Biomedical subjects
Publications and source records attributed to M Yotoriyama.
Intraperitoneal pretreatment with a large dose of Cd, Zn, Hg, Mn or Ag remarkably depressed the lethal effects of X-ray. The CHX pretreatment before metal challenge depressed the lethal effects of X-ray more remarkably. Therefore, metal-binding protein may not play an important role in protective effects of metal pretreatment on the lethal effects of X-ray, but quantum mechanical characters of metals may do so.
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Natural history of cadmium health effects was studied on monkeys and rabbits given cadmium chloride orally or subcutaneously for a long period: 6 male monkeys were given pelleted food containing 100 micrograms Cd/g over a period of 180 weeks, 15 male rabbits pelleted food containing 300 micrograms Cd/g over a period of 24 weeks, 13 male rabbits daily subcutaneous injections at a dose level of 0.5 mg Cd/kg over a period of 44 weeks, and 23 rabbits subcutaneous injections at a dose level of 0.5 mg Cd/kg 6 times a week over a period of 21 weeks, respectively. Sodium dodecyl polyacrylamide gel electrophoresis and silver staining (detection limit of protein: 80 micrograms/dl) revealed that urinary protein of molecular weight 12,000 (probably beta 2-microglobulin) increased slightly prior to the appearance of proteinuria, glycosuria or aminoaciduria. Remarkable increase in urinary protein of molecular weight 12,000 was observed by Amidoblack 10 B staining (detection limit: 4 mg/dl) around the time when renal dysfunctions appeared. The above result might suggest that the remarkable increase in urinary beta 2-microglobulin is associated with renal dysfunctions, while the slight increase is caused by other mechanisms than renal dysfunctions.
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Retinol-binding protein (RBP) in the Rhesus monkey had the same electrophoretic mobility, molecular weight, and common antigens as human RBP; beta 2-microglobulin protein (MG) had similar electrophoretic mobility and partial common antigens to human MG. After a prolonged oral administration of cadmium chloride to 10 monkeys over a period of 55 weeks, one monkey of the 30 mg Cd/day group indicated RBPuria and MGuria with the use of anti-human RBP and MG sera when proteinuria appeared. The immunological assay of low-molecular-weight proteins in urine was not applicable for the early detection of cadmium health effects in monkeys.
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Two groups, each of 4 rabbits, 17 and 4 months old, respectively, were given s.c. administrations of cadmium (Cd) at a dose level of 0.5 mg/kg/day 6 times per week for up to 32 weeks. In 17-month-old rabbits, low-molecular-weight proteinuria appeared in the 3rd week, proteinuria, glycosuria and anemia in the 6th week; and all animals died by the 8th week. In 4-month-old rabbits, low-molecular-weight proteinuria and anemia appeared in the 6th--9th weeks, proteinuria, glycosuria and aminoaciduria by the 12th week; and all animals died by the 32nd week. The results suggest that ageing may aggravate the chronic toxicity of cadmium.
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Ten male rhesus monkeys, each weighing 3.5 kg, were divided into four groups of 3, 3, 2, and 2, and were fed daily with 100 g pelleted food containing 300, 30, 3, and 0 ppm cadmium, respectively. Urine samples were collected every 2 weeks and blood samples every 4 weeks. One monkey each of the 300 and 30 ppm groups was autopsied for pathological examination and tissue cadmium determination at the week 24 of the experiment; the remaining 8 animals were killed after 55 weeks. The lowest exposed group (3 ppm) did not show any specific biological response to cadmium over a period of 55 weeks. In the 30 ppm group, no significant changes were observed for up to 24 weeks, although cadmium concentration in the renal cortex and urine at 24 weeks were 300 mug/g wet weight and 18 mug/l., respectively. Plasma urea nitrogen and urine protein (quantitative determination) increased after 30 and 36 weeks. At 55 weeks of the experiment, qualitative tests were negative for low molecular weight proteinuria and glycosuria, and the results remained normal for renal and liver function tests and blood analysis, although cadmium concentrations in the renal cortex of two monkeys were 460 and 730 mug/g wet weight and those in the liver were 110 and 160 mug/g wet weight, respectively. In the highest exposure group (300 ppm), urine cadmium increased to 250 mug/l. by 11 weeks, and urine retinol-binding protein, plasma GOT, GPT, and LDH increased after 12 weeks. Proteinuria (quantitative determination), glycosuria, aminoaciduria (panaminoaciduria), and erythrocytopenia were observed after 16 weeks, when urine cadmium was 500-900 mug/l. Hypohemoglobinopathy and proteinuria (qualitative determination) were observed after 20 and 24 weeks, while cadmium concentrations in the renal cortex and the liver were 760 and 430 mug/g wet weight at 24 weeks, respectively. Slightly depressed tubular reabsorption of phosphate, increased urine beta(2)-microglobulin, increased plasma urea nitrogen, and increased plasma alpha(2)-globulin fraction (electrophoresis) were observed between 28 and 30 weeks of the experiment. Creatinine clearance and plasma cholinesterase decreased after 47 and 54 weeks, respectively. Cadmium concentrations in the renal cortex and the liver of two monkeys at 55 weeks were 350 and 580 mug/g wet weight and 410 and 630 mug/g wet weight, respectively. Pathological examinations revealed denaturation, destruction, and regeneration of the epithelial cells in renal proximal tubules, but no pathological changes in osseous tissues. Critical cadmium concentration in the renal cortex was estimated to be 380 mug/g wet weight for low molecular weight proteinuria and 470 mug/g wet weight for proteinuria, glycosuria, and aminoaciduria. Critical concentration in the liver was also estimated to be 210 mug/g wet weight. The apparent biological half-time of cadmium in monkeys at autopsied stage was calculated to be 0.66, 6.4, 5.2, and 22.4 years for the 300, 30, 3, and 0 ppm groups, respectively.