Balkan endemic nephropathy

Djukanović, Ljubica; Radovanović, Zoran

doi:10.1007/1-4020-2586-6_30

Cited by 15 publications

(18 citation statements)

References 38 publications

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“…Endemic (Balkan) nephropathy (EN) is a chronic, progressive tubulointerstitial disease that affects residents of rural farming villages located along tributaries of the Danube river in Bosnia and Herzegovina, Bulgaria, Croatia, Romania and Serbia (1). An unusual feature of EN is its close association with urothelial (transitional cell) carcinomas of the renal pelvis and ureter (2,3).…”

Section: Introductionmentioning

confidence: 99%

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Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid

Jelaković

Karanović

Vuković-Lela

et al. 2012

Kidney International

185

208

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Balkan endemic nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation, aristolochic acid reacts with genomic DNA to form aristolactam-DNA adducts that generate a unique TP53 mutational spectrum in urothelium. The aristolactam-DNA adducts are concentrated in the renal cortex, thus serving as biomarkers of internal exposure to aristolochic acid. Here, we present molecular epidemiologic evidence relating carcinomas of the upper urinary tract to dietary exposure to aristolochic acid. DNA was extracted from the renal cortex and urothelial tumor tissue of 67 patients that underwent nephroureterectomy for carcinomas of the upper urinary tract and resided in regions of known endemic nephropathy. Ten patients from non-endemic regions with carcinomas of the upper urinary tract served as controls. Aristolactam-DNA adducts were quantified by 32P-post-labeling, the adduct was confirmed by mass spectroscopy, and TP53 mutations in tumor tissues were identified by chip-sequencing. Adducts were present in 70% of the endemic cohort and in 94% of patients with specific A:T to T:A mutations in TP53. In contrast, neither aristolactam-DNA adducts nor specific mutations were detected in tissues of patients residing in non-endemic regions. Thus, in genetically susceptible individuals, dietary exposure to aristolochic acid is causally related to endemic nephropathy and carcinomas of the upper urinary tract.

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Section: Introductionmentioning

confidence: 99%

“…Over the past 50 years, extensive efforts have been made to elucidate the etiology of EN/UUC (1,5,7). The majority of this research focused on the role of environmental agents, including various heavy metals, mycotoxins, trace elements, and organic chemicals (8,9).…”

Section: Introductionmentioning

confidence: 99%

Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid

Jelaković

Karanović

Vuković-Lela

et al. 2012

Kidney International

185

208

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“…This environmental disease is characterized by renal tubulointerstitial fibrosis associated with a high incidence of upper urinary tract carcinomas (32). Analysis of the mutational profile of the p53 tumor suppressor gene in BEN patients revealed a unique pattern of A : T→T : A transversions characteristic of exposure to AA (14).…”

Section: Introductionmentioning

confidence: 99%

Lack of recognition by global-genome nucleotide excision repair accounts for the high mutagenicity and persistence of aristolactam-DNA adducts

Sidorenko

Yeo

Bonala

et al. 2011

Nucleic Acids Research

110

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Exposure to aristolochic acid (AA), a component of Aristolochia plants used in herbal remedies, is associated with chronic kidney disease and urothelial carcinomas of the upper urinary tract. Following metabolic activation, AA reacts with dA and dG residues in DNA to form aristolactam (AL)-DNA adducts. These mutagenic lesions generate a unique TP53 mutation spectrum, dominated by A : T to T : A transversions with mutations at dA residues located almost exclusively on the non-transcribed strand. We determined the level of AL-dA adducts in human fibroblasts treated with AA to determine if this marked strand bias could be accounted for by selective resistance to global-genome nucleotide excision repair (GG-NER). AL-dA adduct levels were elevated in cells deficient in GG-NER and transcription-coupled NER, but not in XPC cell lines lacking GG-NER only. In vitro, plasmids containing a single AL-dA adduct were resistant to the early recognition and incision steps of NER. Additionally, the NER damage sensor, XPC-RAD23B, failed to specifically bind to AL-DNA adducts. However, placing AL-dA in mismatched sequences promotes XPC-RAD23B binding and renders this adduct susceptible to NER, suggesting that specific structural features of this adduct prevent processing by NER. We conclude that AL-dA adducts are not recognized by GG-NER, explaining their high mutagenicity and persistence in target tissues.

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“…stitial disease found in Bosnia, Bulgaria, Croatia, Romania, and Serbia occurs exclusively in farming villages situated in valleys of tributaries of the Danube River (1,2). This striking geographic distribution has remained constant since the disease was first described in the late 1950s (3)(4)(5).…”

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confidence: 99%