Isotopic Fractionation of Natural Uranium in Mice as a Potential Biomarker of Renal Accumulation

Chronic low-level uranium (U) exposure through drinking water is a public health risk in the United States. Nearly two-thirds of community water systems, serving 320 million people, have detectable U levels, with 2% exceeding the EPA's maximum contaminant level of 30 μg/L. Ingested U accumulates in kidneys and is nephrotoxic at high levels. Uranium binds to proximal tubule cells, causing injury and interfering with kidney function. Epidemiological studies suggest that even low-level (<30 μg/L) of U exposure could damage kidneys. Current biomarkers, like urinary U levels, fail to indicate tissue-specific concentrations and metabolic interactions in kidneys. Fractionation of ²³⁸U/²³⁵U may potentially serve as a biomarker for the metabolic interaction of U with organs. Our experiments with mice showed changes in U isotopic composition (²³⁸U/²³⁵U expressed as δ²³⁸U) in organs after administering 50 mg/L U via drinking water for 2, 7, and 14 days. We found ²³⁵U enrichment in kidneys and bones, the target organs, while urine was enriched in ²³⁸U. Our results provide evidence of isotopic fractionation resulting from U accumulation in kidneys. Urinary U isotopic composition may, thus, provide a sensitive, noninvasive measurement of renal U bioaccumulation that could aid early detection of nephrotoxicity and prevention of irreversible kidney damage.