The present study investigated the effects of citrinin (CIT) on a yeast-transformed human DNA methyltransferase (DNMT) associated with flocculation that can be inhibited by epigenetic mutagens. CIT (0.5–2 μmol/L) inhibited the flocculation levels of yeast transfected with DNMT-genes (DNMT yeast) and the reporter gene activity of FLO1, which has been associated with flocculation. In contrast, the same concentrations of CIT had little effect on reporter activity under the control of a less methylation-sensitive FLO1 promoter. It was also shown that bacterial DNMT activity could be inhibited in the presence of CIT (4 and 40 μmol/L). These results show that CIT has inhibitory activity of DNMT, suggesting that the cytotoxicity of CIT may be involved in epigenetic mutagenicity.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Arai M, Hibino T (1983) Tumorigenicity of citrinin in male F344 rats. Cancer Lett 17:281–287
Ashby J, Tennant RW (1991) Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the US NTP. Mutat Res Rev Mutat Res 257:229–306
Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Clin Oncol 11:726
Bennett JW, Klich M (2003) Mycotoxins. Curr Clin Microbiol Rep 16:497–516
Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21
Blaszkewicz M, Muñoz K, Degen GH (2013) Methods for analysis of citrinin in human blood and urine. Arch Toxicol 87:1087–1094
Bouslimi A, Bouaziz C, Ayed-Boussema I, Hassen W, Bacha H (2008) Individual and combined effects of ochratoxin A and citrinin on viability and DNA fragmentation in cultured Vero cells and on chromosome aberrations in mice bone marrow cells. Toxicology 251:1–7
Chang CH, Yu FY, Wu TS, Wang LT, Liu BH (2010) Mycotoxin citrinin induced cell cycle G2/M arrest and numerical chromosomal aberration associated with disruption of microtubule formation in human cells. Toxicol Sci 119:84–92
Chevalier S, Roberts RA (1998) Perturbation of rodent hepatocyte growth control by nongenotoxic hepatocarcinogens: mechanisms and lack of relevance for human health. Oncol Rep 5:1319–1346
Denis H, Ndlovu MN, Fuks F (2011) Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBO Rep 12:647–656
[EFSA] European Food Safety Authority (2012) EFSA Panel on Contaminants in the Food Chain (CONTAM) - scientific opinion on the risks for public and animal health related to the presence of citrinin in food and feed. EFSA Journal 10:2605
Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463
Flajs D, Peraica M (2009) Toxicological properties of citrinin. Arch Ind Hyg Toxicol 60:457–464
Fleming AB, Beggs S, Church M, Tsukihashi Y, Pennings S (2014) The yeast Cyc8-Tup1 complex cooperates with Hda1p and Rpd3p histone deacetylases to robustly repress transcription of the subtelomeric FLO1 gene. Biochim Biophys Acta 1839:1242–1255
Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514
Herceg Z, Hainaut P (2007) Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis. Mol Oncol 1:26–41
Hökby E, Hult K, Gatenbeck S, Rutqvist L (1979) Ochratoxin A and citrinin in 1976 crop of barley stored on farms in Sweden. Acta Agric Scand 29:174–178
Hood R, Hayes A, Scammell J (1976) Effects of prenatal administration of citrinin and viriditoxin to mice. Food Cosmet Toxicol 14:175–178
IARC (1987) Monographs on the evaluation of carcinogenic risks to humans: overall evaluations of carcinogenicity: an updating of IARC monographs. International Agency for Research on Cancer, Lyon, pp 1–403
Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428
Jones PA, Laird PW (1999) Cancer-epigenetics comes of age. Nat Genet 21:163
Knasmuller S, Cavin C, Chakraborty A, Darroudi F, Majer BJ, Huber WW, Ehrlich VA (2004) Structurally related mycotoxins ochratoxin A, ochratoxin B, and citrinin differ in their genotoxic activities and in their mode of action in human-derived liver (HepG2) cells: implications for risk assessment. Nutr Cancer 50:190–197
Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3:662–673
Nelson TS, Kirby LK, Beasley JN, Johnson ZB, Ciegler A (1985) The effect of drying method and storage time on citrinin activity in corn. Poult Sci 64:464–468
Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257
Osborne B (1980) The occurrence of ochratoxin A in mouldy bread and flour. Food Cosmet Toxicol 18:615–617
Petkova-Bocharova T, Castegnaro M, Michelon J, Maru V (1991) Ochratoxin A and other mycotoxins in cereals from an area of Balkan endemic nephropathy and urinary tract tumours in Bulgaria. IARC Sci Publ:83–87
Sabater-Vilar M1, Maas RF, Fink-Gremmels J (1999) Mutagenicity of commercial Monascus fermentation products and the role of citrinin contamination. Mutat Res 444:7–16
Scott PM, Van Walbeek W, Kennedy B, Anyeti D (1972) Mycotoxins (ochratoxin A, citrinin, and sterigmatocystin) and toxigenic fungi in grains and other agricultural products. J Agric Food Chem 20:1103–1109
Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36
Sugiyama KI, Takamune M, Furusawa H, Honma M (2015) Human DNA methyltransferase gene-transformed yeasts display an inducible flocculation inhibited by 5-aza-2-deoxycytidine. Biochem Biophys Res Commun 456:689–694
Sugiyama KI, Furusawa H, Shimizu M, Grúz P, Honma M (2016) Epigenetic mutagen as histone modulator can be detected by yeast flocculation. Mutagenesis 31:687–693
Sugiyama KI, Furusawa H, Grúz P, Honma M (2017a) Detection of epigenetic mutagens including anthracene-derived compounds using yeast FLO1 promoter GFP reporter gene assay. Mutagenesis 32:429–435
Sugiyama KI, Furusawa H, Grúz P, Honma M (2017b) Functional role of DNA methylation at the FLO1 promoter in budding yeast. FEMS Microbiol Lett 364:fnx221
Tang Y, Gao XD, Wang Y, Yuan BF, Feng YQ (2012) Widespread existence of cytosine methylation in yeast DNA measured by gas chromatography/mass spectrometry. Anal Chem 84:7249–7255
Wawrzyniak J, Waśkiewicz A (2014) Ochratoxin A and citrinin production by Penicillium verrucosum on cereal solid substrates. Food Addit Contam Part A 31:139–148
This work was supported by JSPS KAKENHI Grant Number 18K11661 and a Health and Labor Sciences Research Grant.
Conflict of interest
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Sugiyama, K., Furusawa, H. & Honma, M. Detection of epigenetic effects of citrinin using a yeast-based bioassay. Mycotoxin Res 35, 363–368 (2019). https://doi.org/10.1007/s12550-019-00361-z
- Epigenetic mutagen
- DNA methyltransferase