Discovery of a Tamoxifen-related compound that suppresses glial l-glutamate transport activity without interaction with estrogen receptors.

We recently found that tamoxifen suppresses l-glutamate transport activity of cultured astrocytes. Here, in an attempt to separate the l-glutamate transporter-inhibitory activity from the estrogen receptor-mediated genomic effects, we synthesized several compounds structurally related to tamoxifen. Among them, we identified two compounds, 1 (YAK01) and 3 (YAK037), which potently inhibited l-glutamate transporter activity. The inhibitory effect of 1 was found to be mediated through estrogen receptors and the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K) pathway, though 1 showed greatly reduced transactivation activity compared with that of 17ß-estradiol. On the other hand, compound 3 exerted its inhibitory effect through an estrogen receptor-independent and MAPK-independent, but PI3K-dependent pathway, and showed no transactivation activity. Compound 3 may represent a new platform for developing novel l-glutamate transporter inhibitors with higher brain transfer rates and reduced adverse effects.

Urinary cadmium and mortality among inhabitants of a cadmium-polluted area in Japan.

The influence of cadmium (Cd) body burden on mortality remains controversial. Excess mortality and the dose-response relationship between mortality and urinary cadmium excretion were investigated in this study among environmentally exposed subjects. A 15-year follow-up study was carried out on 3119 inhabitants (1403 men and 1716 women) of the Cd-polluted Kakehashi River basin, whose urinary Cd concentration was examined in a 1981-1982 health impact survey. The mortality risk of high urinary Cd (> or = 10 microg/g Cr) subjects after adjustment for age using Cox's proportional hazard model was higher than that of moderate urinary Cd (< 10 microg/g Cr) subjects in both sexes. When the subjects were divided into five groups according to the amount of urinary Cd (<3, 3-5, 5-10, 10-20, > or = 20 microg/g Cr), the mortality risk was significantly increased among the subjects with urinary Cd > or = 3 microg/g Cr in proportion to the increases in the amount of urinary Cd concentration after adjustment for age, especially in women. Furthermore, special causes of death among high and moderate urinary Cd were investigated, and mortality risk ratio for heart failure, which is a cause of death often diagnosed in cases with a gradual deterioration culminating in death, was significantly increased in both sexes, compared with the moderate urinary Cd subjects. Also, in women the mortality risk for renal diseases in the high urinary Cd subjects was significantly higher than that in the moderate urinary Cd subjects. These results suggest that a causal association between Cd body burden and mortality exists among inhabitants environmentally exposed to Cd but that no special disease may be induced except renal diseases.

Effects of cadmium exposure during pregnancy on trace elements in fetal rat liver and kidney.

Female rats were exposed by intragastric administration with a cannula 1mg/kg/day or 10mg/kg/day CdCl2 for the 11 days from the 9th to 19th day of pregnancy, and the effects of Cd exposure on eight elements, Na, K, Ca, Mg, P, Fe, Zn, and Cu in fetal liver, kidney, brain, fetal membrane and placenta then examined. We found that: (1) although Cd was not detected in fetal kidney and brain, significant Cd accumulation was found in fetal liver, fetal membrane and placenta in the 10 mg/kg Cd group, (2) the Zn and Fe concentrations in fetal liver in the 10 mg/kg Cd group were significantly lower than those in the control group, but no difference was found in the placenta, (3) the Cu concentrations in the placenta, fetal membrane and liver in the 10 mg Cd groups were significantly lower than those in the control group, (4) Na/K ratio in the placenta and fetal kidney and the Ca concentration in the placenta in the 10 mg/kg Cd group were lower than those in the controls. These results suggest that Cd exposure inhibits Zn and Fe transportation from the placenta to fetus, as well as Cu, Ca, Na and K uptake and transportation across the placenta, possibly influencing fetal growth and metabolism.

Cadmium and nutritional intake in pregnant Japanese women.

A study to clarify the food composition and nutritional factors that contribute to the levels of blood and urinary cadmium (Cd) was conducted on 50 pregnant Japanese women with mean age of 29 years. The mean iron (Fe) intake of subjects was 9.2 mg, which is much lower than the recommended level of 20 mg for pregnant women. Cd in urine samples collected at 30-32 weeks of gestation were correlated (r = 0.354), but urinary Cd was related to age more than blood Cd. Urinary Cd and blood Cd levels were inversely related to total energy (rpartial = -0.325, and -0.334, respectively) and fat intake (rpartial = -0.419, and -0.379, respectively), even after adjustment for age. Blood Cd was also correlated to protein and iron intake (rpartial = -0.299, and -0.353, respectively). These results indicate that Cd exposure levels of pregnant women with low energy intake, especially less fat intake, were higher than those of women with more energy and fat intake. In particular, blood Cd may be affected by protein and iron intake in pregnant women with increased these nutrients demand.

Mortality in a cadmium polluted area in Japan.

A 15-year follow-up study of 3178 inhabitants (1424 men and 1754 women) living in the cadmium (Cd) polluted Kakehashi River basin was conducted. The results clarified effects on mortality of renal dysfunction induced by Cd indicated by urinary beta-2-microglobulin (beta2-MG), total protein, glucose, and total amino acids. This study used Cox's proportional hazard model. The mortality risk ratio of urinary beta2-MG positive (>= 1000 microg/gCr) subjects was significantly increased in both sexes: 1.35 for men and 1.73 for women. The increased mortality ratio of the urinary protein positive (>= 10 mg/dl) subjects was also significant for both sexes, with risk ratios of 1.82 for men and 2.01 for women. Only the women showed significantly increased mortality of the urinary glucose positive (>= 20 mg/dl) subjects and amino acids positive (> = 300 microg/gCr) subjects. When the subjects were divided into four categories according to urinary beta2-MG, <300, 300-1000, 1000-10000, >= 10000 microg/gCr, the mortality risk ratios were increased in proportion to the increase of urinary beta2-MG in both sexes. These results suggest that mortality of Cd-exposed subjects increased with increasing excretion of four urinary markers of renal tubular dysfunction, and in proportion to increases in the amount of urinary beta2-MG excretion including under 1000 microg/gCr.