Balkan endemic nephropathy (BEN) is a chronic kidney disease that predominantly affects inhabitants of rural farming communities along the Danube River tributaries in the Balkans. Long-standing research has identified dietary exposure to aristolochic acids (AAs) as the principal toxicological cause. This study investigates the pathophysiological role of anemia in BEN, noting its earlier and more severe manifestation in BEN patients compared to those with other chronic kidney diseases. Utilizing a mouse model, our research demonstrates that prolonged exposure to aristolochic acid I (AA-I) (the most prevalent AA variant) leads to significant red blood cell depletion through DNA damage, such as DNA adduct formation in bone marrow, prior to observable kidney function decline. Furthermore, in vitro experiments with kidney cells exposed to lowered oxygen and pH conditions mimicking an anemia environment show enhanced DNA adduct formation, suggesting increased AA-I mutagenicity and carcinogenicity. These findings indicate for the first time a positive feedback mechanism of AA-induced anemia, DNA damage, and kidney impairment in BEN progression. These results not only advance our understanding of the underlying mechanisms of BEN but also highlight anemia as a potential target for early BEN diagnosis and therapy.

Simple Summary: This study was designed to find the cause of microcytic anemia in the Przewalski's gazelle by investigating the mineral contents in its habitat. We found that the cause of the disease was selenium deficiency in the habitat, and then, a cure for the disease was discovered. It is extremely beneficial to protect the rare species of the Przewalski's gazelle. Due to the fencing of the Przewalski's gazelle (Procapra przewalskii), the microcytic anemia incidence rate continues to increase. The primary pathological symptoms include emaciation, anemia, pica, inappetence, and dyskinesia. To investigate the cause of microcytic anemia ailment in the Przewalski's gazelle, the Upper Buha River Area with an excessive incidence was chosen as the experimental pasture, and the Bird Island Area without microcytic anemia disease was chosen as the control field. Then, the mineral contents in the soil, forage, blood, and liver, as well as the blood routine parameters and biochemical indexes were measured. The findings showed that the experimental pasture had much lower Se content in the soil and forage than the control field (p < 0.01), while the impacted pasture had significantly higher S content in the forage. The damaged gazelles had considerably lower Se and Cu contents and higher S content in the blood and liver than the healthy gazelles (p < 0.01). The presences of Hb, HCT, MCV, and MCH were significantly decreased compared to those in healthy gazelles (p < 0.01). The experimental group had a significantly lower level of GSH-Px activity in their serums compared to the control group (p < 0.01). In the treatment experiment, ten gazelles from the affected pasture were orally administered CuSO4, 6 g/animal once every 10 days for two consecutive times, and all gazelles were successfully cured. Therefore, it is possible that low Se content in the soil induced an increase in the absorption of S content by forage, leading to the deficiency of secondary Cu in the Przewalski's gazelles, resulting in microcytic anemia.