Uranium dynamics and developmental sensitivity in rat kidney

Abstract

Renal toxicity is the principal health concern after uranium exposure. Children are particularly vulnerable to uranium exposure; with contact with depleted uranium in war zones or groundwater contamination the most likely exposure scenarios. To investigate renal sensitivity to uranium exposure during development, we examined uranium distribution and uranium-induced apoptosis in the kidneys of neonate (7-day-old), prepubertal (25-day-old) and adult (70-day-old) male Wistar rats. Mean renal uranium concentrations increased with both age-at-exposure and exposure level after subcutaneous administration of uranium acetate (UA) (0.1-2 mg kg(-1) body weight). Although less of the injected uranium was deposited in the kidneys of the two younger rat groups, the proportion of the peak uranium content remaining in the kidneys after 2 weeks declined with age-at-exposure, suggesting reduced clearance in younger animals. In situ high-energy synchrotron radiation X-ray fluorescence analysis revealed site-specific accumulation of uranium in the S3 segment of the proximal tubules, distributed in the inner cortex and outer stripe of the outer medulla. Apoptosis and cell loss in the proximal tubules increased with age-at-exposure to 0.5 mg kg(-1) UA. Surprisingly, prepubertal rats were uniquely sensitive to uranium-induced lethality from the higher exposure levels. Observations of increased apoptosis in generating/re-generating tubules particularly in prepubertal rats could help to explain their high mortality rate. Together, our findings suggest that age-at-exposure and exposure level are important parameters for uranium toxicity; uranium tends to persist in developing kidneys after low-level exposures, although renal toxicity is more pronounced in adults.

Unexpected Lack of Deleterious Effects of Uranium on Physiological Systems following a Chronic Oral Intake in Adult Rat

“…Other publications have noted histological lesions of rat kidneys, but at higher uranium exposure levels (200 mg/L, [43]; 30 mg/L, [55]). Recently, Homma-Takeda et al published deleterious effects of uranium in different rat models (neonate, prepubertal, and adult) after subcutaneous administration of uranium acetate [56]. The discrepancy is very likely due to the difference of the administration mode.…”

Biochemical and histopathological responses of the Swiss albino mice treated with uranyl nitrate and its recovery

“…9 It was demonstrated that uranium specially accumulates in the S3 segment of the proximal tubule, mild renal tubular lesions was observed at a dose 0.5 mg/kg by subcutaneous injection exposure of rat to uranium acetate. 10 It was reported that maximal effect on kidney is seen after 5 d of uranyl acetate oral administration with dietary consumption ad libitum oral administration in Swiss albino mice. 11 A single dose of 5 mg/kg of uranyl nitrate induced renal damage after 2 d in C57 BI/6J mice has been reported.…”

Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity

“…DU is a heavy metal and can emit α and β particles; thus, it exhibits both heavy metal toxicity and radiotoxicity. The kidney is the major target organ of acute DU exposure, and DU can cause severe necrosis of renal proximal tubule endothelial cells, ultimately leading to acute renal failure or even death345. The following mechanisms of action underlie the nephrotoxicity of DU6: (1) altering ion transport in cells to inhibit the oxidative phosphorylation of mitochondria and utilization of adenosine triphosphate (ATP); (2) altering the expression of certain genes (associated with inflammation, oxidative stress, and homeostasis); and (3) increasing oxidative stress levels and decreasing anti-oxidation in cells, thus increasing DNA damage and promoting apoptosis.…”