Renal toxicity and biokinetics models after repeated uranium instillation

Laurie de Castro (1) , Annabelle Manoury (1) , Olivier Claude (2) , Bastien Simoneau (1) , V. Monceau (3) , David Suhard (1) , Christelle Elie (3) , Victor Magneron (3) , Laurence Roy (2) , Celine Bouvier Capely (1) , Chrystelle Ibanez (3) , Estelle Davesne (4) , Yann Guéguen (1)

1 IRSN/PSE-SANTE/SESANE/LRSI - Laboratoire de recherche en Radiochimie, Spéciation et Imagerie
2 IRSN/PSE-SANTE/SESANE - Service de recherche sur les effets biologiques et Sanitaires des rayonnements ionisants
3 IRSN/PSE-SANTE/SESANE/LRTOX - Laboratoire de radiotoxicologie et radiobiologie expérimentale
4 IRSN/PSE-SANTE/SDOS/LEDI - Laboratoire d'évaluation de la dose interne

During nuclear fuel processing, workers can potentially be exposed to repeated inhalations of uranium compounds. Uranium nephrotoxicity is well documented after acute uranium intake, but it is controversial after long-term or protracted exposure. This study aims to analyze the nephrotoxicity threshold after repeated uranium exposure through upper airways and to investigate the resulting uranium biokinetics in comparison to reference models. Mice (C57BL/6J) were exposed to uranyl nitrate (0.03-3 mg/kg/day) via intranasal instillation four times a week for two weeks. Concentrations of uranium in urines and tissues were measured at regular time points (from day 1 to 91 postexposure). At each exposure level, the amount of uranium retained in organs/tissues (kidney, lung, bone, nasal compartment, carcass) and excreta (urine, feces) reflected the two consecutive weeks of instillation except for renal uranium retention for the highest uranium dose. Nephrotoxicity biomarkers, KIM-1, clusterin and osteopontin, are induced from day 4 to day 21 and associated with changes in renal function (arterial fluxes) measured using non-invasive functional imaging (Dopplerultrasonography) and confirmed by renal histopathological analysis. These results suggest that specific biokinetic models should be developed to consider altered uranium excretion and retention in kidney due to nephrotoxicity. The threshold is between 0.25 and 1 mg/kg/day after repeated exposure to uranium via upper airways.

Mots clés: Immunohistochemistry; Ultrasound; RNA; Risk factors; Respiratory system models; Metals; Kidney

Domaines: Sciences du Vivant [q-bio]

Laurie de Castro, Annabelle Manoury, Olivier Claude, Bastien Simoneau, V. Monceau, et al.. Renal toxicity and biokinetics models after repeated uranium instillation. Scientific Reports, 2023, 13 (1), pp.4111. ⟨10.1038/s41598-023-31073-1⟩. ⟨irsn-04032713⟩