Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells.

Currently, animal experiments in rodents are the gold standard for developmental neurotoxicity (DNT) investigations; however, testing guidelines for these experiments are insufficient in terms of animal use, time, and costs. Thus, alternative reliable approaches are needed for predicting DNT. We chose rat neural stem cells (rNSC) as a model system, and used a well-known neurotoxin, domoic acid (DA), as a model test chemical to validate the assay. This assay was used to investigate the potential neurotoxic effects of Ochratoxin A (OTA), of which the main target organ is the kidney. However, limited information is available regarding its neurotoxic effects. The effects of DA and OTA on the cytotoxicity and on the degree of differentiation of rat rNSC into astrocytes, neurons, and oligodendrocytes were monitored using cell-specific immunofluorescence staining for undifferentiated rNSC (nestin), neurospheres (nestin and A2B5), neurons (MAP2 clone M13, MAP2 clone AP18, and Doublecortin), astrocytes (GFAP), and oligodendrocytes (A2B5 and mGalc). In the absence of any chemical exposure, approximately 46% of rNSC differentiated into astrocytes and neurons, while 40.0% of the rNSC differentiated into oligodendrocytes. Both non-cytotoxic and cytotoxic concentrations of DA and OTA reduced the differentiation of rNSC into astrocytes, neurons, and oligodendrocytes. Furthermore, a non-cytotoxic nanomolar (0.05 µM) concentration of DA and 0.2 µM of OTA reduced the percentage differentiation of rNSC into astrocytes and neurons. Morphometric analysis showed that the highest concentrations (10 µM) of DA reduced axonal length. These indicate that low, non-cytotoxic concentrations of DA and OTA can interfere with the differentiation of rNSC.

The effect of polyphenols and vitamin E on the antioxidant status and meat quality of broiler chickens fed diets naturally contaminated with ochratoxin A.

The aim of this study was to determine the effect of a polyphenol product (PP) (Proviox) and vitamin E on the antioxidant status and meat quality of broiler chickens fed diets contaminated with ochratoxin A (OTA). One hundred and twenty ROSS 308 broiler chickens were randomly divided into six groups (10 replications, 2 birds per replication). Group I received an uncontaminated and unsupplemented diet, diets of groups II to VI were contaminated with OTA at 172 µg and 200 µg/kg for the starter and grower period, respectively. Furthermore, diets of groups III, IV and V were supplemented with vitamin E at 100, 200 and 100 mg, respectively, and to diets of groups V and VI additionally 100 and 2200 mg PP was added, respectively. Supplementation with PP and vitamin E had no significant effects on the growth performance, dressing percentage or carcass trait parameters of broiler chickens. In chickens exposed to stress, dietary supplementation with vitamin E and/or PP improved the total antioxidant status (p ≤ 0.05), enhanced the blood activity of antioxidant enzymes (p ≤ 0.01) and increased the concentrations of non-enzymatic antioxidants (p ≤ 0.01) in the liver and breast muscles. Regardless of the administered antioxidants, chickens fed diets contaminated with OTA were characterised by lower dressing percentage (p ≤ 0.01), a higher proportion of the liver in the carcass (p ≤ 0.01), lower carcass fat content (p ≤ 0.01), and longer small intestines (p ≤ 0.01) and caeca (p ≤ 0.01). Dietary supplementation with PP improved the water-holding capacity of meat (p ≤ 0.01). The breast muscles of chickens fed diets supplemented with PP and vitamin E were characterised by higher (p ≤ 0.05) concentrations of eicosapentaenoic acid (C20:5). It was concluded that PP can be an insufficient component of diets for broiler chickens to improve growth performance and mitigate the negative effects of high dose of OTA in diets.

Impact of mycotoxins on the intestine: are mucus and microbiota new targets?

There is an increasing awareness of the deleterious effects attributed to mycotoxins during their fate within the gut, particularly for deoxynivalenol (DON), zearalenone (ZEN), ochratoxin A (OTA), fumonisin B1 (FB1), aflatoxin B1 (AFB1), and patulin (PAT). Evidence indicates that disruption of the epithelial barrier is well established. However, intestinal barrier function on its luminal side involves two other partners, mucus and microbiota, which have rarely been considered in the context of mycotoxin exposure. The current review aimed at providing a summary of DON, ZEN, OTA, FB1, AFB1, and PAT effects on intestinal barrier function, with special focus on mucus and microbiota. DON, ZEN, OTA, FB1, AFB1, and PAT are known to markedly affect epithelial cell integrity and functions. Regarding mucus, DON is the most documentated mycotoxin. In vivo, toxicological impact of DON generally has only been assessed through goblet cell number. Evaluation of the mycotoxins/mucus interplay considering other indicators such as composition, thickness, and penetrability of mucus, mucin O-glycosylation thus warrants further attention. With respect to microbiota, few short-term studies to date have been reported indicating deleterious effects. However, long-term exposure to mycotoxins may also produce significant changes in microbiota composition and metabolic activity, which requires further experimentation. In conclusion, mucus and microbiota are key targets for dietary mycotoxins although assessment of induced effects is preliminary. A significant research effort is now underway to determine the adverse consequences of mycotoxins on mucus and microbiota considered as individual but also as tightly connected gut players.

Identification and safety evaluation of a product from the biodegradation of ochratoxin A by an Aspergillus strain.

BACKGROUND: Ochratoxin A (OTA) poses a serious health hazard throughout the world and is often reported in food commodities. At present, biological approaches to detoxifying OTA are now widely considered to be the most promising methods. RESULTS: In this study, a strain that was identified as Aspergillus niger was isolated, and it has a strong ability to detoxify OTA. The degradation product (compound 1) of OTA was treated with crude enzyme. The product has been isolated and identified as C11 H9 O5 Cl (ochratoxin α), which is a weak lipophilic molecule, in contrast to fat-soluble OTA. The cytotoxic response of compound 1 was revealed to be different to that of OTA. Compound 1 does not induce cellular oxidative damage in comparison with OTA, which may cause lipid peroxidation (MDA), reduce SOD activity and induce DNA damage. CONCLUSION: This study indicates that A. niger has the ability to detoxify OTA. The OTA degradation product, ochratoxin α, does not exert cytotoxic effects on cell metabolism. A. niger has prospective uses for the OTA decontamination of food and agricultural fields. © 2016 Society of Chemical Industry.

Human Proximal Tubule Epithelial Cells (HK-2) as a Sensitive In Vitro System for Ochratoxin A Induced Oxidative Stress.

Ochratoxin A (OTA) is a mycotoxin that is potentially carcinogenic to humans. Although its mechanism remains unclear, oxidative stress has been recognized as a plausible cause for the potent renal carcinogenicity observed in experimental animals. The effect of OTA on oxidative stress parameters in two cell lines of LLC-PK1 and HK-2 derived from the kidneys of pig and human, respectively, were investigated and compared. We found that the cytotoxicity of OTA on LLC-PK1 and HK-2 cells was dose- and time-dependent in both cell lines. Furthermore, increased intracellular reactive oxygen species (ROS) induced by OTA in both cell lines were observed in a time-dependent manner. Glutathione (GSH) was depleted by OTA at >48 h in HK-2 but not in LLC-PK1 cells. While the mRNA levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione peroxidase 1 (GPX1) in LLC-PK1 were down-regulated by 0.67- and 0.66-fold, respectively, those of catalase (CAT), glutathione reductase (GSR), and superoxide dismutase 1 (SOD) in HK-2 were up-regulated by 2.20-, 2.24-, and 2.75-fold, respectively, after 72 h exposure to OTA. Based on these results, we conclude that HK-2 cells are more sensitive to OTA-mediated toxicity than LLC-PK1, and OTA can cause a significant oxidative stress in HK-2 as indicated by changes in the parameter evaluated.

Ochratoxin A Levels in Tissues of Wild Boars (Sus scrofa) from Northern Italy.

Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium, capable of contaminating several foodstuffs. OTA damages primarily the kidneys, and is suspected to be a carcinogenic substance, thus maximum levels for OTA in foodstuffs have been established in the EU. Italian Ministry of Health suggested a maximum level of 1 µg/kg OTA in pork meat and derived products. In this study, OTA concentrations in liver, kidney, and muscle of 64 wild boars (Sus scrofa) killed in two areas (area A and B) of Parma province (northern Italy), characterized by different habitat types, were assessed by HPLC-FLD technique. OTA was detected in 54% liver, 52% kidney, and 16% muscle samples. OTA levels were significantly higher in liver and kidney compared with muscle, and were above 1 µg/kg in 19 liver, 17 kidney, and 4 muscle samples. OTA levels in wild boars from area A resulted significantly higher with respect to those from area B, suggesting an environmental influence on OTA contamination in wild boars. This study seems to confirm that wild boar meat is a potential source of OTA, thus monitoring the presence of this mycotoxin in game meat might be recommended to prevent risks for human health.

Selenium Yeast Alleviates Ochratoxin A-Induced Apoptosis and Oxidative Stress via Modulation of the PI3K/AKT and Nrf2/Keap1 Signaling Pathways in the Kidneys of Chickens.

The purpose of this study was to investigate the protective effect and mechanism of yeast selenium (Se-Y) on ochratoxin- (OTA-) induced nephrotoxicity of chickens. A total of 80 one-day-old healthy chickens were randomly divided into 4 equal groups: control, OTA (50 µg/kg OTA), Se-Y (0.4 mg/kg Se-Y), and OTA+Se-Y (50 µg/kg OTA+0.4 mg/kg Se-Y). In the OTA chickens, differences in body weight, kidney coefficient, biochemical histological analysis, antioxidant capability, and the expression levels of the PI3K/AKT and Nrf2/Keap1 signaling pathway-related genes were observed. The levels of total superoxide dismutase (T-SOD), antioxidant capacity (T-AOC), catalase (CAT), and glutathione (T-GSH) significantly decreased, but the malondialdehyde (MDA) level of the kidneys significantly increased in the OTA treatment group. More importantly, treatment with Se-Y improved the antioxidant enzyme activities within the kidneys of chickens exposed to OTA. In addition, administration of OTA resulted in apoptosis and was associated with decreased expression of AKT, PI3K, and Bcl-2, which in turn enhanced expression of Caspase3, Bax, and P53. However, Se-Y improved the antioxidant defense system through activation of the Nrf2/Keap1 signaling pathway. Gene expression of Nrf2 and its target genes (HO-1, GSH-px, GLRX2, MnSOD, and CAT) was downregulated following OTA exposure. Conversely, Se-Y treatment resulted in a significant upregulation of the same genes. Besides, significant downregulations of protein expression of HO-1, CAT, MnSOD, Nrf2, and Bcl-2 and a significant upregulation of Caspase3 and Bax levels were observed after contaminated with OTA. Notably, OTA-induced apoptosis and oxidative damage in the kidney of chickens were reverted back to normal level in the OTA+Se-Y group. Taken together, the data suggest that Se-Y alleviates OTA-induced nephrotoxicity in chickens, possibly through the activation of the PI3K/AKT and Nrf2/Keap1 signaling pathways.

Protective effect of curcumin on ochratoxin A-induced liver oxidative injury in duck is mediated by modulating lipid metabolism and the intestinal microbiota.

Curcumin has antioxidant functions, regulates the intestinal microbial composition, and alleviates mycotoxin toxicity. The present study aimed to explore whether curcumin could alleviate ochratoxin A (OTA)-induced liver injury via the intestinal microbiota. A total of 720 mixed-sex 1-day-old White Pekin ducklings were randomly assigned into 4 groups: CON (control group, without OTA), OTA (fed a diet with 2 mg/kg OTA), CUR (ducks fed a diet with 400 mg/kg curcumin), and OTA + CUR (2 mg/kg OTA plus 400 mg/kg curcumin). Each treatment consisted of 6 replicates and 30 ducklings per replicate. Treatment lasted for 21 D. Results were analyzed by a two-tailed Student t test between 2 groups. Our results demonstrated that OTA treatment had the highest serum low-density lipoprotein (LDL) level among 4 groups. Compared with OTA group, OTA + CUR decreased serum LDL level (P < 0.05). OTA decreased liver catalase (CAT) activity in ducks (P < 0.05), while addition of curcumin in OTA group increased liver CAT activity (P < 0.05). 16S ribosomal RNA sequencing suggested that curcumin increased the richness indices (ACE index) and diversity indices (Simpson index) compared with OTA group (P < 0.05) and recovered the OTA-induced alterations in composition of the intestinal microbiota. Curcumin supplementation relieved the decreased abundance of butyric acid producing bacteria, including blautia, butyricicoccus, and butyricimonas, induced by OTA (P < 0.05). OTA also significantly influenced the metabolism of the intestinal microbiota, such as tryptophan metabolism and glyceropholipid metabolism. Curcumin could alleviate the upregulation of oxidative stress pathways induced by OTA. OTA treatment also increased SREBP-1c expression (P < 0.05). The curcumin group had the lowest expression of FAS and PPARG mRNA (P < 0.05) and the highest expression of NRF2 and HMOX1 mRNA. These results indicated that curcumin could alleviate OTA-induced oxidative injury and lipid metabolism disruption by modulating the cecum microbiota.

Predominant mycotoxins, mycotoxigenic fungi and climate change related to wine.

Wine is a significant contributor to the economies of many countries. However, the commodity can become contaminated with mycotoxins produced by certain fungi. Most information on mycotoxins in wine is from Spain, Italy and France. Grapes can be infected by mycotoxigenic fungi, of which Aspergillus carbonarius producing ochratoxin A (OTA) is of highest concern. Climate is the most important factor in determining contamination once the fungi are established, with high temperatures being a major factor for OTA contamination: OTA in wine is at higher concentrations in warmer southern Europe than northern. Contamination by fumonisins is a particular concern, related to Aspergillus niger producing these compounds and the fungus being isolated frequently from grapes. Aflatoxins can be present in wine, but patulin is seldom detected. Alternaria mycotoxins (e.g. alternariol) have been frequently observed. There are indications that T-2 toxin may be common. Also, the combined effects of mycotoxins in wine require consideration. No other mycotoxins are currently of concern. Accurate fungal identifications and mycotoxin detection from the fungi are important and a consideration of practical methods are required. There is a diversity of wines that can be contaminated (e.g. red, white, sweet, dry and fortified). The occurrence of OTA is higher in red and sweet than white wines. Steps to control mycotoxins in wine involve good agriculture practices. The effect of climate change on vines and mycotoxins in wine needs urgent consideration by well-constructed modelling studies and expert interpretation of existing data. Reliable models of the effect of climate change on vines is a priority: the health of vines affects mycotoxin contamination. A modelling study of OTA in grapes at higher temperatures over 100years is required. Progress has been made in reducing OTA in wine. The other mycotoxins require consideration and the effects of climate change will become crucial.

Role of exposure analysis in solving the mystery of Balkan endemic nephropathy.

We evaluated the role of exposure analysis in assessing whether ochratoxin A or aristolochic acid are the agents responsible for causing Balkan endemic nephropathy. We constructed a framework for exposure analysis using the lessons learned from the study of endemic goiter within the context of an accepted general model. We used this framework to develop an exposure analysis model for Balkan endemic nephropathy, evaluated previous findings from the literature on ochratoxin A and aristolochic acid in the context of this model, discussed the strength of evidence for each, and proposed approaches to address critical outstanding questions. The pathway for exposure to ochratoxin A is well defined and there is evidence that humans have ingested ochratoxin A. Factors causing differential exposure to ochratoxin A and how ochratoxin A is implicated in Balkan endemic nephropathy are not defined. Although there is evidence of human exposure to aristolochic acid and that its effects are consistent with Balkan endemic nephropathy, a pathway for exposure to aristolochic acid has been suggested but not demonstrated. Factors causing differential exposure to aristolochic acid are not known. Exposure analysis results suggest that neither ochratoxin A nor aristolochic acid can be firmly linked to Balkan endemic nephropathy. However, this approach suggests future research directions that could provide critical evidence on exposure, which when linked with findings from the health sciences, may be able to demonstrate the cause of this disease and provide a basis for effective public health intervention strategies. One of the key unknowns for both agents is how differential exposure can occur.

Opposite effect of Cu(II) and Se(IV) ions on the antibacterial-toxic action of mycotoxins.

The effect of Se(IV) and Cu(II) ions on the antibacterial activity of aflatoxins and ochratoxin A (mycotoxins) was studied in BioArena as a complex bioautographic system. In the presence of 0.23 and 0.46 mg/100 mL Se(IV) the inhibition zones of mycotoxins were decreased, however, lower concentration (0.046 mg/100 mL) increased the antibacterial effect of aflatoxin B1. Cu(II) (1.53 mg/100 mL) enhanced the toxicity of mycotoxins. The results supported the possible role of formaldehyde and its reaction products (e.g. 1O2, O3) in the antibacterial-toxic action of mycotoxins. Cu(II) can probably generate and mobilise the formaldehyde molecules and so it could increase the toxicity with its potential reaction products. It is possible that the enzymatic or spontaneous methylation of Se(IV) takes place through formaldehyde, which may cause partial formaldehyde depletion in the system. The enhanced antibacterial effect at low concentration Se(IV) is overlapping with the often experienced prooxidant effect in cases of natural antioxidants.

Daily uptake of mycotoxins - TDI might not be protective for nursed infants.

Exclusive breast feeding is recommended by international bodies for the first six months of life. Because of the presence of contaminants, breast feeding might lead to toxicologically relevant exposure of the nursed child. Exposure towards mycotoxins is of specific interest because of their widespread occurrence in food and of their toxicological profile. We calculated the relationship between maternal intake at the level of the existing TDIs and the exposure in the nursed infants of several mycotoxins to evaluate whether maternal exposure at the TDI is also safe for the nursed infant. If published information was not available we used in silico methods for estimating toxicokinetic parameters and the lactational transfer. A single dose and a continuous daily intake scenario were considered. Maternal intake at the TDI exceeds the age-adjusted TDI (TDI/3) values for infants in case of deoxynivalenol and patulin in the single dose scenario. Exceedance is particularly pronounced for ochratoxin A in the continuous daily intake scenario (29.2 fold above the child adjusted TDI). According to published data in infants impaired kidney function may result from this exceedance. When setting a TDI, the safety of the exclusively nursed infant should be considered in the continuous daily intake scenario.

Influence of repeated ochratoxin A ingestion on milk production and its carry-over into the milk, blood and tissues of lactating cows.

An experiment was conducted to investigate the influence of repeated ingestion of ochratoxin A (OTA) on milk production of lactating Holstein cows over 28 days, and the carry-over of OTA from the diets into the milk and tissues of the cows. Nine cows were divided into three groups, labeled OTA5, OTA50 and OTA100, and fed a diet containing 5, 50 and 100 µg OTA/kg of dry matter, respectively. Body weight, feed intake and daily milk yield in cows were not different among the three groups during the OTA-intake period. OTA residues were neither detected in the tissues, such as liver, kidney, muscles, fat and jejunoileum, nor in the milk of any cows in the OTA intake groups. In contrast, a small amount of OTA (0.1 µg/kg) was detected in the blood plasma of one sample in the OTA50 group and multiple samples in the OTA100 group. The results of this study show that the ingestion of diets containing up to 100 µg/kg of OTA over 28 days does not affect feed intake or milk production of cows, and the dietary OTA is not carried over into milk and edible tissues such as the liver, muscles and fat.

Lack of an Apparent Association between Mycotoxin Concentrations in Red Chili Peppers and Incidence of Gallbladder Cancer in India : an Ecological Study.

Our recent studies conducted in South America have shown that mycotoxin contamination of red chili peppers (RCPs) may be associated with an increased risk of gallbladder cancer (GBC). Whether this relationship exists in India, a country with a high incidence of GBC and high consumption of RCPs, is unclear. We therefore measured concentrations of aflatoxins (AFs) and ochratoxin A (OTA) in RCPs from areas of low, medium, and high incidence of GBC in India, and compared these concentrations with GBC incidence in each area. Twentyone RCP samples were collected from nine cities (eight from a lowincidence area, five from a mediumincidence area, and eight from a highincidence area). Concentrations of AFs and OTA were measured using highperformance liquid chromatography. No significant differences in mean concentrations of AFs and OTA were found in the three areas. AFB1 levels in the lowincidence area (10.81 ?g/kg) and highincidence area (12.00 ?g/kg) were more than 2.2 and 2.4 times higher compared with the maximum permitted level of AFB1 in spices (5.0 ?g/kg) set by the Commission of the European Communities, or that (4.4 ?g/kg) obtained in our previous study in Chile. Our results show that the mean concentrations of mycotoxins in RCPs are similar among the three areas in India with different incidences of GBC. Further studies with human subjects are needed to evaluate any association between AFB1 and GBC.

Ochratoxin A Contamination of Red Chili Peppers from Chile, Bolivia and Peru, Countries with a High Incidence of Gallbladder Cancer.

Our previous study detected aflatoxins in red chili peppers from Chile, Bolivia, and Peru, each of which have a high incidence of gallbladder cancer (GBC). Since the aflatoxin B1 concentration was not so high in these peppers, it is important to clarify the presence of other mycotoxins. Here we attempted to determine any associations between the concentrations of aflatoxins and ochratoxin A (OTA) in red chili peppers, and the corresponding GBC incidences. We collected red chili peppers from three areas in Peru: Trujillo (a high GBC incidence area), Cusco (an intermediate GBC incidence area), and Lima (a low GBC incidence rate), and from Chile and Bolivia. Aflatoxins and OTA were extracted with organic solvents. The concentrations of aflatoxins B1, B2, G1, and G2, and OTA were measured by high-performance liquid chromatography. The values obtained were compared with the incidence of GBC in each area or country. All of the red chili peppers from the three areas showed contamination with aflatoxins below the Commission of the European Communities (EC) recommended limits (5 µg/kg), but the OTA contamination of two samples was above the EC recommended limit (15 µg/kg). The mean concentrations of OTA in the peppers from Chile (mean 355 µg/kg, range <5-1,059 µg/kg) and Bolivia (mean 207 µg/kg, range 0.8-628 µg/kg), which has a high incidence of GBC, were higher than that in Peru (14 µg/kg, range <5-47 µg/kg), which has an intermediate GBC incidence. The OTA contamination in the red chili peppers from Chile, Bolivia, and Peru was stronger than that of aflatoxins. Our data suggest that OTA in red chili peppers may be associated with the development of GBC.

The etiology of Balkan endemic nephropathy: still more questions than answers.

Balkan endemic nephropathy (BEN) has attracted increasing attention as a possible environmental disease, and a significant amount of research from complementary scientific fields has been dedicated to its etiology. There are two actual competing theories attempting to explain the cause of this kidney disease: 1) the mycotoxin hypothesis, which considers that BEN is produced by ochratoxin A ingested intermittently in small amounts by the individuals in the endemic regions, and 2) the Pliocene lignite hypothesis, which proposes that the disease is caused by long-term exposure to polycyclic aromatic hydrocarbons and other toxic organic compounds leaching into the well drinking water from low rank coals underlying or proximal to the endemic settlements. We outline the current developments and future prospects in the study of BEN and differentiate possible factors and cofactors in disease etiology.

Determination of the epigenetic effects of ochratoxin in a human kidney and a rat liver epithelial cell line.

Epidemiological studies have implicated ochratoxin A (OTA), a fungal metabolic-contaminant of animal and human food sources, in Balkan Endemic Nephropathy and renal tumors. Many environmental toxicants operate through nongenotoxic mechanisms that epigenetically control gene expression leading to a diseased state. Gap junctional intercellular communication (GJIC) plays a central role in the epigenetic control of genes in which alteration of normal GJIC has been implicated in many human pathologies, including cancer, teratogenesis, reproductive dysfunction and peripheral neuropathies. The cell proliferative stages of human diseases, such as cancer, also involves the induction of signal transduction pathways controlling the mitogenic steps, in which the mitogen activated protein kinases (MAPK), such as extracellular receptor kinase (ERK) and p38, are central to mitogenesis. We therefore determined the effects of OTA on GJIC and MAPK in a human kidney and rat liver epithelial cell line. OTA reversibly inhibited GJIC at noncytotoxic doses in the rat liver but not the human kidney cell line. Similarly, OTA was also a strong activator of MAPK, ERK and p38, in the rat liver cells but only weakly activated ERK and had no affect on p38 in the human kidney cell line. Another hallmark of human diseases is an abnormal alteration of apoptosis, also known as programmed cell death. We used our myc-transfected cell line, which exhibits higher levels of apoptosis, to test the effects of OTA on apoptosis. OTA greatly induced apoptosis in this cell line, which is contrary to the effects of most tumor promoters. In summary, OTA exhibits tumor promoting properties in the liver, but the effects of OTA on the human kidney epithelial cells suggested a lack of tumorigenic activity assuming that these epithelial cells, like the rat liver epithelial cells, are a primary target for carcinogens. These results also indicate that the nephrotoxicity of OTA either does not involve GJIC, assuming these epithelial cells play a vital role in kidney physiology, or that a more differentiated kidney cell type is the target for OTA toxicity, of which the role of GJIC remains unknown.

Ochratoxin A and beta2-microglobulinuria in healthy individuals and in chronic interstitial nephropathy patients in the centre of Tunisia: a hot spot of Ochratoxin A exposure.

Ochratoxin A (OTA) is a nephrotoxic mycotoxin considered to be the causal agent of the Balkan endemic nephropathy (BEN). In Tunisia, a chronic interstitial nephropathy (CIN) of unknown aetiology, resembling BEN, has been characterised wherein OTA seems to be implicated too. However, despite the considerable number of investigations conducted so far, the role of OTA in the outcome of this human nephropathy is still uncertain. In this study, an attempt is being made to consolidate the link between OTA and the Tunisian CIN of unknown aetiology. Blood OTA and beta(2)-microglobulinuria levels were measured in several groups of healthy individuals and patients having different renal diseases of known and unknown aetiologies (100 nephropathy patients and 40 healthy subjects). The high blood OTA and beta(2)-microglobulinuria levels seem to be strongly associated to the CIN of unknown aetiology. Our results support the involvement of this nephrotoxic agent in the outcome of this particular human nephropathy and underline furthermore the importance of beta(2)-microglobulinuria in the characterization of this disease.

Ochratoxin A in human sera in the area with endemic nephropathy in Croatia.

Ochratoxin A (OA) is nephrotoxic fungal metabolite (mycotoxin) occurring in foodstuffs. The compound is causally associated with mycotoxin porcine nephropathy, a disease comparable with a human kidney disease called endemic nephropathy (EN). In this paper we presented results obtained over a 10-year period in the hyperendemic village Kaniza, and in control villages where no clinical cases of nephropathy had been found. In the hyperendemic village Kaniza and non-endemic villages the incidence of OA in human blood was up to 4.5% (range 2-50 ng/ml) and up to 2.4% (range 2-10 ng/ml), respectively. Almost all samples of food and feed, collected randomly in the hyperendemic village were found to contain OA. Considering marked exposure to OA in Kaniza, it was assumed that incidence of EN in this population could be related to OA contamination of food and feed.