Toxicity of the mycotoxin ochratoxin A in the light of recent data

Abstract

Ochratoxin A (OTA) is a ubiquitous, naturally occurring chlorophenolic mycotoxin produced in contaminated food and feed by fungi of genera Penicillium and Aspergillus. OTA is a common contaminant of various foodstuffs of both plant and animal origin. OTA represents significant risk to human and animal health. OTA has been shown to be nephrotoxic, hepatotoxic, teratogenic, immunotoxic, neurotoxic, genotoxic and carcinogenic (possible human carcinogen-group 2B), being characterized by species and sex differences in sensitivity. In some aspects OTA remains as a controversial topic. Its metabolism, genotoxicity and mechanism of action for renal carcinogenicity have been discussed.     

The Efficacy of a Smectite-Based Mycotoxin Binder in Reducing Aflatoxin B1 Toxicity on Performance,Health and Histopathology of Broiler Chickens

The aim of the experiment was to investigate the efficacy of a smectite-based clay binder (Toxo-MX) in reducing the toxicological effects of aflatoxin B₁ (AFB₁) in commercial broiler chickens. A total of 450 one-day old male broiler chickens were randomly allocated into three treatment groups with ten replicates of 15 birds each in a 42-day feeding experiment. The dietary treatments included a negative control (NC, a basal diet with no AFB₁ and binder), a positive control (PC, a basal diet contaminated with 500 ppb of AFB₁) and a smectite-based mycotoxin binder(Toxo-MX, PC with smectite clay binder). AFB₁ challenge resulted in 14 to 24% depression in growth performance, elevated levels of aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), organ enlargement and immuno-suppression.As compared to PC, feeding of Toxo-MX improved the final weight (15%; p < 0.0001), average daily gain (ADG) (15%; p < 0.001) and feed efficiency of broilers (13%; p < 0.0003) but did not have any effects on liver enzyme activities. Supplementation of smectite claysignificantly increased serum globulin levels and reduced the weight of the liver (p < 0.05) as compared to AFB₁-fed broiler chickens. The severity of lesions (inflammatory and degenerative changes) observed in the liver, kidney, heart, pancreas, and lymphoid organs in PC birds was reduced by feeding smectite clay. The immuno-suppression caused by AFB₁ was moderately ameliorated in Toxo-MX groupby stimulating the production of antibodies against IBD at day 42 (p < 0.05). In conclusion, dietary supplementation of a smectite-based mycotoxin binder to the diet containing AFB₁ improved growth performance, reduced toxicological effects in liver and improved humoral immune response in broilers, suggesting its protective effect against aflatoxicosis.     

3种同步化疗方案在中晚期宫颈癌放疗中的疗效及不良反应

目的 比较3种同步化疗方案在中晚期宫颈癌放疗中的疗效及不良反应。方法 将符合入组标准的105例ⅡB-ⅢB中晚期宫颈癌患者随机分为DDP组、FP组、TP组,每组各35例,均行根治性放疗,DDP组放疗期间给予顺铂单药周疗,共4~5程,FP组给予氟尿嘧啶及顺铂联合化疗,间隔3周疗法,共2程,TP组给予紫杉醇及顺铂联合化疗,间隔3周疗法,共2程,对3组患者的疗效及不良反应分别进行记录。结果 根治性放疗结束1月后3组患者的完全缓解率（complete remission rate,CR）分别为88.6%,82.9%,82.9%,部分缓解率（partial remission rate,PR）分别11.4%,17.1%,11.4%;治疗结束3月后3组患者的CR率分别为97.1%,97.1%,94.3%,3组比较差异均无统计学意义。3组的2年总生存率分别为97.1%,85.7%,91.4%,2年的无瘤生存率分别为82.9%,85.7%,88.6%,差异均无统计学意义。主要近期不良反应为骨髓抑制和胃肠道反应,TP组3~4度白细胞减少及中性粒细胞减少的发生率最显著,FD组3~4度恶心、呕吐、腹泻及肠梗阻的发生率最显著,差异均有统计学意义（P<0.05）,远期不良反应为放射性肠炎及放射性膀胱炎,3组的发生率均无统计学意义。结论 中晚期宫颈癌根治性放疗中3种同步化疗方案的近期疗效相似,2年的总生存率及无瘤生存率无差异,紫杉醇联合顺铂组的骨髓抑制最严重,氟尿嘧啶联合顺铂组的胃肠道反应最严重。     

Efficacy of a Modified Clinoptilolite Based Adsorbent in Reducing Detrimental Effects of Ochratoxin A in Laying Hens

Background: The objective of this study was to evaluate the efficacy of modified clinoptilolite (Minazel Plus^®, MZ) as a mycotoxin adsorbent for preventing the negative the effects of ochratoxin A (OTA) on performance, pathohistological changes, and OTA residue in the eggs of laying hens. Methods: Forty eight (n = 48) laying hens (27 weeks old) were equally divided into six groups and depending on the type of addition were allocated to the following experimental treatments for 7 weeks: E-I group-1 mg/kg OTA; E-II group 0.25 mg/kg OTA; E-III group 1 mg/kg OTA + 0.2% of MZ; E-IV group 0.25 mg/kg OTA + 0.2% of MZ; MZ group supplemented with 0.2% of the adsorbent; and control (K, without feed additive). Results: Overall, the addition of 0.2% MZ to laying hen feed mitigated the harmful effects of OTA on target organs and reduced the presence of OTA residue in eggs. The groups that received 0.2% of MZ achieved better production results in terms of body weight, number of eggs, and feed consumption, compared to the other treatments. Conclusions: The current findings confirm the efficacy of MZ in preventing performance losses in laying hens exposed to OTA, as well as for improving the welfare and health of food producing animals.     

Toxicity of Ochratoxin A and Its Modulation by Antioxidants: A Review

Ochratoxin A (OTA) is a mycotoxin involved in the development of different types of cancers in rats, mice and humans. A growing number of in vitro and in vivo studies has been collected and has described evidence compatible with a role for oxidative stress in OTA toxicity and carcinogenicity. Because the contribution of the oxidative stress response in the development of cancers is well established, a role in OTA carcinogenicity is plausible. Several studies have been performed to try to counteract the adverse effects of oxygen radicals generated under OTA-exposure. A number of molecules with various antioxidant properties were tested, using in vivo or in vitro models. Protection against OTA-induced DNA damage, lipid peroxidation, as well as cytotoxicity were observed, further confirming the link between OTA toxicity and oxidative damage. These studies demonstrated that antioxidants are able to counteract the deleterious effects of chronic consumption or exposure to OTA and confirmed the potential effectiveness of dietary strategies to counteract OTA toxicity.     

Comparative incidence of oral ochratoxicosis and aflatoxicosis on the activity of drug-metabolizing enzymes in rat liver

Mycotoxicosis has been produced in the rat by daily oral administrations of ochratoxin A (1.5 mg/kg/day) or aflatoxin B1 (1 mg/kg/day). Hepatic microsomal cytochrome P-450 and b5 contents and many phase I and II biotransformation systems have been measured in the course of ochratoxicosis (4 to 15 dosings) and aflatoxicosis (1 to 8 dosings). In case of ochratoxicosis, decreases in cytochrome P-450 level, aminopyrine demethylase and aniline hydroxylase activities were observed in rats receiving 15 administrations of the toxin. Aflatoxicosis induced more severe decreases in cytochrome P-450, aminopyrine demethylase and ethoxycoumarin deethylase following 8 daily gavages. In the two studies, there was no significant change in activities of liver phase II biotransformation enzymes.     

Occurrence of Ochratoxin A in Different Types of Cheese Offered for Sale in Italy

The detection of Ochratoxin A (OTA) in the milk of ruminants occurs infrequently and at low levels, but its occurrence may be higher in dairy products such as cheese. The aim of this study was to investigate the presence of OTA in cheeses purchased in the metropolitan city of Bologna (Italy) and the surrounding area. For the analysis, a LC-MS/MS method with a limit of quantification (LOQ) of 1 µg/kg was used. OTA was detected in seven out of 51 samples of grated hard cheese (concentration range 1.3–22.4 µg/kg), while it was not found in the 33 cheeses of other types which were also analysed. These data show a low risk of OTA contamination for almost all types of cheese analysed. To improve the safety of cheese marketed in grated form, more regulations on cheese rind, which is the part most susceptible to OTA-producing moulds, should be implemented or, alternatively, producers should consider not using the rind as row material for grated cheese. It would be interesting to continue these investigations particularly on grated hard cheeses to have more data to update the risk assessment of OTA in cheese, as also suggested by EFSA in its 2020 scientific opinion on OTA.     

Comparative Evaluation of the Capacity of Commercial and Autochthonous Saccharomyces cerevisiae Strains to Remove Ochratoxin A from Natural and Synthetic Grape Juices

In this paper, we assessed the ability of two strains of Saccharomyces cerevisiae, in viable and dead forms, to remove ochratoxin A (OTA) from an artificially contaminated synthetic grape juice medium (SGM) (10 µg OTA/L) and a naturally contaminated grape juice (6.64 µg OTA/L). The first strain, named Levulin FB, is a commercial yeast used in making wine. The second, named SC5, is an autochthonous strain isolated from table grapes. OTA concentrations in juices before and after their contact with yeast cells were assessed. A significant decrease in OTA level (p < 0.05) in the SGM medium and in the natural grape juice was observed after 1 h of adding yeast cells (20 g/L) in viable and heat-treated forms. It was inferred that the dead forms of the two strains were more able to eliminate OTA than their viable forms in both media. This study demonstrates the potential application of an autochthonous yeast for the natural decontamination of grape juice from fungal toxins.     

Comparative mechanisms of zearalenone and ochratoxin A toxicities on cultured HepG2 cells: Is oxidative stress a common process?

Zearalenone (ZEN) and Ochratoxin A (OTA) are structurally diverse fungal metabolites that can contaminate feed and foodstuff and can cause serious health problems for animals as well as for humans. In this study, we get further insight of the molecular aspects of ZEN and OTA toxicities in cultured human HepG2 hepatocytes. In this context, we have monitored the effects of ZEN and OTA on (i) cell viability, (ii) heat shock protein (Hsp) 70 and Hsp 27 gene expressions as a parameter of protective and adaptive response, (iii) oxidative damage, and (iv) cell death pathways. Our results clearly showed that both ZEN and OTA inhibit cell proliferation. For ZEN, a significant induction of Hsp 70 and Hsp 27 was observed. In the same conditions, ZEN generated an important amount of reactive oxygen species (ROS). Antioxidant supplements restored the major part of cell mortality induced by ZEN. However, OTA treatment downregulated Hsp 70 and Hsp 27 protein and mRNA levels and did not induce ROS generation. Antioxidant supplements did not have a significant effect on OTA‐induced cell mortality. Using another cell system (Vero monkey kidney cells), we demonstrated that OTA downregulates three members of HSP 70 family: Hsp 70, Hsp 75, and Hsp 78. Our findings showed that oxidative damage seemed to be the predominant toxic effect for ZEN, while OTA toxicity seemed to be rather because of the absence of Hsps protective response. Furthermore, the two mycotoxins induced an apoptotic cell death. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2009.     

不同麻醉方法在子宫切除术中的疗效对比研究

目的对不同麻醉方法在子宫切除术中的疗效进行分析研究。方法随机选择我院2009年6月至2011年6月子宫切除术患者79例,分成A、B两组,A组34例患者为对照组,给予硬膜外麻醉方法进行手术;B组45例患者为观察组,给予腰麻和硬膜外麻醉联合方法进行手术。结果 B组患者麻药用量少于A组,麻醉起效时间少于A组,镇痛效果明显优于A组患者,并发症概率低于A组。结论腰麻联合硬膜外麻醉方法应用于子宫切除术,患者麻药用量小,起效快,镇痛效果较好。     

Investigation of a Novel Multicomponent Mycotoxin Detoxifying Agent in Amelioration of Mycotoxicosis Induced by Aflatoxin-B1 and Ochratoxin A in Broiler Chicks

The present study was designed to determine the efficacy of a novel multicomponent mycotoxin detoxifying agent (MMDA) containing modified zeolite (Clinoptilolite), Bacillus subtilis, B. licheniformis, Saccharomyces cerevisiae cell walls and silymarin against the deleterious effects of Aflatoxin B₁ (AFB₁) and Ochratoxin A (OTA) in broiler chicks. A total of 160 one-day-old Ross 308^® broiler chicks were randomly allocated in four treatment groups, with four replicates, according to the following experimental design for 42 days. Group A received a basal diet; Group B received a basal diet contaminated with AFB₁ and OTA at 0.1 mg/kg and 1 mg/kg, respectively; Group C received a basal diet contaminated with AFB₁ and OTA and MMDA at 1 g/kg feed, and Group D received a basal diet contaminated with AFB₁ and OTA and MMDA at 3 g/kg feed. Results showed that ingested mycotoxins led to significant (p ≤ 0.05) reduction in body weight and feed conversion from 25 days of age, induced histopathological changes, increased the pH of the intestinal content, and altered the biochemical profile of birds with significantly (p ≤ 0.05) increased aspartate aminotransferase (AST) values (p ≤ 0.05). On the other hand, the supplementation of MMDA significantly (p ≤ 0.05) improved the feed conversion ratio (FCR) during the second part of the study, diminished biochemical alterations, reduced pH in jejunal and ileal content, and E. coli counts in the caeca of birds (p ≤ 0.05). It may be concluded that the dietary supplementation of the MMDA partially ameliorated the adverse effects of AFB₁ and OTA in broilers and could be an efficient tool in a mycotoxin control program.     

不同治疗方法在色素痣治疗中的疗效对比

目的探讨超脉冲CO2激光和手术疗法在色素痣中的疗效。方法将本院收治的64例色素痣患者按照随机原则分为激光组32例和手术组32例,激光组患者给予超脉冲CO2激光进行治疗,手术组患者给予手术治疗,比较两组患者的疗效和副反应。结果手术治疗组痊愈31例,占96.875%,好转1例,占3.125%;激光治疗组痊愈30例,占93.750%,好转2例,占6.250%。手术治疗组7例患者发生切口红肿;6个月后复发1例;切口瘢痕形成2例。激光治疗组32例患者激光治疗后均有浅表性结痂形成,于术后1周左右消失;6个月后复发11例;瘢痕形成2例。结论激光和手术治疗色素痣的疗效均显著,但是手术疗法的效果优于激光,手术疗法可作为色素痣的首选治疗方法。     

Reduction of the Adverse Impacts of Fungal Mycotoxin on Proximate Composition of Feed and Growth Performance in Broilers by Combined Adsorbents

Synergistic interaction of adsorbents in reducing the adverse impacts of mycotoxin on performance and proximate composition of broiler feeds was investigated. Fungal growth was induced by sprinkling water on the feed. S. cerevisiae + bentonite, kaolin + bentonite or S. cerevisiea + kaolin adsorbent combinations (1.5 g/kg feed) were added and the feeds were stored in black polythene bags. An untreated group was kept as a positive control while fresh uncontaminated feed was used as a negative control. Mycotoxins were extracted from the feeds and quantified using reverse phase HPLC. Proximate composition, nutrient digestibility of the feeds, feed intake and weight gain of the broilers were measured. Deoxynivalenol (DON) concentration in the contaminated/untreated feed was 347 µg/kg while aflatoxin B1 (AFB1) was 34 µg/kg. Addition of bentonite and kaolin in the contaminated feed reduced AFB1 and DON to significantly lower levels. Feed intake and weight gain were low in the broilers fed the contaminated feed. The carbohydrate level was significantly (p < 0.05) reduced from 62.31 to 40.10%, crude protein digestibility dropped from 80.67 to 49.03% in the fresh feed and contaminated feed respectively. Addition of the adsorbents (S. cerevisiae and bentonite) significantly (p < 0.05) improved these parameters.     

An Immunoenzymatic Method for the Determination of Ochratoxin A in Biological Liquids (Colostrum and Cow’s Milk)

Ochratoxins are mycotoxins that have been extensively studied lately due to the multiple toxic effects such as nephrotoxicity, hepatotoxicity, and carcinogenicity. These toxins contaminate plant and animal foods and after ingestion they reach into body fluids. The method of competitive direct enzyme immunoassay, in the solid phase, was validated through the determination of specific parameters (performance, linearity, recovery percentage, limit of detection, limit of quantification). The validated method was used to determine ochratoxin A in colostrum and cow’s milk. The method applied for the determination of ochratoxin A was linear for the concentration range of 0.0–0.5 ng/mL, the value for the regression coefficient (r) was 0.9838. Ochratoxin A was present in 91.67% of the colostrum and in 93.33% of cow’s milk samples. The linearity of the method, demonstrated for very low concentrations of analyte, the detection limit as well as the limit of quantification recommend the method for the determinations of micro-pollutants from foods, including biological fluids.     

3种雷公藤制剂对大鼠急性毒性损伤的比较

目的观察并比较临床常用3种雷公藤制剂对大鼠的急性毒性。方法将Wistar大鼠随机分为对照组、雷公藤片组、雷公藤多苷片组、昆明山海棠片组,各组分别灌胃给予相应的人日用量60倍药物,观察一般症状,检测血清谷草转氨酶（AST）、谷丙转氨酶（ALT）、血清尿素氮（BUN）值,肉眼观察心、肝、脾、肺及肾的组织形态并计算脏器指数。对肝肾进行HE染色,观察并比较各组的病理损伤程度。结果与对照组相比,雷公藤片组、雷公藤多苷片组AST值显著升高（P〈0．05）,雷公藤多苷片组ALT值显著升高（P〈0．05）,各给药组AST／ALT、BUN变化均不显著（P〉0．05）;各给药组肝、肾组织均出现一定程度病理损伤,其中肾组织损伤更严重,给药组间比较,昆明山海棠片肝肾损伤轻于另外两组。结论3种雷公藤制剂一次性大剂量给予大鼠均出现不同程度的急性中毒症状,造成肝肾损害,雷公藤片及雷公藤多苷片的急性毒性损伤较昆明山海棠片严重,而前两者之间的急性毒性无显著性差异。     

Wavelength-Dependent Degradation of Ochratoxin and Citrinin by Light in Vitro and in Vivo and Its Implications on Penicillium

It has previously been shown that the biosynthesis of the mycotoxins ochratoxin A and B and of citrinin by Penicillium is regulated by light. However, not only the biosynthesis of these mycotoxins, but also the molecules themselves are strongly affected by light of certain wavelengths. The white light and blue light of 470 and 455 nm are especially able to degrade ochratoxin A, ochratoxin B and citrinin after exposure for a certain time. After the same treatment of the secondary metabolites with red (627 nm), yellow (590 nm) or green (530 nm) light or in the dark, almost no degradation occurred during that time indicating the blue light as the responsible part of the spectrum. The two derivatives of ochratoxin (A and B) are degraded to certain definitive degradation products which were characterized by HPLC-FLD-FTMS. The degradation products of ochratoxin A and B did no longer contain phenylalanine however were still chlorinated in the case of ochratoxin A. Citrinin is completely degraded by blue light. A fluorescent band was no longer visible after detection by TLC suggesting a higher sensitivity and apparently greater absorbance of energy by citrinin. The fact that especially blue light degrades the three secondary metabolites is apparently attributed to the absorption spectra of the metabolites which all have an optimum in the short wave length range. The absorption range of citrinin is, in particular, broader and includes the wave length of blue light. In wheat, which was contaminated with an ochratoxin A producing culture of Penicillium verrucosum and treated with blue light after a pre-incubation by the fungus, the concentration of the preformed ochratoxin A reduced by roughly 50% compared to the control and differed by > 90% compared to the sample incubated further in the dark. This indicates that the light degrading effect is also exerted in vivo, e.g., on food surfaces. The biological consequences of the light instability of the toxins are discussed.     

Mycotoxicosis Caused by Either T-2 Toxin or Diacetoxyscirpenol in the Diet of Broiler Chickens

Mycotoxicosis Caused by Either T-2 Toxin or Diacetoxyscirpenolin the Diet of Broiler Chickens. Hoerr, F.J., Carlton, W.W.,Yagen, B. and Joffe, A.Z. (1982). Fundam. Appl. Toxicol. 2:121-124.Seven-day-old male broiler chickens were fed either T-2 toxinor diacetoxyscirpenol at 4 and 16 ppm for 21 days and had reductionsof feed consumption and of weight gain. Focal, yellow, oralplaques developed by day 2 and were located around salivaryduct openings on the palate, tongue, and buccal floor. The plaquesprogressed to raised, yellowish-gray crusts which covered ulcers.Microscopically, the ulcers had a base of granulation tissueand inflammatory cells, and the crusts comprised exudate, bacterialcolonies and feed components. T-2 toxin and diacetoxyscirpenolproduced similar effects at these concentrations. Comparablelesions also occurred in chickens fed T-2 toxin at 50, 100,or 300 ppm for 7 days. Six of 10 chickens died in the 300-ppmgroup which received an average daily exposure of about 10 mgT-2 toxin/kg body weight. In dead chickens, the lymphoid andhematopoietic tissues and alimentary mucosa were necrotic. Necrosiswas seen less frequently in the liver, kidney and the feather.Survivors of the 7-day studies had atrophied lymphoid organsand were anemic.     

脊髓型颈椎病3种前路术式疗效比较

目的比较3种前路术式治疗脊髓型颈椎病的疗效。方法对分别经颈椎前路减压自体髂骨植骨融合术、颈椎前路椎间盘切除和椎间融合器植入融合术、颈椎前路减压钛网内植骨并前路钢板内固定术治疗的脊髓型颈椎病患者术前与术后3个月的JOA评分进行比较。结果采取颈椎前路椎间盘切除和椎间融合器植入融合术或颈椎前路减压钛网内植骨并前路钢板内固定术术式患者的JOA减分率优于颈椎前路减压自体髂骨植骨融合术患者(P<0.05),颈椎前路椎间盘切除和椎间融合器植入融合术与颈椎前路减压钛网内植骨并前路钢板内固定术术式之间减分率差异无统计学意义(P>0.05)。结论颈椎前路椎间盘切除和椎间融合器植入融合术或颈椎前路减压钛网内植骨并前路钢板内固定术治疗脊髓型颈椎病效果优于颈椎前路减压自体髂骨植骨融合术。     

鸦胆子不同组分对小鼠急性毒性的比较研究

目的比较鸦胆子全组分、水提组分、醇提组分对小鼠的急性毒性反应。方法采用经典的急性毒性实验方法测定鸦胆子全组分、水提组分、醇提组分的小鼠口服半数致死量,观察其急性毒性症状谱,记录累积死亡数及小鼠体重变化。结果鸦胆子全组分、水提组分、醇提组分的小鼠口服LD50分别为3．14g·kg^-1,4．023g·kg^-1、3．320g·kg^-1,分别相当于临床日用量的110倍、140．8倍、116倍。腹泻、尾部紫绀是主要的急性毒性症状。结论鸦胆子不同组分急性毒性大小顺序依次是全组分、水提组分、醇提组分,其毒性成分与中毒机理尚待进一步研究。     

半夏不同组分小鼠急性毒性的比较研究

目的对半夏全组分、水提组分和醇提组分进行小鼠急性毒性比较研究,以观察、评价半夏药材的急性毒性,为临床安全、合理用药提供依据。方法制备半夏全组分、水提组分和醇提组分样品,采用经典的小鼠急性毒性实验方法分别测定半夏全组分、水提组分的最大给药量和醇提组分的最大耐受量。结果半夏全组分的最大给药量（MLD）为34.8g/kg,水提组分的最大给药量（MLD）为300.0g/kg,醇提组分的最大耐受量（MTD）为99.2g/kg,分别相当于临床70kg人每公斤体重日用量的270.7倍、2333.3倍和771.6倍。结论半夏药材具有一定毒性,与药典、文献记载及临床应用相符。半夏醇提组分毒性大于水提组分及全组分,后两者基本安全、低毒。