Keiko Aoshima

The gender differences in health effects of environmental cadmium exposure and potential mechanisms

On a viewpoint of gender differences in Cd body burden and its health effects, we reviewed the population-based research including our own which conducted in Japan, Thailand, Australia, Poland, Belgium and Sweden to assess health effects of human exposure to environmental cadmium and their potential mechanisms. As a result, six risk factors in Cd health effects in women have been identified; (1) more serious type of renal tubular dysfunction, (2) difference in calcium metabolism and its regulatory hormones, (3) kidney sensitivity; difference in P450 phenotype, (4) pregnancy, (5) body iron store status, and (6) genetic factors. Further studies of Cd toxicity targeted to women would now appear necessary.

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.

Urinary trehalase activity as an indicator of kidney injury due to environmental cadmium exposure

One hundred and seventy-eight subjects, patients with Itai-itai disease and their family members, aged 12–87 years living in a cadmium (Cd)-polluted area in the Jinzu River basin (Cd-exposed group) and 176 controls (control group) were examined. In the Cd-exposed group urinary trehalase increased with increasing age, urinary β2-microglobulin (β2-m) and retinol-binding protein. Although urinary cadmium was higher in the Cd-exposed group, no particular correlation was found between urinary trehalase and urinary cadmium. Seventeen men and 11 women showed raised urinary trehalase activities despite normal values of urinary β2-m (<300 μg/g.creatinine), suggesting that urinary trehalase increases earlier than urinary β2-m. In 19 patients with Itai-itai disease included in the Cd-exposed group, urinary trehalase decreased with decreasing reciprocal of serum creatinine, suggesting that urinary trehalase decreases in the most advanced cases of chronic cadmium nephropathy due to reduced tubular cell mass.

Elevation of urinary trehalase activity in patients of itai-itai disease.

The elevation of urinary trehalase activity in patients of itai-itai disease was examined. Urinary trehalase was correlated with tubular reabsorption of phosphorus (%TRP): the lower the trehelase activity, the worse was %TRP. Furthermore, this activity was inversely correlated with urinary glucose and urinary total protein. In itai-itai disease, the excretion of β2-microglobulin seems to be maximal, and urinary trehelase activity was low in the latter stages of the disease. It is inferred that itai-itai disease produces extremely severe tubular damage as well as glomerular dysfunction.

Severity of tubular brush border damage in cadmium-polluted area (Jinzu River Basin): Clinical role of urinary trehalase

Urinary trehalase activity and leucine aminopeptidase activity were parabolically correlated with urinary beta 2-microglobulin, and these enzymes were observed to be biphasic in relation to urinary beta 2-microglobulin when the study populations included patients of Itai-itai disease and inhabitants of a cadmium-polluted area. Furthermore, urinary trehalase activity was parabolically correlated with urinary total protein and urinary glucose. From these results, it is inferred that by measuring both urinary trehalase and urinary beta 2-microglobulin, one can elucidate the degree of tubular damage.

Itai-itai disease: Lessons from the investigations of environmental epidemiology conducted in the 1970’s, with special reference to the studies of the Toyama Institute of Health: ―1970年代の環境疫学研究の成果と教訓，とくに富山県衛生研究所の研究について―

The outbreak of itai-itai disease, which is the most severe stage of chronic cadmium poisoning, has occurred in the cadmium-polluted Jinzu River basin in Toyama. In this area, the river was contaminated by slags from a mine upstream; consequently, the soil in rice paddies became polluted with heavy metals including cadmium through irrigation water streams from around 1910 to the 1960s. The inhabitants of the Jinzu River basin used the river water for drinking and cooking until around 1960. In this paper, we review the geographical features of the Jinzu River basin and the endemic area of itai-itai disease, and reevaluated the studies conducted in 1970s by the Toyama Institute of Health, because these studies have revealed a clear relationship between renal dysfunction or occurrence of itai-itai disease and exposure to cadmium through irrigation water streams.