Ochratoxin A in corn and wheat: geographical association with endemic nephropathy. (1/31)

AIM: To determine the presence and concentration of ochratoxin A in wheat and corn from Slavonski Brod surroundings, the area of endemic nephropathy allegedly caused by ochratoxin. METHODS: Thin-layer chromatography was used to determine ochratoxin A concentrations in 92 wheat and 51 corn samples from the surroundings of Slavonski Brod, Osijek, Hrvatsko Zagorje, Istria, and Celje (Slovenia). RESULTS: Ochratoxin A was present in 74 of 92 (75.8%) wheat samples and 17 of 51 (33.3%) corn samples, in a concentration range of 0.02-160.00 mg/kg in wheat and 0.02-40.00 mg/kg in corn. Wheat samples from the Slavonski Brod surroundings contained the highest level of ochratoxin A (38.8 +/- 27.2 mg/kg), followed by Osijek (8.7 +/- 8.3 mg/kg). Ochratoxin A levels in the wheat from Hrvatsko Zagorje, Istria, and Celje were considerably lower (2.1 +/- 1.5, 1.3 +/- 2.6 and 0.2 +/- 0.5 mg/kg, respectively). Wheat samples from Slavonski Brod significantly differed from all other sample groups (p < 0.001), and wheat samples from Osijek differed from those from Hrvatsko Zagorje, Istria, and Celje (p < 0.001, p = 0.003, p < 0.001, respectively). Ochratoxin A level was the highest in the corn samples from the Slavonski Brod surroundings (20.0 +/- 14.8 mg/kg) and considerably lower in samples from Osijek, Celje, Hrvatsko Zagorje, and Istria (0.8 +/- 1.4, 0.7 +/- 1.9, 0.4 +/- 0.4, and 0.4 +/- 0.8 mg/kg, respectively). A statistically significant difference was also observed between the Slavonski Brod samples and all other corn samples (p < 0.001). CONCLUSION: Irrespective of the real association between ochratoxin A and endemic nephropathy, our data clearly demonstrate their geographical overlap.  (+info)

Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. (2/31)

The old herbal drug aristolochic acid (AA), derived from Aristolochia spp., has been associated with the development of a novel nephropathy, designated aristolochic acid nephropathy (AAN), and urothelial cancer in AAN patients. There is clear evidence that the major components of the plant extract AA, aristolochic acid I (AAI) and aristolochic acid II (AAII), both nitrophenanthrene carboxylic acids, are genotoxic mutagens forming DNA adducts after metabolic activation through simple reduction of the nitro group. Several mammalian enzymes have been shown to be capable of activating both AAI and AAII in vitro and in cells. The activating metabolism has been elucidated and is consistent with the formation of a cyclic nitrenium ion with delocalized charge leading to the preferential formation of purine adducts bound to the exocyclic amino groups of deoxyadenosine and deoxyguanosine. The predominant DNA adduct in vivo, 7-(deoxyadenosin-N(6)-yl)aristolactam I (dA-AAI), which is the most persistent of the adducts in target tissue, is a mutagenic lesion leading to AT-->TA transversions in vitro. This transversion mutation is found at high frequency in codon 61 of the H-ras oncogene in tumours of rodents induced by AAI, suggesting that dA-AAI might be the critical lesion in the carcinogenic process in rodents. DNA-binding studies confirmed that both AAs bind to the adenines of codon 61 in the H-ras mouse gene and preferentially to purines in the human p53 gene. In contrast, the molecular mechanism of renal interstitial fibrosis in humans after chronic administration of AA remains to be explored. However, preliminary findings suggest that DNA damage by AA is not only responsible for the tumour development but also for the destructive fibrotic process in the kidney. It is concluded that there is significant evidence that AA is a powerful nephrotoxic and carcinogenic substance with an extremely short latency period, not only in animals but also in humans. In particular, the highly similar metabolic pathway of activation and resultant DNA adducts of AA allows the extrapolation of carcinogenesis data from laboratory animals to the human situation. Therefore, all products containing botanicals known to or suspected of containing AA should be banned from the market world wide.  (+info)

Endemic nephropathy: the case for chronic poisoning by aristolochia. (3/31)

AIM: To explore the hypothesis that chronic dietary poisoning by aristolochic acid could account for the unique geographical distribution, specific pattern of tubulointerstitial fibrosis, occurrence of chronic renal insufficiency, and an increased risk of developing upper urothelial cancer, all of which are associated with endemic nephropathy. METHODS: This case-controlled epidemiologic study consisted of three groups of subjects residing in an endemic region of Croatia: (a) patients meeting WHO criteria for endemic nephropathy (n=28), (b) individuals who have been treated for renal insufficiency secondary to other forms of renal disease (n=30), and (c) apparently healthy residents of the endemic village (n= 30). A detailed questionnaire, designed to collect information on demographics, exposure to potentially toxic substances, diet, agricultural practices, and other factors potentially impacting endemic nephropathy was administered to the three study groups. The seeds of Aristolochia clematitis, obtained from plants growing in the endemic region, were extracted with ethanol and analyzed by high-performance liquid chromatography for their aristolochic acid content. RESULTS: The majority of subjects, including 90% of endemic nephropathy patients, recall that the plant Aristolochia clematitis (birthwort, vucja stopa in Croatian) was frequently found in local meadows and wheat fields between 20 and 30 years ago. At that time, endemic nephropathy patients encountered Aristolochia clematitis significantly more frequently than controls (P=0.035). Since then, all three study groups reported a significant increase in the use of herbicides (P<0.001) and reduction in the prevalence of Aristolochia clematitis (P<0.001). Chemical analysis established that the seeds of A. clematitis contain 0.65% aristolochic acid. It is likely that the harvesting process used by local farmers permitted the seeds of A. clematitis to mingle with the wheat grain. CONCLUSION: Flour used to bake bread, a dietary staple in the endemic region of Croatia, is derived from wheat grain which, in the past, is likely to have been contaminated with seeds of A. clematitis during harvesting. This observation supports the hypothesis that aristolochic acid, a major constituent of the seeds, plays a central role in the development of endemic nephropathy.  (+info)

Increased blood pressure in adult offspring of families with Balkan endemic nephropathy: a prospective study. (4/31)

BACKGROUND: Previous studies have linked smaller kidney dimensions to increased blood pressure. However, patients with Balkan Endemic Nephropathy (BEN), whose kidneys shrink during the course of the disease, do not manifest increased blood pressure. The authors evaluated the relationship between kidney cortex width, kidney length, and blood pressure in the offspring of BEN patients and controls. METHODS: 102 offspring of BEN patients and 99 control offspring of non-BEN hospital patients in the Vratza District, Bulgaria, were enrolled in a prospective study and examined twice (2003/04 and 2004/05). Kidney dimensions were determined using ultrasound, blood pressure was measured, and medical information was collected. The parental disease of BEN was categorized into three groups: mother, father, or both parents. Repeated measurements were analyzed with mixed regression models. RESULTS: In all participants, a decrease in minimal kidney cortex width of 1 mm was related to an increase in systolic blood pressure of 1.4 mm Hg (p = 0.005). There was no association between kidney length and blood pressure. A maternal history of BEN was associated with an increase in systolic blood pressure of 6.7 mm Hg (p = 0.03); paternal BEN, +3.2 mm Hg (p = 0.35); or both parents affected, +9.9 mm Hg (p = 0.002). There was a similar relation of kidney cortex width and parental history of BEN with pulse pressure; however, no association with diastolic blood pressure was found. CONCLUSION: In BEN and control offspring, a smaller kidney cortex width predisposed to higher blood pressure. Unexpectedly, a maternal history of BEN was associated with average increased systolic blood pressure in offspring.  (+info)

Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer. (5/31)

Balkan endemic nephropathy (BEN) is found in certain rural areas of the Balkans and affects at least 25,000 inhabitants. Of the many hypotheses on BEN, the Aristolochia hypothesis has recently gained ground substantiated by the investigations on aristolochic acid nephropathy (AAN). On both clinical and morphological grounds, AAN is very similar to BEN. That exposure to aristolochic acid (AA) of individuals living in endemic areas through consumption of bread made with flour contaminated with seeds of Aristolochia clematitis is responsible for BEN is an old hypothesis, but one which is fully consistent with the unique epidemiologic features of BEN. Here, we propose an approach to investigate AA-induced mutagenesis in BEN that can provide molecular clues to the aetiology of its associated urothelial cancer. The molecular mechanism of AA-induced carcinogenesis demonstrates a strong association between DNA adduct formation, mutation pattern and tumour development. A clear link between urothelial tumours, p53 mutations and AA exposure should emerge as more tumour DNA from BEN patients from different endemic areas becomes available for mutation analysis. We predict that the observed p53 mutation spectrum will be dominated by AT --> TA transversion mutations as has already been demonstrated in the human p53 gene of immortalized cells after exposure to AAI and urothelial tumours from BEN patients in Croatia. Moreover, the detection of AA-specific DNA adducts in renal tissue of a number of BEN patients and individuals living in areas endemic for BEN in Croatia provides new evidence that chronic exposure to AA is a risk factor for BEN and its associated cancer.  (+info)

Role of exposure analysis in solving the mystery of Balkan endemic nephropathy. (6/31)

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.  (+info)

Aristolochic acid and the etiology of endemic (Balkan) nephropathy. (7/31)

Endemic (Balkan) nephropathy (EN), a devastating renal disease affecting men and women living in rural areas of Bosnia, Bulgaria, Croatia, Romania, and Serbia, is characterized by its insidious onset, invariable progression to chronic renal failure and a strong association with transitional cell (urothelial) carcinoma of the upper urinary tract. Significant epidemiologic features of EN include its focal occurrence in certain villages and a familial, but not inherited, pattern of disease. Our experiments test the hypothesis that chronic dietary poisoning by aristolochic acid is responsible for EN and its associated urothelial cancer. Using (32)P-postlabeling/PAGE and authentic standards, we identified dA-aristolactam (AL) and dG-AL DNA adducts in the renal cortex of patients with EN but not in patients with other chronic renal diseases. In addition, urothelial cancer tissue was obtained from residents of endemic villages with upper urinary tract malignancies. The AmpliChip p53 microarray was then used to sequence exons 2-11 of the p53 gene where we identified 19 base substitutions. Mutations at A:T pairs accounted for 89% of all p53 mutations, with 78% of these being A:T --> T:A transversions. Our experimental results, namely, that (i) DNA adducts derived from aristolochic acid (AA) are present in renal tissues of patients with documented EN, (ii) these adducts can be detected in transitional cell cancers, and (iii) A:T --> T:A transversions dominate the p53 mutational spectrum in the upper urinary tract malignancies found in this population lead to the conclusion that dietary exposure to AA is a significant risk factor for EN and its attendant transitional cell cancer.  (+info)

Role of environmental toxins in endemic (Balkan) nephropathy. October 2006, Zagreb, Croatia. (8/31)

An international symposium, held in Zagreb, Croatia, in October 2006, brought together basic scientists and clinical investigators engaged in research on endemic (Balkan) nephropathy, a chronic renal tubulointerstitial disease of previously unknown cause that often is accompanied by upper urinary tract urothelial cancer. Although this disease is endemic in rural areas of Bosnia, Bulgaria, Croatia, Romania, and Serbia, a similar clinical entity occurs throughout Europe, Asia, and North America. Recent advances in the understanding of endemic nephropathy now favor the causative role of aristolochic acid over the ubiquitous mycotoxin known as ochratoxin A. Specifically, aristolactam-DNA adducts have been found in renal tissues and urothelial cancers of affected patients. A "signature" p53 mutation in the upper urothelial cancer associated with this disease provides evidence of long-term exposure to aristolochic acid. In addition, the renal pathophysiology and histopathology observed in endemic nephropathy most closely resemble the entity known as aristolochic acid nephropathy. Public health authorities in countries harboring this disease are encouraged to reduce the potential for dietary exposure to Aristolochia clematitis.  (+info)

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