Clinical diagnostic indicators of renal and bone damage in rats intramuscularly injected with depleted uranium

Abstract

The toxic effects and changes in biochemical markers related to kidney and bone in depleted uranium (DU)-injected rats were examined in order to clarify the relation between clinical biochemical markers and the degree of damage in these organs. Male Wistar rats received a single injection in the femoral muscles of 0.2, 1.0 or 2.0 mg kg(-1) of DU which was dissolved in nitric acid solution adjusted to pH 3.2, for comparison with the group injected with nitric acid solution, and the control group. Urine and faeces were collected periodically over a 24 h period. Thereafter, the rats were killed at 28 d after DU injection. The body weights of the DU-injected groups decreased dose-dependently for the first 3-7 d, and then began to increase. The DU concentrations in the urine and faeces decreased rapidly within 3-7 d after DU injection. Urinary N-acetyl-beta-D-glucosaminidase (NAG)/creatinine peaked at the third day after DU injection, with a high correlation to the injected DU doses. There were high correlations among the injected DU doses, DU concentrations in the kidney and urinary NAG/creatinine values that were obtained at 28 d, respectively. The blood urea nitrogen (BUN) and creatinine in the serum also showed a high correlation with the DU-injected doses. The results indicated that urinary NAG/creatinine, BUN and creatinine in serum were useful indicators to diagnose the renal damage by DU, as well as to estimate the DU intake and concentration in the kidney when the intake is >2 mg kg(-1) DU. The total bone mineral density of the proximal metaphysis of the tibia decreased in the 2 mg kg(-1) DU group. In addition, alterations of the trabecular bone structure by inhibiting bone formation and promoting bone resorption were observed by bone histomorphometery. The bone biochemical markers osteocalcin, tartrate-resistance acid phosphatase, pyridinoline and rat-parathyroid hormone increased in all the DU injected groups, indicating that these markers were useful as sensitive indicators for diagnosing bone damage, even if the DU dose injected is low.

Données nouvelles sur la néphrotoxicité de l’uranium

“…Plusieurs études ont rapporté une augmentation plasmatique de deux marqueurs communément utilisés mais peu discriminatifs des lésions rénales (la créatinine et l'urée) en cas d'exposition aiguë à l'uranium (par voie intramusculaire ou sous cutanée) (Banday et al, 2008b ;Blantz, 1975 ;Fukuda et al, 2006 ;Gueguen et al, 2006 ;Kobayashi et al, 1984). En parallèle, il a été décrit chez le rongeur, une diminution de la clairance de la créatinine (indicatif d'une diminution du taux de filtration glomérulaire) (Banday et al, 2008b ;Haley, 1982).…”

“…Conformément à cette atteinte tubulaire, l'augmentation de la concentration urinaire d'enzymes révélatrices de lésions tissulaires (N-acétylglucosaminidase, phosphatase alkaline, gamma glutamyl transpeptidase) a largement été décrite (Banday et al, 2008b ;Diamond et al, 1989 ;Fukuda et al, 2006) ainsi que l'augmentation d'excrétion d'électrolytes, de protéines telles que de béta2-microglobuline qui sont des signes d'altérations tubulaires fonctionnelles (Banday et al, 2008b ;Fukuda et al, 2006 ;Haley, 1982).…”

Modes of action associated with uranium induced adverse effects in bone function and development

“…In Wistar rats, uranium exposure reduced bone growth, volume, and mineralization of the tibial metaphysis (Diaz Sylvester et al, 2002;Fukuda et al, 2006;Guglielmotti et al, 1984;Ubios et al, 1994) and decreased mandibular bone growth (Diaz Sylvester et al, 2002;Pujadas Bigi and Ubios, 2007;Ubios et al, 1994). Similar effects have been reported in the femoral metaphysis of Balb/c mice and the tibial metaphysis of Wistar rats, in which uranium exposure was associated with decreased growth cartilage, bone volume, bone formation surfaces and mineralization (Bozal et al, 2005;Fukuda et al, 2006;Guglielmotti et al, 1984) (see Supplementary Table S1).…”

“…In Wistar rats, uranium exposure reduced bone growth, volume, and mineralization of the tibial metaphysis (Diaz Sylvester et al, 2002;Fukuda et al, 2006;Guglielmotti et al, 1984;Ubios et al, 1994) and decreased mandibular bone growth (Diaz Sylvester et al, 2002;Pujadas Bigi and Ubios, 2007;Ubios et al, 1994). Similar effects have been reported in the femoral metaphysis of Balb/c mice and the tibial metaphysis of Wistar rats, in which uranium exposure was associated with decreased growth cartilage, bone volume, bone formation surfaces and mineralization (Bozal et al, 2005;Fukuda et al, 2006;Guglielmotti et al, 1984) (see Supplementary Table S1). Cabrini et al (1984), Guglielmotti et al (1984Guglielmotti et al ( , 1985Guglielmotti et al ( , 1987, and Ubios et al (1991) observed that acute uranium exposure resulted in decreased osteoblast activity and intramembranous ossification in Wistar rats (Table 1) Guglielmotti et al, 1985Guglielmotti et al, , 1984Ubios et al, 1990).…”

“…In Wistar rats, Guglielmotti et al (1987) and Ubios et al (1991) reported that bone resorption in the metaphysis of the tibial bone was significantly increased at 60 days post-exposure to a single uranium dose (Guglielmotti et al, 1987;Ubios et al, 1991). Fukuda et al (2006) reported similar findings in Wistar rats where bone resorption measured in trabecular bone was significantly increased at 28 days post exposure to a single dose of uranium, and Bozal et al, 2005 observed that in Balb/c mice acute (48 h) exposure to uranium increased bone resorption in the metaphysis of the femoral bone (Bozal et al, 2005;Fukuda et al, 2006). Furthermore, an epidemiological study by Kurttio et al (2005) reported an association between uranium exposure via drinking Ubios et al, 1994;Diaz-Sylvester et al, 2002;Pujadas Bigi and Ubios, 2007 # Femoral bone volume in metaphysis # Femoral growth cartilage width # Femoral cell proliferation in growth cartilage Bozal et al, 2005 Intramembranous ossification # Alveolar bone formation and volume in healing sockets Guglielmotti et al, 1984Guglielmotti et al, , 1985Guglielmotti et al, 1987;Ubios et al, 1990 # Alveolar bone volume in healing sockets Cabrini et al, 1984 Bone modeling and remodeling # Mandibular bone formation in lingual side # Mandibular bone formation in vestibular side Ubios et al, 1991;Pujadas Bigi et al, 2003 # Mandible growth (length and height) Diaz- Sylvester et al, 2002;Ubios et al, 1994 water and increased serum levels of type I collagen carboxy terminal telopeptide, a marker of bone resorption (ATSDR, 2013; Kurttio et al, 2005).…”