Comparative toxicokinetics of Fusarium mycotoxins in pigs and humans.
Schelstraete Wim,Devreese Mathias,Croubels Siska
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
Mycotoxins frequently contaminate food and feed materials, posing a threat to human and animal health. Fusarium species produce important mycotoxins with regard to their occurrence and toxicity, especially deoxynivalenol (DON), fumonisin B1 (FB1), zearalenone (ZEN) and T-2 toxin (T-2). The susceptibility of an animal species towards the effects of these toxins in part depends on the absorption, distribution, metabolism and excretion (ADME processes) of these toxins from the body. For humans, in vivo information is scarce and often animal data is used for extrapolation to humans. From a kinetic and safety point of view, the pig seems to be a promising animal model to aid in the assessment of the toxicological risk of mycotoxins to humans. Qualitatively, the ADME processes seem to be quite similar between pigs and humans. In addition, similar metabolite and excretion patterns are observed, although some quantitative differences are noticed which are subject of this review. The high sensitivity of pigs towards mycotoxins and the similar kinetics are an advantage for the use of this animal species in the risk assessment of mycotoxins, and for the establishment of legal limits of mycotoxins.
10.1016/j.fct.2020.111140
The effect of experimental, long-term exposure to low-dose zearalenone mycotoxicosis on the histological condition of ovaries in sexually immature gilts.
Gajęcka M,Rybarczyk L,Zwierzchowski W,Jakimiuk E,Zielonka L,Obremski K,Gajęcki M
Theriogenology
Farm animals are at risk of exposure to zearalenone (ZEA) in feedstuffs, which may lead to aberrations in their reproductive development, thereby adversely affecting production outcomes. The objective of this study was to determine the effect of long-term (48 days), per os administration of low ZEA doses (50% [20 μg ZEA/kg body weight (bw)] and 100% [40 μg ZEA/kg bw] NOAEL values) on anatomopathological changes in the ovaries of sexually immature gilts. The experiment involved 12 clinically healthy gilts aged 2 months with an initial body weight of about 40 kg and a determined immune status. The animals were randomly divided into two experimental groups (E1, E2) and a control group (C; all n = 4). Group E1 received per os 20 μg ZEA/kg bw for 48 days; group E2 received per os 40 μg ZEA/kg bw for 48 days; and group C received per os placebo for 48 days. Analytical samples of the mycotoxin were administered daily per os in gelatine capsules before morning feeding. Animals were sacrificed at the end of the experiment. The results of anatomopathological examinations of the ovaries in immature gilts subjected to long-term, low-dose ZEA exposure showed that ZEA-induced experimental hyperoestrogenism lowered the proliferative ability of granulosa cells of the ovarian follicle walls and of the connective tissue of the ovarian stroma, in particular at the lower ZEA dose.
10.1016/j.theriogenology.2010.11.017
Toxic effects of maternal zearalenone exposure on uterine capacity and fetal development in gestation rats.
Zhang Yuanyuan,Jia Zhiqiang,Yin Shutong,Shan Anshan,Gao Rui,Qu Zhe,Liu Min,Nie Shaoping
Reproductive sciences (Thousand Oaks, Calif.)
The objectives of this study were to determine the effects of high-dose and early gestational exposure to zearalenone (ZEN) in female Sprague-Dawley (SD) rats, to correlate the maternal uterus with the fetus, and to explore the development and malformation of fetuses. Pregnant female SD rats were fed diets containing 0.3, 48.5, 97.6, or 146.0 mg/kg ZEN on gestational days (GDs) 0 through 7. All the females survived until GD 20, at which point a cesarean section was performed to harvest the organs, blood, and fetuses. The results indicated that exposure to ZEN during early gestation can impact the maternal reproductive capability. Delayed fetal development was directly linked to maternal toxicity. The toxic effects of ZEN caused early deaths more frequently than late deaths, and the deleterious effects lasted through the end of pregnancy.
10.1177/1933719113512533
Melatonin alleviates β-zearalenol and HT-2 toxin-induced apoptosis and oxidative stress in bovine ovarian granulosa cells.
Yang Fangxiao,Li Lian,Chen Kunlin,Li Chengmin,Wang Yiru,Wang Genlin
Environmental toxicology and pharmacology
β-zearalenol (β-zol) and HT-2 are mycotoxins which cause apoptosis and oxidative stress in mammalian reproductive cells. Melatonin is an endogenous antioxidant involved in apoptosis and oxidative stress-related activities. This study investigated the effects of β-zol and HT-2 on bovine ovarian granulosa cells (BGCs), and how melatonin may counteract these effects. β-zol and HT-2 inhibited cell proliferation in a dose-dependent manner, and induced apoptosis of BGCs. They also yielded upregulation of the apoptosis-related genes Bax/Bcl-2 and Caspase3 and phosphorylation of p38MAPK. Increases in intracellular ROS were observed along with higher levels of mRNA anti-oxidation markers SOD1, SOD2, and CAT. SOD1, SOD2, malonaldehyde (MDA), and glutathione peroxidase (GSH-px) activities increased, as did the levels of SOD1 and SOD2 proteins. All of these effects were reduced or entirely attenuated in BGCs pre-treated with melatonin. Our results demonstrate that melatonin has protective effects against mycotoxin-induced apoptosis and oxidative stress in BGCs.
10.1016/j.etap.2019.03.005
Transgenerational toxicity of Zearalenone in pigs.
Schoevers Eric J,Santos Regiane R,Colenbrander Ben,Fink-Gremmels Johanna,Roelen Bernard A J
Reproductive toxicology (Elmsford, N.Y.)
Zearalenone (ZEN) is a mycotoxin that can be a contaminant of food and feed commodities. ZEN acts as a xenoestrogen and is considered an endocrine disruptor. Since estrogens influence oogenesis during fetal growth, the effect of ZEN on oocytes was investigated in the F1-generation. Pregnant and lactating pigs were exposed to feed naturally contaminated with ZEN (200, 500 and 1000μg/kg feed). Ovaries of F1-animals were examined for follicle development, expression of estrogen converting enzymes and estrogen receptors, and oocyte quality. In F1-newborns, ZEN did not affect follicle dynamics, but follicle integrity decreased with increasing ZEN concentrations. Expression of estrogen receptor beta mRNA increased following ZEN exposure, whereas expression of genes coding for estrogen converting enzymes remained unchanged. In F1-prepubertal gilts, follicular atresia and oocyte maturation with subsequent embryo development remained unchanged. In conclusion, ZEN reduced the quantity of healthy follicles, which may lead to premature oocyte depletion in adulthood.
10.1016/j.reprotox.2012.03.004
Individual and combined effects of deoxynivalenol and α-zearalenol on cell proliferation and steroidogenesis of granulosa cells in cattle.
Pizzo Fabiola,Caloni Francesca,Schutz Luis F,Totty Morgan L,Spicer Leon J
Environmental toxicology and pharmacology
This study was conducted to evaluate the impact of deoxynivalenol (DON) and zearalenone (ZEA) metabolite, α-zearalenol (α-Zol), on cell proliferation and steroidogenesis of bovine large (LG) follicle granulosa cells (GC). LGGC were obtained from bovine ovarian follicles (8-22 mm) and were cultured for 2 days in medium containing 10% fetal bovine serum followed by 1 or 2 days in serum-free medium without (control) or with treatments. Three different experiments were performed using different dosages of DON and α-Zol and in different combinations and a fourth experiment evaluated estradiol effects on granulosa cell proliferation. DON inhibited progesterone (P4) and estradiol (E2) production at high dose. α-Zol alone and in combination with DON increased cell growth. Estradiol inhibited cell growth indicating α-Zol is not acting as an estrogen agonist. This study demonstrates that α-Zol and DON can impact in vitro GC function, however further studies will be required to better understand the mechanism of action and reproductive effects of Fusarium mycotoxins.
10.1016/j.etap.2015.08.025
Alternariol disturbs oocyte maturation and preimplantation development.
Schoevers Eric J,Santos Regiane R,Roelen Bernard A J
Mycotoxin research
Alternariol (AOH) is produced by fungi of the genus Alternaria and can be found in fruits, vegetables, and grains. Besides the oestrogenic activity demonstrated in vitro, this mycotoxin causes DNA damage and cell cycle arrest. Based on this, the effect of AOH was investigated on porcine female gametes during in vitro maturation and subsequent initial embryo development. A first experiment assessed a dose-response effect of AOH (5, 10, or 20 μmol/l) on cumulus expansion and in vitro oocyte nuclear maturation, in the presence or absence of follicular fluid (FF). A second experiment evaluated the effect of AOH (5, 10, or 20 μmol/l) exposure during porcine oocyte maturation, initial embryo development, or both periods, on preimplantation embryo development. Although FF protected oocytes from the deleterious effect of AOH, it did not avoid a decrease in cumulus cells expansion (5 μmol/l AOH regardless of the presence of FF). Moreover, exposure to AOH resulted in the degeneration of oocytes (10 μmol/l AOH in the absence of FF) and the occurrence of nuclear aberrations in mature oocytes (10 μmol/l AOH in the absence of FF and 20 μmol/l AOH in the presence of FF). Exposure to 5 μmol/l AOH during oocyte in vitro maturation was sufficient to impair initial embryo development.
10.1007/s12550-019-00372-w
The effect of HT-2 toxin on ovarian steroidogenesis and its response to IGF-I, leptin and ghrelin in rabbits.
Kolesarova A,Maruniakova N,Kadasi A,Halenar M,Marak M,Sirotkin A V
Physiological research
T-2 toxin and its metabolite HT-2 toxin are one of the most toxic mycotoxins of type A-trichothecenes, which are produced mainly by Fusarium species. Therefore, study of Fusarium toxins T-2 toxin and HT-2 toxin is an essential issue because they could also play role in failures of reproductive functions as well as endocrine system of domestic animals. Assessment of the effect of A-trichothecene mycotoxin HT-2 toxin alone or combined with insulin-like growth factor (IGF-I), leptin and ghrelin on estradiol secretion by rabbit ovarian fragments in vitro was done. Rabbit ovarian fragments were incubated without (control group) or with HT-2 toxin, or its combinations with IGF-I, leptin and ghrelin at various concentrations for 24 h. Secretion of 17beta-estradiol was determined by ELISA. Firstly, HT-2 toxin at the doses 10 and 100 ng.ml(-1), but not at 1 ng.ml(-1) decreased 17beta-estradiol secretion by ovarian fragments. Secondly, 17beta-estradiol secretion was not affected by HT-2 toxin exposure combined with growth factor IGF-I, metabolic hormones leptin and ghrelin. In conclusion, HT-2 toxin has potent direct dose-dependent effects on ovarian steroidogenesis in rabbits. These direct effects of HT-2 mycotoxin on ovarian steroidogenesis could impact negatively on the reproductive performance of rabbits.
10.33549/physiolres.933610
Assessment of T-2 toxin effect and its metabolite HT-2 toxin combined with insulin-like growth factor I, leptin and ghrelin on progesterone secretion by rabbit ovarian fragments.
Maruniakova Nora,Kadasi Attila,Sirotkin Alexander V,Leśniak Agnieszka,Ferreira Ana M M,Bulla Jozef,Kolesarova Adriana
Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes
Assessment of A-trichothecene mycotoxins (T-2 and HT-2 toxins) effect combined with growth factor IGF-I, and the metabolic hormones leptin and ghrelin on progesterone secretion by rabbit ovarian fragments was studied. Rabbit ovarian fragments were incubated without (control group) or with T-2/HT-2 toxin, or their combinations with insulin-like growth factor I (IGF-I), leptin or ghrelin at various concentrations for 24 h. Secretion of progesterone was determined by ELISA. First, T-2 toxin and HT-2 toxins at all doses used (0.01, 0.1, 1, 10, and 100 ng mL(-1)) were not shown to be potential regulators of progesterone secretion in rabbit ovarian fragments. Second, T-2 toxin but not HT-2 toxin combined with IGF-I was shown to be potential regulator of progesterone secretion in rabbit ovarian fragments. T-2 toxin at all doses used (0.01; 0.1; 1; 10; and 100 ng mL(-1)) combined with IGF-I (at dose 100 ng mL(-1)) significantly (P < 0.05) decreased progesterone secretion by rabbit ovarian fragments. Third, T-2 toxin and HT-2 toxin at all doses used in the study (0.01, 0.1, 1, 10, and 100 ng mL(-1)) combined with leptin (at dose 1000 ng mL(-1)) were not shown to be potential regulators of progesterone secretion in rabbit ovarian fragments. Furthermore, T-2 toxin and HT-2 toxin at all doses used in the study (0.01, 0.1, 1, 10, and 100 ng mL(-1)) combined with ghrelin (500 ng mL(-1)) were not shown to be potential regulators of progesterone secretion in rabbit ovarian fragments. Results in this study showed that trichothecene as T-2 toxin combined with IGF-I but not HT-2 toxin was able to decrease progesterone secretion in rabbit ovarian fragments in vitro. Experimental results of T-2 and HT-2 toxins combined with leptin and ghrelin did not confirm ability to modulate progesterone secretion by ovarian fragments in rabbits.
10.1080/03601234.2015.975622
In vitro effects of the Fusarium mycotoxins fumonisin B and beauvericin on bovine granulosa cell proliferation and steroid production.
Albonico Marco,Schutz Luis F,Caloni Francesca,Cortinovis Cristina,Spicer Leon J
Toxicon : official journal of the International Society on Toxinology
Fusarium mycotoxins are natural contaminants of various commodities representing significant problem worldwide. Since the co-occurrence of beauvericin (BEA) and fumonisin B (FB) in grains is frequent, the present study was carried out to evaluate the individual and combined effects of FB and BEA on cell proliferation, steroid production and gene expression using bovine granulosa cells (GC). When tested alone FB did not show (P ≥ 0.05) effects on cell proliferation at any dose. Whereas BEA at 3, 6, and 10 μM significantly decreased (P < 0.05) cell numbers. FB alone had no significant effect (P ≥ 0.05) on progesterone production at any tested doses, whereas FB at 1, 1.5 and 3 μM slightly inhibited (P < 0.05) estradiol production. At concentrations ≥3 μM, BEA was found to strongly decrease (P < 0.05) steroid production, and FB did not influence these effects of BEA. At 10 μM, both mycotoxins decreased (P < 0.001) serum-induced GC proliferation. At 30 μM, BEA showed inhibitory effects on FSH plus IGF1-induced CYP11A1 and CYP19A1 mRNA abundance (P < 0.05), whereas FB at 30 μM had no effect on CYP11A1 and CYP19A1 gene expression. Taken together these results demonstrate that the Fusarium mycotoxins BEA and FB may impair reproductive function in cattle.
10.1016/j.toxicon.2017.01.019
Zearalenone exposure elevated the expression of tumorigenesis genes in mouse ovarian granulosa cells.
Zhang Rui-Qian,Sun Xiao-Feng,Wu Rui-Ying,Cheng Shun-Feng,Zhang Guo-Liang,Zhai Qiu-Yue,Liu Xue-Lian,Zhao Yong,Shen Wei,Li Lan
Toxicology and applied pharmacology
Zearalenone (ZEA) is one of mycotoxins which are from corn, sorghum and wheat. As an estrogenic compound, ZEA mainly affects animal growth and reproduction with causing abnormal reproduction capability. Previous studies have shown that ZEA poses adverse effects on follicular development, but the mechanism of genetic toxicity of ZEA is not understood. The purpose of this study was to explore the effects of ZEA exposure on granulosa cells which play vital roles during follicular development. Mouse granulosa cells were exposed to 10 μM or 30 μM ZEA for 72 h in vitro, and the differences in gene expression patterns between control and ZEA exposures were analyzed by RNA-seq. The data demonstrated that 30 μM ZEA had a significant effect on the gene expression, especially ZEA exposure increased the expression of many genes related to different kinds of cancers and cancer related pathways like Hippo signaling pathway and the related genes, such as Ccnd1, Smad3, Tead3, Yap1 and Wwtr1. Furthermore, immunohistochemistry confirmed the increase in the protein levels of YAP1, WWTR1 and CCND1 in 30 μM ZEA exposure group. Collectively, this investigation indicated that ZEA exposure promoted the expression of tumorigenesis genes in mouse granulosa cells to.
10.1016/j.taap.2018.08.013
Molecular and biochemical evidence on the role of zearalenone in rat polycystic ovary.
Abbasian Nakisa,Momtaz Saeideh,Baeeri Maryam,Navaei-Nigjeh Mona,Hosseini Rohollah,Abdollahi Mohammad
Toxicon : official journal of the International Society on Toxinology
Globally, food and animal feed contamination with mycotoxins is one of the most important challenges affecting human health. Zearalenone is a non-steroidal mycotoxin with estrogen-like activity that has been reported to induce reproductive dysfunctions including polycystic ovary in women. The aim of this study was to assess the possible impact of prolonged low dose zearalenone (0.1 mg/kg b.w.) exposure to increase the risk of developing polycystic ovary in rats. We found that zearalenone increases the plasma insulin, glucose, testosterone, progesterone and luteinizing hormone levels, while the plasma estradiol level was reduced. Zearalenone also incited tumor necrosis factor-α and the secreted frizzled-related protein-4 expressions. Histological examination showed atresia of follicles in the treated group. It is concluded that zearalenone intoxication intensely manipulates the plasma hormonal factors and the level of gene expressions related to the polycystic ovary in rats, thus increases the risk of its progression.
10.1016/j.toxicon.2018.07.022
Zearalenone and its metabolites in the tissues of female wild boars exposed per os to mycotoxins.
Gajęcka Magdalena,Sławuta Piotr,Nicpoń Jakub,Kołacz Roman,Kiełbowicz Zdzisław,Zielonka Łukasz,Dąbrowski Michał,Szweda Wojciech,Gajęcki Maciej,Nicpoń Józef
Toxicon : official journal of the International Society on Toxinology
The study was performed on 18 clinically healthy female wild boars with initial body weight of 35 ± 2 kg. The animals were divided into two experimental groups (group I and group II) and one control group (group C) of 6 female wild boars per group. Group I animals were administered per os pure zearalenone (ZEN) at 150 μg/kg BW every two months for 7 subsequent days, whereas group II animals received feed naturally contaminated with ZEN at 50 μg/kg BW/day. Female wild boars were exposed to ZEN over a period of 1 year. Control group animals were fed a placebo. Tissue samples (dorsal muscles, left lobe of liver, left kidney, spleen, apical part of the cardiac muscle, cranial lobe of lung, left ovary, central part of the left horn of the uterus) were collected on the last day of the experiment within 3 min after slaughter. In group I, the highest ZEN levels were noted in the spleen (19.813 ng/g), cardiac muscle (18.105 ng/g) and kidneys (14.555 ng/g). In group II, the highest concentrations of ZEN were observed in muscle tissue (12.033 ng/g), uterus (10.821 ng/g) and kidneys (10.463 ng/g). The highest values of the carry-over factor were noted in the same tissues. In the examined female wild boars, per os exposure to natural sources of the parent substance or a combination of ZEN and its metabolites led to different concentrations of ZEN in the analyzed tissues. Zearalenone concentrations were compatible with CF values in both experimental groups.
10.1016/j.toxicon.2016.02.012
The effect of selected environmental Fusarium mycotoxins on the ovaries in the female wild boar (Sus scrofa).
Zielonka Ł,Gajęcka M,Żmudzki J,Gajęcki M
Polish journal of veterinary sciences
The contamination of agricultural crops with Fusarium mycotoxins poses one of the greatest problems in food production. Wild boars live in specific habitats and are physiologically sensitive to Fusarium mycotoxins, therefore, they are an interesting model for studies investigating the effects of the discussed toxin, in particular under low-dose exposure. The objective of this study was to determine potential effects of Fusarium mycotoxins ingested with naturally contaminated food on reproductive function based on the proliferation and apoptotic indices of ovarian follicles in female wild boars. The experiment was conducted on 40 wild boars inhabiting north-eastern Poland. The effect of seasonal variations in the quantity and quality of ingested food on the concentrations of Fusarium mycotoxins and their metabolites in the blood of wild boars was analyzed. The observed differences in toxin levels were accompanied by changes in proliferation and apoptotic indices. Proliferation processes were most intense in autumn-winter and were least advanced in winter-spring. The intensity of apoptotic processes was inversely correlated with proliferation.
10.1515/pjvs-2015-0050
The effect of environmental mycotoxins on selected ovarian tissue fragments of multiparous female wild boars at the beginning of astronomical winter.
Zielonka Łukasz,Gajęcka Magdalena,Rozicka Anna,Dąbrowski Michał,Żmudzki Jan,Gajęcki Maciej
Toxicon : official journal of the International Society on Toxinology
The contamination of plant material with mycotoxins, in particular of the genus Fusarium, is common in the natural environment. Multiparous female wild boars are exposed to feed contaminated with zearalenone (ZEN) and deoxynivalenol throughout the year. The aim of this study was to determine the concentrations of the above mycotoxins in multiparous female wild boars and to describe their effect on the histological structure of the ovaries at the beginning of astronomical winter. Toxicological examinations revealed 0.291 ng/ml of ZEN, 0.406 ng/ml of α-zearalenol (α-ZEL), 0.392 ng/ml β-zearalenol (β-ZEL) and an absence of deoxynivalenol (values below the sensitivity of the method) in the blood plasma of multiparous female wild boars. Numerous ovarian follicles at various stages of development, characterized by different degree of damage, were observed. Numerous deformed resting ovarian follicles were noted directly under the epithelium, and signs of follicular atresia and hyalinization were observed. Blood vessels in the medulla of the ovary were dilated, which probably improved the distribution of ZEN in the ovaries. Higher substrate (ZEN) concentrations in the ovaries led to an insignificant increase in the staining intensity of 3β-HSD and 17β-HSD clusters. The observed changes could contribute to prolonging the initial stage of late anestrus in multiparous female wild boars.
10.1016/j.toxicon.2014.06.021