While to date investigations provided convincing evidence on the role of aristolochic acids (AAs) in the etiology of Balkan endemic nephropathy (BEN) and upper urothelial cancer (UUC), the exposure pathways by which AAs enter human bodies to cause BEN and UUC remain obscure. The goal of this study is to test the hypothesis that environmental pollution by AAs and root uptake of AAs in the polluted soil may be one of the pathways by which AAs enter the human food chain. The hypothesis driving this study was that the decay of Aristolochia clematitis L., a AA-containing herbaceous plant that is found growing widespread in the endemic regions, could release free AAs to the soil, which could be taken up by food crops growing nearby, thereby transferring this potent human nephrotoxin and carcinogen into their edible parts. Using the highly sensitive and selective high-performance liquid chromatography coupled with fluorescence detection method, we identified and quantitated in this study for the first time AAs in corn, wheat grain, and soil samples collected from the endemic village Kutles in Serbia. Our results provide the first direct evidence that food crops and soil in the Balkans are contaminated with AAs. It is possible that the presence of AAs in edible parts of crops originating from the AA-contaminated soil could be one of the major pathways by which humans become exposed to AAs.

Exposure to aristolochic acids (AAs) from Aristolochia plants is one of the major global causes of nephropathy, renal failure and urothelial cancer, including Balkan endemic nephropathy (BEN). The high incidence of BEN on the Balkan Peninsula is assumed to result from consumption of Aristolochia clematitis L. seeds co-harvested with crops. Here we show that AAs are long-lived soil contaminants that enter wheat and maize plants by root uptake, with strong pH-dependence. Soil and crops from Serbian farms in areas endemic for A. clematitis were found to be extensively contaminated with AAs, with contamination strongly correlated with local incidence of BEN. The persistence of AAs as soil contaminants suggests that weed control for A. clematitis plants is needed to reduce the incidence of BEN and aristolochic acid nephropathy, and that systematic surveys of soil and crop AA levels would identify high-risk regions and it is imperative to research soil remediation methods.

Aristolochic acids (AAs) are nephrotoxic and carcinogenic derivatives found in several Aristolochia species. To date, the toxicity of AAs has been inferred only from the effects observed in patients suffering from a kidney disease called "aristolochic acid nephropathy" (AAN, formerly known as "Chinese herbs nephropathy"). More recently, the chronic poisoning with Aristolochia seeds has been considered to be the main cause of Balkan endemic nephropathy, another form of chronic renal failure resembling AAN. So far, it was assumed that AAs can enter the human food chain only through ethnobotanical use (intentional or accidental) of herbs containing self-produced AAs. We hypothesized that the roots of some crops growing in fields where Aristolochia species grew over several seasons may take up certain amounts of AAs from the soil, and thus become a secondary source of food poisoning. To verify this possibility, maize plant (Zea mays) and cucumber (Cucumis sativus) were used as a model to substantiate the possible significance of naturally occurring AAs' root uptake in food chain contamination. This study showed that the roots of maize plant and cucumber are capable of absorbing AAs from nutrient solution, consequently producing strong peaks on ultraviolet HPLC chromatograms of plant extracts. This uptake resulted in even higher concentrations of AAs in the roots compared to the nutrient solutions. To further validate the measurement of AA content in the root material, we also measured their concentrations in nutrient solutions before and after the plant treatment. Decreased concentrations of both AAI and AAII were found in nutrient solutions after plant growth. During this short-term experiment, there were much lower concentrations of AAs in the leaves than in the roots. The question is whether these plants are capable of transferring significant amounts of AAs from the roots into edible parts of the plant during prolonged experiments.

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