, H., Beisl, J., Kutt, M. L., Warth, B., & Marko, D. (2018). Delphinidin protects colon carcinoma cells against the genotoxic effects of the mycotoxin altertoxin II. Toxicology Letters, 284, 136-142. https://doi.org/10.1016/j.toxlet.2017.12.002
Aichinger, G., Živná, N., Varga, E., Crudo, F., Warth, B., & Marko, D. (2020c). Microfiltration results in the loss of analytes and affects the in vitro genotoxicity of a complex mixture of Alternaria toxins. Mycotox Res, 36(4), 399-408. https://doi.org/10.1007/s12550-020-00405-9
Asam, S., Habler, K., & Rychlik, M. (2013). Determination of tenuazonic acid in human urine by means of a stable isotope dilution assay. Analytical and Bioanalytical Chemistry, 405, 4149-4158. https://doi.org/10.1007/s00216-013-6793-5
Badal, S., & Delgoda, R. (2014). Role of the modulation of CYP1A1 expression and activity in chemoprevention. Journal of Applied Toxicology, 34(7), 743-753. https://doi.org/10.1002/jat.2968
Bensassi, F., Gallerne, C., Sharaf El Dein, O., Hajlaoui, M. R., Bacha, H., & Lemaire, C. (2012). Cell death induced by the Alternaria mycotoxin alternariol. Toxicology in Vitro, 26(6), 915-923. https://doi.org/10.1016/j.tiv.2012.04.014
Bensassi, F., Gallerne, C., Sharaf el dein, O., Rabeh Hajlaoui, M., Bacha, H., & Lemaire, C. (2015). Combined effects of alternariols mixture on human colon carcinoma cells. Toxicology Mechanisms and Methods, 25(1), 56-62. https://doi.org/10.3109/15376516.2014.985354
Berthiller, F., Crews, C., Dall'Asta, C., Saeger, S. D., Haesaert, G., Karlovsky, P. Oswald, I. P., Seefelder, W., Speijers, G., & Stroka, J. (2013). Masked mycotoxins: A review. Molecular Nutrition & Food Research, 57(1), 165-186. https://doi.org/10.1002/mnfr.201100764
Bouvier d'Yvoire, M., Prieto, P., Blaauboer, B., Bois, F., Boobis, A., Brochot, C., Coecke, S., Freidig, A., Gundert-Remy, U., Hartung, T., Jacobs, M. N., Lavé, T., Leahy, D. E., Lennernäs, H., Loizou, G. D., Meek, B., Pease, C., Rowland, M., Spendiff, M., Yang, J., & Zeilmaker, M. (2008). Physiologically-based kinetic modelling (PBK modelling): Meeting the 3Rs agenda. The report and recommendations of ECVAM Workshop 63. ATLA, 35, 661-671. https://doi.org/10.1177/026119290703500606
Braun, D., Eiser, M., Puntscher, H., Marko, D., & Warth, B. (2020). Natural contaminants in infant food: The case of regulated and emerging mycotoxins. Food Control, 123, 107676. https://doi.org/10.1016/j.foodcont.2020.107676
Braun, D., Ezekiel, C., Marko, D., & Warth, B. (2020). Exposure to mycotoxin-mixtures via breast milk: An ultra-sensitive LC-MS/MS biomonitoring approach. Front Chem, 8, 423. https://doi.org/10.3389/fchem.2020.00423
Braun, D., Schernhammer, E., Marko, D., & Warth, B. (2020). Longitudinal assessment of mycotoxin co-exposures in exclusively breastfed infants. Environment International, 142, 105845. https://doi.org/10.1016/j.envint.2020.105845
Bueschl, C., Kluger, B., Neumann, N. K. N., Doppler, M., Maschietto, V., Thallinger, G. G., Meng-Reiterer, J., Krska, R., & Schuhmacher, R. (2017). MetExtract II: A software suite for stable isotope-assisted untargeted metabolomics. Analytical Chemistry, 89(17), 9518-9526. https://doi.org/10.1021/acs.analchem.7b02518
Burkhardt, B., Pfeiffer, E., & Metzler, M. (2009). Absorption and metabolism of the mycotoxins alternariol and alternariol-9-methyl ether in Caco-2 cells in vitro. Mycotoxin Research, 25(3), 149. https://doi.org/10.1007/s12550-009-0022-2
Burkhardt, B., Wittenauer, J., Pfeiffer, E., Schauer, U. M., & Metzler, M. (2011). Oxidative metabolism of the mycotoxins alternariol and alternariol-9-methyl ether in precision-cut rat liver slices in vitro. Molecular Nutrition & Food Research, 55(7), 1079-1086. https://doi.org/10.1002/mnfr.201000487
Chiesi, C., Fernandez-Blanco, C., Cossignani, L., Font, G., & Ruiz, M. J. (2015). Alternariol-induced cytotoxicity in Caco-2 cells. Protective effect of the phenolic fraction from virgin olive oil. Toxicon, 93, 103-111. https://doi.org/10.1016/j.toxicon.2014.11.230
Crudo, F., Aichinger, G., Mihajlovic, J., Dellafiora, L., Varga, E., Puntscher, H., Warth, B., Dall'Asta, C., Berry, D., & Marko, D. (2020). Gut microbiota and undigested food constituents modify toxin composition and suppress the genotoxicity of a naturally occurring mixture of Alternaria toxins in vitro. Archives of Toxicology, 94(10), 3541-3552. https://doi.org/10.1007/s00204-020-02831-1
Crudo, F., Aichinger, G., Mihajlovic, J., Varga, E., Dellafiora, L., Warth, B., Dall'Asta, C., Berry, D., & Marko, D. (2021). In vitro interactions of Alternaria mycotoxins, an emerging class of food contaminants, with the gut microbiota: A bidirectional relationship. Archives of Toxicology. 95, 2533-2549. https://doi.org/10.1007/s00204-021-03043-x
Crudo, F., Varga, E., Aichinger, G., Galaverna, G., Marko, D., Dall'Asta, C., & Dellafiora, L. (2019). Co-occurrence and combinatory effects of Alternaria mycotoxins and other xenobiotics of food origin: Current scenario and future perspectives. Toxins (Basel), 11(11), 640. https://doi.org/10.3390/toxins11110640
Del Favero, G., Hohenbichler, J., Mayer, R. M., Rychlik, M., & Marko, D. (2020a). Mycotoxin altertoxin ii induces lipid peroxidation connecting mitochondrial stress response to NF-κB inhibition in THP-1 macrophages. Chem Res Tox. 33(2), 492-504. https://doi.org/10.1021/acs.chemrestox.9b00378
Del Favero, G., Mayer, R. M., Dellafiora, L., Janker, L., Niederstaetter, L., Dall'Asta, C., Gerner, C., & Marko, D. (2020b). Structural similarity with cholesterol reveals crucial insights into mechanisms sustaining the immunomodulatory activity of the mycotoxin alternariol. Cells, 9(4), 847. https://doi.org/10.3390/cells9040847
Del Favero, G., Zaharescu, R., & Marko, D. (2018). Functional impairment triggered by altertoxin II (ATXII) in intestinal cells in vitro: Cross-talk between cytotoxicity and mechanotransduction. Archives of Toxicology, 92(12), 3535-3547. https://doi.org/10.1007/s00204-018-2317-6
Dellafiora, L., Dall'Asta, C., Cruciani, G., Galaverna, G., & Cozzini, P. (2015). Molecular modelling approach to evaluate poisoning of topoisomerase I by alternariol derivatives. Food Chemistry, 189, 93-101. https://doi.org/10.1016/j.foodchem.2015.02.083
Dellafiora, L., Warth, B., Schmidt, V., Del Favero, G., Mikula, H., Frohlich, J., & Marko, D. (2018). An integrated in silico/in vitro approach to assess the xenoestrogenic potential of Alternaria mycotoxins and metabolites. Food Chemistry, 248, 253-261. https://doi.org/10.1016/j.foodchem.2017.12.013
Diamanti-Kandarakis, E., Bourguignon, J. P., Giudice, L. C., Hauser, R., Prins, G. S., Soto, A. M., Thomas Zoeller, R., & Gore, A. C. (2009). Endocrine-disrupting chemicals: An endocrine society scientific statement. Endocrine Reviews, 30(4), 293-342. https://doi.org/10.1210/er.2009-0002
EFSA. (2011). Scientific opinion on the risks for animal and public health related to the presence of Alternaria toxins in feed and food. EFSA journal, 9(10), 2407. https://doi.org/10.2903/j.efsa.2011.2407
EFSA. (2016). Dietary exposure assessment to Alternaria toxins in the European population. EFSA journal, 14(12), e04654-n/a. https://doi.org/10.2903/j.efsa.2016.4654
EFSA. (2020). Risk assessment of aflatoxins in food. EFSA Journal, 18(3), e06040. https://doi.org/10.2903/j.efsa.2020.6040
EFSA Scientific Committee, More, S. J., Bampidis, V., Benford, D., Bennekou, S. H., Bragard, C., Halldorsson, T. I., Hernández-Jerez, A. F., Koutsoumanis, K., Naegeli, H., Schlatter, J. R., Silano, V., Nielsen, S. S., Schrenk, D., Turck, D., Younes, M., Benfenati, E., Castle, L., Cedergreen, N., Hardy, A., … Hogstrand, C. (2019). Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals. EFSA Journal, 17(3), e05634. https://doi.org/10.2903/j.efsa.2019.5634
Egbontan, A. O., Afolabi, C. G., Kehinde, I. A., Enikuomehin, O. A., Ezekiel, C. N., Sulyok, M., Warth, B., & Krska, R. (2017). A mini-survey of moulds and mycotoxins in locally grown and imported wheat grains in Nigeria. Mycotoxin Research, 33(1), 59-64. https://doi.org/10.1007/s12550-016-0264-8
Ezekiel, C. N., Abia, W. A., Braun, D., Sarkanj, B., Ayeni, K. I., Oyedele, O. A., Michael-Chikezie, E. C., Ezekiel, V. C., Mark, B., Ahuchaogu, C. P., Krska, R., Sulyok, M., Turner, P. C., & Warth, B. (2020). Comprehensive mycotoxin exposure biomonitoring in breastfed and non-exclusively breastfed Nigerian children. medRxiv, 2020.2005.2028.20115055. https://doi.org/10.1101/2020.05.28.20115055
Fehr, M., Pahlke, G., Fritz, J., Christensen, M. O., Boege, F., Altemoller, M., Podlech, J., & Marko, D. (2009). Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform. Molecular Nutrition & Food Research, 53(4), 441-451. https://doi.org/10.1002/mnfr.200700379
Flasch, M., Bueschl, C., Woelflingseder, L., Schwartz-Zimmermann, H. E., Adam, G., Schuhmacher, R., Marko, D., & Warth, B. (2020). Stable isotope-assisted metabolomics for deciphering xenobiotic metabolism in mammalian cell culture. Acs Chemical Biology, 15(4), 970-981. https://doi.org/10.1021/acschembio.9b01016
Fleck, S. C., Burkhardt, B., Pfeiffer, E., & Metzler, M. (2012). Alternaria toxins: Altertoxin II is a much stronger mutagen and DNA strand breaking mycotoxin than alternariol and its methyl ether in cultured mammalian cells. Toxicology Letters, 214(1), 27-32. https://doi.org/10.1016/j.toxlet.2012.08.003
Fleck, S. C., Pfeiffer, E., & Metzler, M. (2014). Permeation and metabolism of Alternaria mycotoxins with perylene quinone structure in cultured Caco-2 cells. Mycotoxin Research, 30(1), 17-23. https://doi.org/10.1007/s12550-013-0180-0
Fleck, S. C., Sauter, F., Pfeiffer, E., Metzler, M., Hartwig, A., & Koberle, B. (2016). DNA damage and repair kinetics of the Alternaria mycotoxins alternariol, altertoxin II and stemphyltoxin III in cultured cells. Mutat Res Genet Toxicol Environ Mutagen, 798-799, 27-34. https://doi.org/10.1016/j.mrgentox.2016.02.001
Fliszar-Nyul, E., Lemli, B., Kunsagi-Mate, S., Dellafiora, L., Dall'Asta, C., Cruciani, G., Pethő, G., & Poor, M. (2019). Interaction of mycotoxin alternariol with serum albumin. International Journal of Molecular Sciences, 20(9), 2352. https://doi.org/10.3390/ijms20092352
Fraeyman, S., Devreese, M., Broekaert, N., De Mil, T., Antonissen, G., De Baere, S., Rychlik, M., & Croubels, S. (2015). Quantitative determination of tenuazonic acid in pig and broiler chicken plasma by LC-MS/MS and its comparative toxicokinetics. Journal of Agricultural and Food Chemistry, 63(38), 8560-8567. https://doi.org/10.1021/acs.jafc.5b02828
Giambrone, J. J., Davis, N. D., & Diener, U. L. (1978). Effect of tenuazonic acid on young chickens. Poultry Science, 57(6), 1554-1558. https://doi.org/10.3382/ps.0571554
Gotthardt, M., Asam, S., Gunkel, K., Moghaddam, A. F., Baumann, E., Kietz, R., & Rychlik, M. (2019). Quantitation of six Alternaria toxins in infant foods applying stable isotope labeled standards. Front Microbiol, 10(109), 109. https://doi.org/10.3389/fmicb.2019.00109
Grover, S., & Lawrence, C. B. (2017). The Alternaria alternata mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation. Int J of Mol Sci, 18(7), 1577. https://doi.org/10.3390/ijms18071577
Gruber-Dorninger, C., Novak, B., Nagl, V., & Berthiller, F. (2017). Emerging mycotoxins: Beyond traditionally determined food contaminants. Journal of Agricultural and Food Chemistry, 65(33), 7052-7070. https://doi.org/10.1021/acs.jafc.6b03413
Hickert, S., Bergmann, M., Ersen, S., Cramer, B., & Humpf, H.-U. (2016). Survey of Alternaria toxin contamination in food from the German market, using a rapid HPLC-MS/MS approach. Mycotoxin Research, 32(1), 7-18. https://doi.org/10.1007/s12550-015-0233-7
Hickert, S., Hermes, L., Marques, L. M. M., Focke, C., Cramer, B., Lopes, N. P., Flett, B., & Humpf, H.-U. (2017). Alternaria toxins in South African sunflower seeds: Cooperative study. Mycotoxin Research, 33(4), 309-321. https://doi.org/10.1007/s12550-017-0290-1
Hildebrand, A. A., Kohn, B. N., Pfeiffer, E., Wefers, D., Metzler, M., & Bunzel, M. (2015). Conjugation of the mycotoxins alternariol and alternariol monomethyl ether in tobacco suspension cells. Journal of Agricultural and Food Chemistry, 63(19), 4728-4736. https://doi.org/10.1021/acs.jafc.5b00806
Hohenbichler, J., Aichinger, G., Rychlik, M., Del Favero, G., & Marko, D. (2020). Alternaria alternata toxins synergistically activate the aryl hydrocarbon receptor pathway in vitro. Biomolecules, 10(7), 1018. https://doi.org/10.3390/biom10071018
Hovelmann, Y., Hickert, S., Cramer, B., & Humpf, H. U. (2016). Determination of Exposure to the Alternaria mycotoxin tenuazonic acid and its isomer allo-tenuazonic acid in a german population by stable isotope dilution HPLC-MS(3). Journal of Agricultural and Food Chemistry, 64(34), 6641-6647. https://doi.org/10.1021/acs.jafc.6b02735
Jarolim, K., Del Favero, G., Ellmer, D., Stark, T. D., Hofmann, T., Sulyok, M., Humpf, H.-U., & Marko, D. (2016). Dual effectiveness of Alternaria but not fusarium mycotoxins against human topoisomerase II and bacterial gyrase. Archives of Toxicology. 91(4), 2007-2016. https://doi.org/10.1007/s00204-016-1855-z
Jarolim, K., Del Favero, G., Pahlke, G., Dostal, V., Zimmermann, K., Heiss, E., Ellmer, D., Stark, T. D., Hofmann, T., & Marko, D. (2017). Activation of the Nrf2-ARE pathway by the Alternaria alternata mycotoxins altertoxin I and II. Archives of Toxicology, 91(1), 203-216. https://doi.org/10.1007/s00204-016-1726-7
Kang, Y., Feng, H., Zhang, J., Chen, S., Valverde, B. E., & Qiang, S. (2017). TeA is a key virulence factor for Alternaria alternata (Fr.) Keissler infection of its host. Plant Physiology and Biochemistry, 115, 73-82. https://doi.org/10.1016/j.plaphy.2017.03.002
Kelman, M. J., Renaud, J. B., Seifert, K. A., Mack, J., Sivagnanam, K., Yeung, K. K., & Sumarah, M. W. (2015). Identification of six new Alternaria sulfoconjugated metabolites by high-resolution neutral loss filtering. Rapid Communications in Mass Spectrometry: Rcm, 29(19), 1805-1810. https://doi.org/10.1002/rcm.7286
Kollarova, J., Cenk, E., Schmutz, C., & Marko, D. (2018). The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-kappaB signalling pathway. Archives of Toxicology, 92(11), 3347-3358. https://doi.org/10.1007/s00204-018-2299-4
Krewski, D., Acosta, D., Jr., Andersen, M., Anderson, H., Bailar, J. C., 3rd, Boekelheide, K., Brent, R., Charnley, G., Cheung, V. G., Green, S., Jr., Kelsey, K. T., Kerkvliet, N. I., Li, A. A., McCray, L., Meyer, O., Patterson, R. D., Pennie, W., Scala, R. A., Solomon, G. M., Stephens, M., Yager, J., & Zeise, L. (2010). Toxicity testing in the 21st century: A vision and a strategy. Toxicol Env Health Pt B-Crit Rev, 13(2-4), 51-138. https://doi.org/10.1080/10937404.2010.483176
Kruisselbrink, J. W., van der Voet, H., van Donkersgoed, G., & van Klaveren, J. (2018). Proposal for a data model for probabilistic cumulative dietary exposure assessments of pesticides in line with the MCRA software. EFSA Support Publ, 15(4), 1375E. https://doi.org/10.2903/sp.efsa.2018.EN-1375
Lehmann, L., Wagner, J., & Metzler, M. (2006). Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. Food and Chemical Toxicology, 44(3), 398-408. https://doi.org/10.1016/j.fct.2005.08.013
Liu, Y., & Rychlik, M. (2015). Biosynthesis of seven carbon-13 labeled Alternaria toxins including altertoxins, alternariol, and alternariol methyl ether, and their application to a multiple stable isotope dilution assay. Analytical and Bioanalytical Chemistry, 407(5), 1357-1369. https://doi.org/10.1007/s00216-014-8307-5
Liu, Z., Zhao, X., Wu, L., Zhou, S., Gong, Z., Zhao, Y., & Wu, Y. (2020). Development of a sensitive and reliable UHPLC-MS/MS method for the determination of multiple urinary biomarkers of mycotoxin exposure. Toxins, 12(3), 193. https://doi.org/10.3390/toxins12030193
López, P., Venema, D., de Rijk, T., de Kok, A., Scholten, J. M., Mol, H. G. J., & de Nijs, M. (2016). Occurrence of Alternaria toxins in food products in The Netherlands. Food Control, 60, 196-204. https://doi.org/10.1016/j.foodcont.2015.07.032
Man, Y., Liang, G., Li, A., & Pan, L. (2017). Analytical methods for the determination of Alternaria mycotoxins. Chromatographia, 80(1), 9-22. https://doi.org/10.1007/s10337-016-3186-x
Martins, C., Vidal, A., De Boevre, M., De Saeger, S., Nunes, C., Torres, D., Goios, A., Lopes, C., Assunção, R., & Alvito, P. (2019). Exposure assessment of Portuguese population to multiple mycotoxins: The human biomonitoring approach. International Journal of Hygiene and Environmental Health, 222(6), 913-925. https://doi.org/10.1016/j.ijheh.2019.06.010
Meena, M., & Samal, S. (2019). Alternaria host-specific (HSTs) toxins: An overview of chemical characterization, target sites, regulation and their toxic effects. Toxicol Rep, 6, 745-758. https://doi.org/10.1016/j.toxrep.2019.06.021
Mescher, M., & Haarmann-Stemmann, T. (2018). Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options. Pharmacology & Therapeutics, 187, 71-87. https://doi.org/10.1016/j.pharmthera.2018.02.012
Mikula, H., Skrinjar, P., Sohr, B., Ellmer, D., Hametner, C., & Fröhlich, J. (2013). Total synthesis of masked Alternaria mycotoxins-Sulfates and glucosides of alternariol (AOH) and alternariol-9-methyl ether (AME). Tetrahedron, 69(48), 10322-10330. https://doi.org/10.1016/j.tet.2013.10.008
Murray, I. A., Patterson, A. D., & Perdew, G. H. (2014). Aryl hydrocarbon receptor ligands in cancer: Friend and foe. Nature Reviews Cancer, 14(12), 801-814. https://doi.org/10.1038/nrc3846
Pahlke, G., Tiessen, C., Domnanich, K., Kahle, N., Groh, I. A. M., Schreck, I., Weiss, C., & Marko, D. (2016). Impact of Alternaria toxins on CYP1A1 expression in different human tumor cells and relevance for genotoxicity. Toxicology Letters, 240(1), 93-104. https://doi.org/10.1016/j.toxlet.2015.10.003
Pavicich, M. A., De Boevre, M., Vidal, A., Iturmendi, F., Mikula, H., Warth, B., Marko, D., De Saeger, S., & Patriarca, A. (2020). Fate of free and modified Alternaria mycotoxins during the production of apple concentrates. Food Control, 118, 107388. https://doi.org/10.1016/j.foodcont.2020.107388
Pero, R. W., Posner, H., Blois, M., Harvan, D., & Spalding, J. W. (1973). Toxicity of metabolites produced by the “Alternaria”. Environmental Health Perspectives, 4, 87-94. https://doi.org/10.1289/ehp.730487
Pfeiffer, E., Burkhardt, B., Altemoller, M., Podlech, J., & Metzler, M. (2008). Activities of human recombinant cytochrome P450 isoforms and human hepatic microsomes for the hydroxylation ofAlternaria toxins. Mycotoxin Research, 24(3), 117-123. https://doi.org/10.1007/bf03032337
Pfeiffer, E., Eschbach, S., & Metzler, M. (2007). Alternaria toxins: DNA strand-breaking activity in mammalian cells in vitro. Mycotoxin Research, 23(3), 152-157. https://doi.org/10.1007/bf02951512
Pfeiffer, E., Schebb, N. H., Podlech, J., & Metzler, M. (2007). Novel oxidative in vitro metabolites of the mycotoxins alternariol and alternariol methyl ether. Molecular Nutrition & Food Research, 51(3), 307-316. https://doi.org/10.1002/mnfr.200600237
Pfeiffer, E., Schmit, C., Burkhardt, B., Altemöller, M., Podlech, J., & Metzler, M. (2009). Glucuronidation of the mycotoxins alternariol and alternariol-9-methyl ether in vitro: Chemical structures of glucuronides and activities of human UDP-glucuronosyltransferase isoforms. Mycotoxin Research, 25(1), 3-10. https://doi.org/10.1007/s12550-008-0001-z
Pohl, J., Ring, A., & Stremmel, W. (2002). Uptake of long-chain fatty acids in HepG2 cells involves caveolae: Analysis of a novel pathway. Journal of Lipid Research, 43(9), 1390-1399. https://doi.org/10.1194/jlr.m100404-jlr200
Preindl, K., Braun, D., Aichinger, G., Sieri, S., Fang, M., Marko, D., & Warth, B. (2019). A generic liquid chromatography-tandem mass spectrometry exposome method for the determination of xenoestrogens in biological matrices. Analytical Chemistry, 91(17), 11334-11342. https://doi.org/10.1021/acs.analchem.9b02446
Puntscher, H., Aichinger, G., Grabher, S., Attakpah, E., Krüger, F., Tillmann, K., Motschnig, T., Hohenbichler, J., Braun, D., Plasenzotti, R., Pahlke, G., Höger, H., Marko, D., & Warth, B. (2019a). Bioavailability, metabolism, and excretion of a complex Alternaria culture extract versus altertoxin II: A comparative study in rats. Archives of Toxicology. 93, 3153-3167. https://doi.org/10.1007/s00204-019-02575-7
Puntscher, H., Cobankovic, I., Marko, D., & Warth, B. (2019b). Quantitation of free and modified Alternaria mycotoxins in European food products by LC-MS/MS. Food Control, 102, 157-165. https://doi.org/10.1016/j.foodcont.2019.03.019
Puntscher, H., Hankele, S., Tillmann, K., Attakpah, E., Braun, D., Kütt, M.-L., Del Favero, G., Aichinger, G., Pahlke, G., Höger, H., Marko, D., & Warth, B. (2019c). First insights into Alternaria multi-toxin in vivo metabolism. Toxicology Letters, 301, 168-178. https://doi.org/10.1016/j.toxlet.2018.10.006
Puntscher, H., Kütt, M.-L., Skrinjar, P., Mikula, H., Podlech, J., Fröhlich, J., Marko, D., & Warth, B. (2018a). Tracking emerging mycotoxins in food: Development of an LC-MS/MS method for free and modified Alternaria toxins. Analytical and Bioanalytical Chemistry, 410(18), 4481-4494. https://doi.org/10.1007/s00216-018-1105-8
Puntscher, H., Marko, D., & Warth, B. (2018b). The fate of altertoxin II during tomato food processing. Front Nutr, 6, 92. https://doi.org/10.3389/fnut.2019.00092
Puntscher, H., Marko, D., & Warth, B. (2020). First determination of the highly genotoxic fungal contaminant altertoxin II in a naturally infested apple sample. Emerg Contam, 6, 82-86. https://doi.org/10.1016/j.emcon.2020.01.002
Qiao, X., Zhang, J., Yang, Y., Yin, J., Li, H., Xing, Y., & Shao, B. (2020). Development of a simple and rapid LC-MS/MS method for the simultaneous quantification of five Alternaria mycotoxins in human urine. Journal of Chromatography B, 1144, 122096. doi: 10.1016/j.jchromb.2020.122096
Qiu, X., Ma, J., Jiao, C., Mao, X., Zhao, X., Lu, M., Wang, K., & Zhang, H. (2017). Alterations in the mucosa-associated fungal microbiota in patients with ulcerative colitis. Oncotarget, 8(64), 107577-107588. doi:10.18632/oncotarget.22534
Qiu, X., Zhang, F., Yang, X., Wu, N., Jiang, W., Li, X. & Liu, Y. (2015). Changes in the composition of intestinal fungi and their role in mice with dextran sulfate sodium-induced colitis. Scientific Reports, 5(1), 10416. https://doi.org/10.1038/srep10416
Rofiat, A.-S., Fanelli, F., Atanda, O., Sulyok, M., Cozzi, G., Bavaro, S., Krska, R., Logrieco, A. F., & Ezekiel, C. N. (2015). Fungal and bacterial metabolites associated with natural contamination of locally processed rice (Oryza sativa L.) in Nigeria. Food Addit Contam A, 32(6), 950-959. https://doi.org/10.1080/19440049.2015.1027880
Rychlik, M., Humpf, H. U., Marko, D., Danicke, S., Mally, A., Berthiller, F., Klaffke, H., & Lorenz, N. (2014). Proposal of a comprehensive definition of modified and other forms of mycotoxins including “masked” mycotoxins. Mycotoxin Resh, 30(4), 197-205. https://doi.org/10.1007/s12550-014-0203-5
Šarkanj, B., Ezekiel, C. N., Turner, P. C., Abia, W. A., Rychlik, M., Krska, R., Sulyok, M., & Warth, B. (2018). Ultra-sensitive, stable isotope assisted quantification of multiple urinary mycotoxin exposure biomarkers. Analytica Chimica Acta, 1019, 84-92. https://doi.org/10.1016/j.aca.2018.02.036
Schmutz, C., Cenk, E., & Marko, D. (2019). The Alternaria Mycotoxin Alternariol Triggers the Immune Response of IL-1beta-stimulated, Differentiated Caco-2 Cells. Molecular Nutrition & Food Research, 63(20), e1900341. https://doi.org/10.1002/mnfr.201900341
Schreck, I., Deigendesch, U., Burkhardt, B., Marko, D., & Weiss, C. (2012). The Alternaria mycotoxins alternariol and alternariol methyl ether induce cytochrome P450 1A1 and apoptosis in murine hepatoma cells dependent on the aryl hydrocarbon receptor. Archives of Toxicology, 86(4), 625-632. https://doi.org/10.1007/s00204-011-0781-3
Schuchardt, S., Ziemann, C., & Hansen, T. (2014). Combined toxicokinetic and in vivo genotoxicity study on Alternaria toxins. EFSA Support Publ, 11(11), 679E. https://doi.org/10.2903/sp.efsa.2014.EN-679
Schwarz, C., Kreutzer, M., & Marko, D. (2012a). Minor contribution of alternariol, alternariol monomethyl ether and tenuazonic acid to the genotoxic properties of extracts from Alternaria alternata infested rice. Toxicology Letters, 214(1), 46-52. https://doi.org/10.1016/j.toxlet.2012.08.002
Schwarz, C., Tiessen, C., Kreutzer, M., Stark, T., Hofmann, T., & Marko, D. (2012b). Characterization of a genotoxic impact compound in Alternaria alternata infested rice as Altertoxin II. Archives of Toxicology, 86(12), 1911-1925. https://doi.org/10.1007/s00204-012-0958-4
Shi, F., & Sottile, J. (2008). Caveolin-1-dependent β1 integrin endocytosis is a critical regulator of fibronectin turnover. Journal of Cell Science, 121(14), 2360-2371. https://doi.org/10.1242/jcs.014977
Shigeura, H. T., & Gordon, C. N. (1963). The biological activity of tenuazonic acid. Biochemistry, 2, 1132-1137.
Solhaug, A., Eriksen, G. S., & Holme, J. A. (2016). Mechanisms of action and toxicity of the mycotoxin alternariol: A review. Basic & Clinical Pharmacology & Toxicology, 119(6), 533-539. https://doi.org/10.1111/bcpt.12635
Solhaug, A., Holme, J. A., Haglund, K., Dendele, B., Sergent, O., Pestka, J., Lagadic-Gossmann, D., & Eriksen, G. S. (2013). Alternariol induces abnormal nuclear morphology and cell cycle arrest in murine RAW 264.7 macrophages. Toxicology Letters, 219(1), 8-17. https://doi.org/10.1016/j.toxlet.2013.02.012
Solhaug, A., Wisbech, C., Christoffersen, T. E., Hult, L. O., Lea, T., Eriksen, G. S., & Holme, J. A. (2015). The mycotoxin alternariol induces DNA damage and modify macrophage phenotype and inflammatory responses. Toxicology Letters, 239(1), 9-21. https://doi.org/10.1016/j.toxlet.2015.08.1107
Soukup, S. T., Fleck, S. C., Pfeiffer, E., Podlech, J., Kulling, S. E., & Metzler, M. (2020). DNA reactivity of altertoxin II: Identification of two covalent guanine adducts formed under cell-free conditions. Toxicology Letters, 331, 75-81. https://doi.org/10.1016/j.toxlet.2020.05.018
Soukup, S. T., Kohn, B. N., Pfeiffer, E., Geisen, R., Metzler, M., Bunzel, M., & Kulling, S. E. (2016). Sulfoglucosides as novel modified forms of the mycotoxins alternariol and alternariol monomethyl ether. Journal of Agricultural and Food Chemistry, 64(46), 8892-8901. https://doi.org/10.1021/acs.jafc.6b03120
Stack, M. E., & Prival, M. J. (1986). Mutagenicity of the Alternaria metabolites altertoxins I, II, and III. Applied and Environmental Microbiology, 52(4), 718-722. https://doi.org/10.1128/aem.52.4.718-722.1986.
Stypuła-Trębas, S., Minta, M., Radko, L., Jedziniak, P., & Posyniak, A. (2017). Nonsteroidal mycotoxin alternariol is a full androgen agonist in the yeast reporter androgen bioassay. Environmental Toxicology and Pharmacology, 55, 208-211. https://doi.org/10.1016/j.etap.2017.08.036
Tiessen, C., Ellmer, D., Mikula, H., Pahlke, G., Warth, B., Gehrke, H., Zimmermann, K., Heiss, E., Fröhlich, J., & Marko, D. (2017). Impact of phase I metabolism on uptake, oxidative stress and genotoxicity of the emerging mycotoxin alternariol and its monomethyl ether in esophageal cells. Archives of Toxicology, 91(3), 1213-1226. https://doi.org/10.1007/s00204-016-1801-0
Tiessen, C., Fehr, M., Schwarz, C., Baechler, S., Domnanich, K., Bottler, U., Pahlke, G., & Marko, D. (2013a). Modulation of the cellular redox status by the Alternaria toxins alternariol and alternariol monomethyl ether. Toxicology Letters, 216(1), 23-30. https://doi.org/10.1016/j.toxlet.2012.11.005
Tiessen, C., Gehrke, H., Kropat, C., Schwarz, C., Bachler, S., Fehr, M., Pahlke, G., & Marko, D. (2013b). Role of topoisomerase inhibition and DNA repair mechanisms in the genotoxicity of alternariol and altertoxin-II. World Mycotoxin J, 6(3), 233-244. https://doi.org/10.3920/wmj2013.1592
Tittlemier, S. A., Cramer, B., Dall'Asta, C., Iha, M., Lattanzio, V. M. T., Maragos, C., Solfrizzo, M., Stranska, M., Stroka, J., & Sumarah, M. (2020). Developments in mycotoxin analysis: An update for 2018-19. World Mycotoxin J, 13, 1-22. https://doi.org/10.3920/WMJ2019.2535
Urra, H., Torres, V. A., Ortiz, R. J., Lobos, L., Díaz, M. I., Díaz, N., Härtel, S., & Leyton, L. (2012). Caveolin-1-enhanced motility and focal adhesion turnover require tyrosine-14 but not accumulation to the rear in metastatic cancer cells. Plos One, 7(4), e33085. https://doi.org/10.1371/journal.pone.0033085.
Valtonen, V. (2017). Clinical diagnosis of the dampness and mold hypersensitivity syndrome: Review of the literature and suggested diagnostic criteria. Frontiers in immunology, 8, 951. https://doi.org/10.3389/fimmu.2017.00951
Vejdovszky, K., Hahn, K., Braun, D., Warth, B., & Marko, D. (2017). Synergistic estrogenic effects of Fusarium and Alternaria mycotoxins in vitro. Archives of Toxicology, 91(3), 1447-1460. https://doi.org/10.1007/s00204-016-1795-7
Vejdovszky, K., Sack, M., Jarolim, K., Aichinger, G., Somoza, M. M., & Marko, D. (2017a). In vitro combinatory effects of the Alternaria mycotoxins alternariol and altertoxin II and potentially involved miRNAs. Toxicology Letters, 267, 45-52. https://doi.org/10.1016/j.toxlet.2016.12.011
Vejdovszky, K., Schmidt, V., Warth, B., & Marko, D. (2017b). Combinatory estrogenic effects between the isoflavone genistein and the mycotoxins zearalenone and alternariol in vitro. Molecular Nutrition & Food Research, 61(3), 1600526. https://doi.org/10.1002/mnfr.201600526
Vejdovszky, K., Warth, B., Sulyok, M., & Marko, D. (2016). Non-synergistic cytotoxic effects of fusarium and Alternaria toxin combinations in Caco-2 cells. Toxicology Letters, 241, 1-8. https://doi.org/10.1016/j.toxlet.2015.10.024
Vidal, A., Mengelers, M., Yang, S., De Saeger, S., & De Boevre, M. (2018). Mycotoxin biomarkers of exposure: A comprehensive review. Compr Rev Food Sci F, 17(5), 1127-1155. https://doi.org/10.1111/1541-4337.12367
Walravens, J., Mikula, H., Rychlik, M., Asam, S., Devos, T., Njumbe Ediage, E., Diana Di Mavungu, J., Jacxsens, L., Van Landschoot, A., Vanhaecke, L., & De Saeger, S. (2016). Validated UPLC-MS/MS methods to quantitate free and conjugated Alternaria toxins in commercially available tomato products and fruit and vegetable juices in belgium. J Agr Food Chem, 64(24), 5101-5109. https://doi.org/10.1021/acs.jafc.6b01029
Walravens, J., Mikula, H., Rychlik, M., Asam, S., Ediage, E. N., Di Mavungu, J. D., Van Landschoot, A., Vanhaecke, L., & De Saeger, S. (2014). Development and validation of an ultra-high-performance liquid chromatography tandem mass spectrometric method for the simultaneous determination of free and conjugated Alternaria toxins in cereal-based foodstuffs. Journal of Chromatography A, 1372, 91-101. https://doi.org/10.1016/j.chroma.2014.10.083
Warth, B., Sulyok, M., & Krska, R. (2013). LC-MS/MS-based multibiomarker approaches for the assessment of human exposure to mycotoxins. Analytical and Bioanalytical Chemistry, 405(17), 5687-5695. https://doi.org/10.1007/s00216-013-7011-1
Zwickel, T., Kahl, S. M., Klaffke, H., Rychlik, M., & Muller, M. E. (2016). Spotlight on the underdogs-An analysis of underrepresented Alternaria mycotoxins formed depending on varying substrate, time and temperature conditions. Toxins (Basel), 8(11). https://doi.org/10.3390/toxins8110344
Zwickel, T., Kahl, S. M., Rychlik, M., & Müller, M. E. H. (2018). Chemotaxonomy of mycotoxigenic small-spored Alternaria fungi-Do multitoxin mixtures act as an indicator for species differentiation? Front Microbiol, (9), 13683. https://doi.org/10.3389/fmicb.2018.01368