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dc.contributor.authorSchmeiser, Heinz H.
dc.contributor.authorKucab, Jill E.
dc.contributor.authorArlt, Volker M.
dc.contributor.authorPhillips, David H.
dc.contributor.authorHollstein, Monica
dc.contributor.authorGluhovschi, Gheorghe
dc.contributor.authorGluhovschi, Cristina
dc.contributor.authorModilca, Mirela
dc.contributor.authorDaminescu, Liviu
dc.contributor.authorPetrica, Ligia
dc.contributor.authorVelciov, Silvia
dc.date.accessioned2013-02-18T09:45:42Z
dc.date.available2013-02-18T09:45:42Z
dc.date.issued2012-10
dc.identifier.citationEnviron. Mol. Mutagen. 2012, 53 (8):636-641en_GB
dc.identifier.issn1098-2280
dc.identifier.pmid22987305
dc.identifier.doi10.1002/em.21732
dc.identifier.urihttp://hdl.handle.net/10146/269692
dc.description.abstractRecently, chronic Aristolochia poisoning was found responsible for the aetiology of Balkan endemic nephropathy (BEN) in Croatia, Serbia, and Bosnia, and diet was the likely route of exposure to aristolochic acid (AA). BEN, often associated with an increased incidence of upper urinary tract carcinoma (UUC), also affects residents of certain rural villages in Romania. AA is a nephrotoxin and human carcinogen that forms DNA adducts after metabolic activation, which induce characteristic TP53 mutations in urothelial tumours. Here we present the first evidence linking AA exposure to UUC in residents of an endemic region in the Romanian Mehedinti County. DNA was extracted from kidney and tumour tissue of seven patients who underwent nephroureterectomy for UUC and resided in BEN villages (endemic group). Five patients with UUC from nonendemic villages served as controls. AA-DNA adducts (7-(deoxyadenosin-N(6) -yl)-aristolactam I), established biomarkers of AA exposure, were identified by (32)P-postlabelling in renal DNA of six patients from the endemic group and in one of the nonendemic group (adduct levels ranged from 0.3 to 6.5 adducts per 10(8) nucleotides). Additionally, an A to T transversion in TP53, a base substitution characteristic of AA mutagenic activity was found in urothelial tumour DNA of one patient from the endemic group. Our results provide a molecular link to the cause of urothelial tumours in BEN regions of Romania indicating that AA is the common aetiological agent for BEN across its numerous geographical foci.
dc.description.sponsorshipCancer Research UK, European Union Network of Excellence ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility), and Institute of Cancer Research (Jill Kucab’s PhD Studentship).en_GB
dc.language.isoenen
dc.relation.urlhttp://onlinelibrary.wiley.com/doi/10.1002/em.21732/abstract;jsessionid=A0D62588F8C63C91ACA994CE0B5E065C.d04t02en_GB
dc.rightsArchived with thanks to Environmental and molecular mutagenesisen_GB
dc.subjectAristolochic aciden_GB
dc.subjectUrothelial canceren_GB
dc.subjectNephropathyen_GB
dc.subjectDNA adductsen_GB
dc.subjectBalkan endemicen_GB
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshAristolochic Acids
dc.subject.meshBalkan Nephropathy
dc.subject.meshDNA Adducts
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshKidney
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshMutation
dc.subject.meshRomania
dc.subject.meshTumor Suppressor Protein p53
dc.subject.meshUrinary Bladder Neoplasms
dc.titleEvidence of exposure to aristolochic acid in patients with urothelial cancer from a Balkan endemic nephropathy region of Romania.en
dc.typeArticleen
dc.identifier.journalEnvironmental and Molecular Mutagenesisen_GB
html.description.abstractRecently, chronic Aristolochia poisoning was found responsible for the aetiology of Balkan endemic nephropathy (BEN) in Croatia, Serbia, and Bosnia, and diet was the likely route of exposure to aristolochic acid (AA). BEN, often associated with an increased incidence of upper urinary tract carcinoma (UUC), also affects residents of certain rural villages in Romania. AA is a nephrotoxin and human carcinogen that forms DNA adducts after metabolic activation, which induce characteristic TP53 mutations in urothelial tumours. Here we present the first evidence linking AA exposure to UUC in residents of an endemic region in the Romanian Mehedinti County. DNA was extracted from kidney and tumour tissue of seven patients who underwent nephroureterectomy for UUC and resided in BEN villages (endemic group). Five patients with UUC from nonendemic villages served as controls. AA-DNA adducts (7-(deoxyadenosin-N(6) -yl)-aristolactam I), established biomarkers of AA exposure, were identified by (32)P-postlabelling in renal DNA of six patients from the endemic group and in one of the nonendemic group (adduct levels ranged from 0.3 to 6.5 adducts per 10(8) nucleotides). Additionally, an A to T transversion in TP53, a base substitution characteristic of AA mutagenic activity was found in urothelial tumour DNA of one patient from the endemic group. Our results provide a molecular link to the cause of urothelial tumours in BEN regions of Romania indicating that AA is the common aetiological agent for BEN across its numerous geographical foci.


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