Latest status of cadmium accumulation and its effects on kidneys, bone, and erythropoiesis in inhabitants of the formerly cadmium-polluted Jinzu River Basin in Toyama, Japan, after restoration of rice paddies.

PURPOSE: The cadmium-polluted Jinzu River Basin in Toyama, Japan, where nephropathy and itai-itai disease were endemic among resident farmers decades ago, has been almost completely restored. The aim of this study is to investigate whether inhabitants there would still exhibit cadmium accumulation and its effects on kidneys, bones, and erythropoiesis. METHODS: We performed a cross-sectional study of 150 subjects from the polluted area and 144 controls from the same prefecture. Participants included female inhabitants from 34 to 74 years of age who underwent examinations to gather anthropometrical and medical information, obtain rice, blood and urine samples, and measure bone mineral density. RESULTS: Cadmium concentration in rice from the polluted area was lower than the level in the control area. Blood and urinary cadmium and urinary ß(2)-microglobulin levels were higher in subjects from the polluted area than controls, and the urinary ß(2)-microglobulin was independently affected by urinary cadmium. Bone mineral density did not differ between the two areas, but it was affected by renal tubular function in subjects from the polluted area. Serum bone alkaline phosphatase was lower in subjects from the polluted area compared to controls. We detected three cases of cadmium nephropathy among the subjects. One of them suffered from a renal anemia type of itai-itai disease. CONCLUSION: Inhabitants in the formerly polluted area still had high cadmium accumulations and showed a characteristic natural history of chronic cadmium toxicity, indicating that the risk remains for developing nephropathy or itai-itai disease in the future.

[Renal effects of environmental exposure to cadmium in middle-aged population of Jinzu River basin in Toyama, Japan: 2000-2002 study].

OBJECTIVE: In 2000-2002, the effects of environmental cadmium (Cd) exposure on renal tubular function were investigated in men and women born between January 1, 1946 and December 31, 1955, and living in the Cd-polluted Jinzu River basin in Toyama. It is assumed that these generations had been exposed to Cd mainly through the consumption of rice and vegetables grown locally, in contrast to older generations who had been exposed not only through the consumption of rice but also by drinking river water polluted with Cd discharged from a mine. METHODS: Morning urine specimens, self-administered questionnaires and polished rice samples consumed daily were collected from 110 men and 121 women living in the polluted area and from 48 men and 45 women living in the reference area. RESULTS: Urinary Cd excretion level, an indicator of Cd accumulation in the kidneys, significantly increased with increased duration (years) of residence in the Cd-polluted area in both men and women. There was no case of urinary beta2-microglobulin (beta2-MG) level exceeding 1,000 microg/g Cr in either sex, in contrast to the high prevalence of beta2-MGuria observed in older generations. However, urinary beta2-MG and alpha1-MG levels were slightly but significantly increased with increased duration (years) of residence in the Cd-polluted area in women. CONCLUSIONS: The results indicate that men and women born between 1946 and 1955 and living in the Cd-polluted Jinzu River basin had Cd accumulation in the kidneys and a slight increase in urinary low-molecular weight protein level due to this accumulation.

Involvement of mitogen-activated protein kinases and protein kinase C in cadmium-induced prostaglandin E2 production in primary mouse osteoblastic cells.

We previously reported that cadmium (Cd) induced prostaglandin E2 (PGE2) biosynthesis through the activation of cytosolic phospholipase A2 (cPLA2) and induction of cyclooxygenase 2 (COX-2) in primary mouse osteoblastic cells. In the present study, we further investigated the mechanism of PGE2 production by Cd focusing on the main mitogen-activated protein kinase (MAPK) subfamilies that mediate prostaglandin synthesis, extracellular signal-regulated kinase (ERK1/2 MAPK), c-jun-amino-terminal kinase (JNK MAPK) and p38 MAPK, and protein kinase C (PKC) which is activated by Cd in several kinds of cells. Cd at 2 microM and above stimulated PGE2 production in osteoblastic cells and its production was inhibited by the kinase-specific inhibitors PD98059, SB203580, curcumin, and calphostin C. Calphostin C also inhibited the production of PGE2 by phorbol 12-myristate 13-acetate (PMA), which is a potent activator of PKC. PD98059 inhibited PGE2 production stimulated by PMA as well as Cd, indicating that activation of PKC by ERK1/2 MAPK was necessary for Cd-stimulated PGE2 production. Moreover, Cd stimulated the phosphorylation of these three MAPKs, and inhibition of the phosphorylation of ERK1/2 MAPK by calphostin C was also observed. On the other hand, Cd was found to phosphorylate cPLA2 and the phosphorylation was inhibited by PD98059, indicating that cPLA2 was activated by Cd through ERK1/2 MAPK and released arachidonic acid (AA), a substrate of COX-2, from membranous phospholipids. From these results, it was suggested that activation of each of the ERK1/2, p38, and JNK MAPK cascades in addition to that of PKC and cPLA2 played an important role in the Cd-stimulated biosynthesis of PGE2 in mouse osteoblastic cells.

Reduction of erythrocyte catalase and superoxide dismutase activities in male inhabitants of a cadmium-polluted area in Jinzu river basin, Japan.

Cadmium (Cd) is a toxic heavy metal which causes oxidative damage in organisms. In this study, we investigated the activities of the antioxidant enzymes erythrocyte catalase and copper/zinc superoxide dismutase (Cu/Zn-SOD) in 22 male inhabitants of the Cd-polluted Jinzu River basin in Toyama Prefecture, Japan (Cd group). The reference group consisted of 21 male inhabitants from an area that was not polluted with Cd (reference group). Urinary Cd levels and two renal tubular dysfunction markers in urine, alpha1-microglobulin (alpha1-m) level and N-acetyl-beta-D-glucosaminidase (NAG) activity, were significantly elevated in the Cd group. Catalase and Cu/Zn-SOD activities were significantly reduced in the Cd group as compared to the reference group. Significant negative correlation was observed between the activities of these two antioxidant enzymes and urinary Cd levels. We also observed significant negative correlations between activities of these two antioxidant enzymes and the renal tubular dysfunction markers. Our results indicate that erythrocyte catalase and Cu/Zn-SOD activities are reduced as a result of long-term Cd exposure. This may be linked to renal tubular dysfunction in the inhabitants of the Cd-polluted area.

Assessment of bone metabolism in cadmium-induced renal tubular dysfunction by measurements of biochemical markers.

Bone metabolism related to the severity of cadmium (Cd)-induced renal tubular dysfunction (RTD) was assessed by measuring several bone biochemical markers. Fifty-three female subjects with RTD aged 65-76 years (mean 70.0+/-3.3 years) and who lived in the Cd-polluted Jinzu River basin in Toyama, Japan were studied. Bone alkaline phosphatase (bone-ALP), intact bone Gla-protein (intact-BGP) and carboxy-terminal propeptide of type I collagen (PICP) in serum as bone formation markers and pyridinoline (Pyr) and deoxypyridinoline (Dpyr) in urine as bone resorption markers were measured. All markers of bone turnover were increased and significantly correlated with each other, suggesting that bone formation and resorption were coupled and increased in Cd-induced RTD. Fractional excretion of beta(2)-microglobulin (beta(2)-m, FE(beta 2-m)) as an index of severity of Cd-induced RTD was extremely varied ranging from 0.45 to 53%. There were no significant correlations between FE(beta 2-m) and each of the five bone biochemical markers. The bone turnover in Cd-induced RTD appeared to be determined by the glomerular filtration rate (GFR): in subjects with GFRs above 50 ml/min, the levels of bone-ALP or intact-BGP tended to be inversely related to the GFRs, whereas in subjects with GFRs below 40 ml/min, those levels tended to decrease. These results suggest that the bone turnover, in particular the bone formation, was influenced by renal tubular function as assessed by the levels of GFR in Cd-induced RTD.

Elevated urinary levels of vitamin D-binding protein in the inhabitants of a cadmium polluted area, Jinzu River basin, Japan.

Environmental cadmium (Cd) pollution and its effects on human health are still important issues. The most severe and representative manifestation of chronic Cd intoxication is Itai-itai disease, which is a syndrome that includes renal tubular dysfunction, osteomalacia, and generalized pain due to multiple bone fractures. The whole mechanism of how renal dysfunction relates to the development of bone lesions is unresolved. Vitamin D-binding protein (DBP) binds, transports and activates vitamin D, which plays a major role in calcium homeostasis and bone turnover. In this study, we measured urinary DBP levels and investigated their relationship to the markers of renal tubular dysfunction in the inhabitants of a Cd-polluted Jinzu River basin in Toyama Prefecture, Japan (Cd group). We also investigated age-matched subjects from an area known to have lower levels of Cd pollution (reference group). Urinary DBP was measured by a fluorometric enzyme-linked immunosorbent assay (ELISA), which was established in our laboratory. Significantly higher levels of urinary DBP were observed in the Cd group compared to the reference group. We observed significant positive correlations between urinary levels of DBP and renal tubular dysfunction markers in both groups. In the Cd group, urinary levels of DBP had a negative correlation with serum phosphate value. These results indicate that excretion of urinary DBP is increased after long-term Cd exposure and that the loss of DBP in urine may be linked to renal tubular dysfunction and possibly bone lesions in the inhabitants of Cd-polluted areas.