[en] The mycotoxin zearalenone (ZEN) is a secondary metabolite of fungi which is produced by certain species of the genus Fusarium and can occur in cereals and other plant products. Reporter gene assays incorporating natural steroid receptors and the H295R steroidogenesis assay have been implemented to assess the endocrine disrupting activity of ZEN and its metabolites alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL). alpha-ZOL exhibited the strongest estrogenic potency (EC(50) 0.022+/-0.001 nM), slightly less potent than 17-beta estradiol (EC(50) 0.015+/-0.002 nM). ZEN was ~70 times less potent than alpha-ZOL and twice as potent as beta-ZOL. Binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of ZEN, alpha-ZOL or beta-ZOL. ZEN, alpha-ZOL or beta-ZOL increased production of progesterone, estradiol, testosterone and cortisol hormones in the H295R steroidogenesis assay, with peak productions at 10 muM. At 100 muM, cell viability decreased and levels of hormones were significantly reduced except for progesterone. beta-ZOL increased estradiol concentrations more than alpha-ZOL or ZEN, with a maximum effect at 10 muM, with beta-ZOL (562+/-59 pg/ml)>alpha-ZOL (494+/-60 pg/ml)>ZEN (375+/-43 pg/ml). The results indicate that ZEN and its metabolites can act as potential endocrine disruptors at the level of nuclear receptor signalling and by altering hormone production.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Frizzell, C
Ndossi, D
Verhaegen, S
Dahl, E
Eriksen, G
Sorlie, M
Ropstad, E
Muller, Marc ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Elliott, C T
Connolly, L
Language :
English
Title :
Endocrine disrupting effects of zearalenone, alpha- and beta-zearalenol at the level of nuclear receptor binding and steroidogenesis.
Publication date :
2011
Journal title :
Toxicology Letters
ISSN :
0378-4274
eISSN :
1879-3169
Publisher :
Elsevier, Amsterdam, Netherlands
Volume :
206
Issue :
2
Pages :
210-217
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2011 Elsevier Ireland Ltd. All rights reserved.
Abid-Essefi S., Bouaziz C., El Golli-Bennour E., Ouanes Z., Bacha H. Comparative study of toxic effects of zearalenone and its two major metabolites alpha-zearalenol and beta-Zearalenol on cultured human Caco-2 cells. J. Biochem. Mol. Toxicol. 2009, 23(4):233-243.
Abid-Essefi S., Ouanes Z., Hassen W., Baudrimont I., Creppy E., Bacha H. Cytotoxicity, inhibition of DNA and protein syntheses and oxidative damage in cultured cells exposed to zearalenone. Toxicol. In Vitro. 2004, 18:467-474.
Ahamed S., Foster J.S., Bukovsky A., Wimalasena J. Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7 cells. Mol. Carcinog. 2001, 30(2):88-98.
Bennett J.W., Klich M. Mycotoxins. Clin. Microbiol. Rev. 2003, 16(3):497-516.
Biehl M., Prelusky D., Koritz G., Hartin K., Buck W., Trenholm H. Bilary-excretion and enterohepatic cycling of zearalenone in immature pigs. Toxicol. Appl. Pharmacol. 1993, 121(1):152-159.
Branham W.S., Dial S.L., Moland C.L., Hass B.S., Blair R.M., Fang H., Shi L.M., Tong W.D., Perkins R.G., Sheehan D.M. Phytoestrogens and mycoestrogens bind to the rat uterine estrogen receptor. J. Nutr. 2002, 132(4):658-664.
Connolly L., Ropstad E., Verhaegen S. In vitro bioassays for the study of endocrine-disrupting food additives and contaminants. Trends Anal. Chem. 2011, 30(2):227-238.
Creppy E.E. Update of survey, regulation and toxic effects of mycotoxins in Europe. Toxicol. Lett. 2002, 127(1-3):19-28.
Dees C., Foster J.S., Ahamed S., Wimalasena J. Dietary estrogens stimulate human breast cells to enter the cell cycle. Environ. Health Perspect. 1997, 105:633-636.
European Commission (EC) Commission Regulation (EC) No 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs. Off. J. Eur. Union 2006, L364:5-24.
Eckert R., Katzenellenbogen B. Effects of estrogens and anti-estrogens on estrogen-receptor dynamics and the induction of progesterone-receptor in MCF-7 human breast cancer cells. Cancer Res. 1982, 42(1):139-144.
Eriksen, G.S., Pennington, J., Schlatter, J., Alexander, J., Thuvander, A., 2000. Zearalenone. In: Joint FAO/WHO Expert Committee on Food Additives (Ed.), Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, (44). WHO, Geneva.
Fazzari A., Catalano M., Comba A., Becchis M., Raineri M., Frairia R. The control of progesterone receptor expression in MCF-7 breast cancer cells: effects of estradiol and sex hormone-binding globulin (SHBG). Mol. Cell. Endocrinol. 2001, 172(1-2):31-36.
Gazdar A.F., Oie H.K., Shackleton C.H., Chen T.R., Triche T.J., Myers C.E., Chrousos G.P., Brennan M.F., Stein C.A., La Rocca R.V. Establishment and characterization of a human adrenocortical carcinoma cell line that expresses multiple pathways of steroid biosynthesis. Cancer Res. 1990, 50:5488-5496.
Gracia T., Hilscherova K., Jones P.D., Newsted J.L., Zhang X., Hecker M., Higley E.B., Sanderson J.T., Yu R.M., Wu R.S., Giesy J.P. The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol. Environ. Saf. 2006, 65(3):293-305.
Hecker M., Giesy J.P. Novel trends in endocrine distributor testing: the H295R steroidogenesis assay for identification of inducers and inhibitors of hormone production. Anal. Bioanal. Chem. 2008, 390:287-291.
Hilscherova K., Jones P.D., Gracia T., Newsted J.L., Zhang X., Sanderson J.T., Yu R.M., Wu R.S., Giesy J.P. Assessment of the effects of chemicals on the expression of ten steroidogenic genes in the H295R cell line using real-time PCR. Toxicol. Sci. 2004, 81(1):78-89.
Horwitz K., Koseki Y., Mcguire W. Estrogen control of progesterone receptor in human breast cancer: role of estradiol and anti-estrogen. Endocrinology 1978, 103(5):1742-1751.
Joint FAO/WHO Expert Committee on Food Additives (JECFA) WHO Food Additives Series: 44, World Health Organization, Geneva, 2000.
Kastner P., Krust A., Turcotte B., Stropp U., Tora L., Gronemeyer H. Two distinct estrogen-regulated promotors generate transcripts encoding the two functionally different human-progesterone receptor form-A and form-B. EMBO J. 1990, 9(5):1603-1614.
Knudsen F.R., Pottinger T.G. Interaction of endocrine disrupting chemicals, singly and in combination, with estrogen-, androgen- and corticosteroid-binding sites in rainbow trout (Oncorhynchus mykiss). Aquat. Toxicol. 1999, 44:159-170.
Kuiper G., Lemmen J., Carlsson B., Corton J., Safe S., van der Saag P. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998, 139(10):4252-4263.
Kuiper-Goodman T., Scott P., Watanabe H. Risk assessment of the mycotoxin zearalenone. Regul. Toxicol. Pharmacol. 1987, 7(3):253-306.
Le Guevel R., Pakdel F. Assessment of oestrogenic potency of chemicals used as growth promoter by in-vitro methods. Human Reprod. 2001, 16:1030-1036.
Malekinejad H., Maas-Bakker R., Fink-Gremmels J. Species differences in the hepatic biotransformation of zearalenone. Vet. J. 2006, 172(1):96-102.
Massart F., Meucci V., Saggese G., Soldani G. High growth rate of girls with precocious puberty exposed to estrogenic mycotoxins. J. Pediatr. 2008, 152:690-695.
Mayr U. Estrogen-controlled gene-expression in tissue-culture cells by zearalenone. FEBS Lett. 1988, 239(2):223-226.
Miles C.O., Erasmuson A.F., Wilkins A.L., Towers N.R., Smith B.L., Garthwaite I., Scahill B.G., Hansen R.P. Ovine metabolism of zearalenone to α-zearalanol (zeranol). J. Agric. Food Chem. 1996, 44(10):3244-3250.
Othmen Z.O., Golli E.E., Abid-Essefi S., Bacha H. Cytotoxicity effects induced by Zearalenone metabolites, α-Zearalenol and β-Zearalenol, on cultured Vero cells. Toxicology 2008, 252:72-77.
Opinion of the Scientific Committee on Food on Fusarium Toxins Part 2: Zearalenone 22 June 2000. European Commission, Health and Consumer Protection Directorate-General.
Parveen M., Zhu Y., Kiyama R. Expression profiling of the genes responding to zearalenone and its analogues using estrogen-responsive genes. FEBS Lett. 2009, 583(14):2377-2384.
Pillay D., Chuturgoon A.A., Nevines E., Manickum T., Deppe W., Dutton M.F. The quantitative analysis of zearalenone and its derivatives in plasma of patients with breast and cervical cancer. Clin. Chem. Lab. Med. 2002, 40(9):946-951.
Saenz de Rodriguez C.A., Bongiovanni A.M., Conge de Borregol L. An epidemic of precocious development in Puerto Rican children. J. Pediatr. 1985, 107(3):393-396.
SCOOP, 2003. Collection of occurrence data of Fusarium toxins in food and assessment of dietary intake by the population of EU member states. In: Vidnes, A., Bergsten, C., Paulsen, B., (Eds.), Sub-task Zearalenone. SCOOP European Project. Task 3.2.10, 241-481.
Shier W.T., Shier A.C., Xie W., Mirocha C.J. Structure-activity relationships for human estrogenic activity in zearalenone mycotoxins. Toxicon. 2001, 39(9):1435-1438.
Staels B., Hum D.W., Miller W.L. Regulation of steroidogenesis in NCI-H295 cells: a cellular model of the human fetal adrenal. Mol. Endocrinol. 1993, 7:423-433.
Tabb M.M., Blumberg B. New modes of action for endocrine-disrupting chemicals. Mol. Endocrinol. 2006, 20:475-482.
Tiemann U., Tomek W., Schneider F., Vanselow J. Effects of the mycotoxins α- and β-zearalenol on regulation of progesterone synthesis in cultured granulosa cells from porcine ovaries. Reprod. Toxicol. 2003, 17:673-681.
Tomaszewski J., Miturski R., Semczuk A., Kotarski J., Jakowicki J. Tissue zearalenone concentration in normal, hyperplastic and neoplastic human endometrium. Ginekol. Pol. 1998, 69:363-366.
Turcotte J.C., Hunt P.J.B., Blaustein J.D. Estrogenic effects of zearalenone on the expression of progestin receptors and sexual behaviour in female rats. Horm. Behav. 2005, 47(2):178-184.
Videmann B., Mazallom M., Tep J., Lecoeur S. Metabolism and transfer of the mycotoxin zearalenone in human intestinal Caco-2 cells. Food Chem. Toxicol. 2008, 46:3279-3286.
Willemsen P., Scippo M., Kausel G., Figueroa J., Maghuin-Rogister G., Martial J. Use of reporter cell lines for detection of endocrine-disrupter activity. Anal. Bioanal. Chem. 2004, 378(3):655-663.
Withanage G.S.K., Murata H., Koyama T., Ishiwata I. Agonistic and antagonistic effects of zearalenone, an estrogenic mycotoxin, on SKN, HHUA, and HepG2 human cancer cell lines. Vet. Hum. Toxicol. 2001, 43(1):6-10.
Witmer C.M., Snyder R.R., Jollow D.J., Kalf G.F., Kocsis J.J., Sipes I.G. Biological Reactive Intermediates IV; Molecular and Cellular Effects and Their Impact on Human Health 1991, Plenum Press, New York.
Yang J., Zhang Y., Wang Y., Cui S. Toxic effects of zearalenone and α-zearalenol on the regulation of steroidogenesis and testosterone production in mouse Leydig cells. Toxicol. In Vitro 2007, 21:558-565.
Zinedine A., Soriano J.M., Molto J.C., Manes J. Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: an oestrogenic mycotoxin. Food Chem. Toxicol. 2007, 45(1):1-18.