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Biomedical subjects
C V Nolan
Publications and source records attributed to C V Nolan.
A STEP forward for European environmental mutagenesis research.
This article introduces a special issue of Mutation Research which contains final synthesis reports of eight multi-national research projects in the STEP (Science and Technology for Environmental Protection) Research Programme of the European Commission. In addition to sketching the scientific, policy and historical background to the research, the contents of the eight reports are summarised and the broader issue of environmental research and its links to chemicals control, risk assessment, and regulation in the European Union is discussed.
Animals↗
Lead nephrotoxicity and associated disorders: biochemical mechanisms.
Lead may exert toxic effects on several organ systems, but those in the kidney are the most insidious. Acute lead nephropathy is characterized by proximal tubular dysfunction with the development of a Fanconi-type syndrome, alterations in mitochondrial structure and the development of cytosolic and nuclear inclusion bodies. Intracellular lead is associated with specific high affinity proteins and can also bind to metallothionein. Chronic lead nephropathy is irreversible and is typically accompanied by interstitial fibrosis, both hyperplasia and atrophy of the tubules, glomerulonephritis and, ultimately, renal failure. In addition, lead produces renal neoplasms in experimental animals. Chronic lead exposure is also implicated in the development of saturnine gout and hypertension. The metal interacts with renal membranes and enzymes and disrupts energy production, calcium metabolism, glucose homeostasis, ion transport processes and the renin-angiotensin system. This review summarizes the biochemical effects of lead on the kidney to understand the mechanisms of lead-induced nephropathy and other associated disorders.
Animals↗
Developmental and sex differences in cadmium distribution and metallothionein induction and localization.
Age- and sex-related differences in hepatic and renal distribution of cadmium (Cd) and the effect of Cd injection (10 mumol/kg) on tissue zinc (Zn), copper (Cu) and metallothionein (MT) levels were investigated in 2- to 84-day old rats. Renal Cd accumulation increased with age of the animal. Sex differences in renal Cd accumulation were noted in young animals where the 2- and 8-day old males had significantly greater concentration than the females. There were no clear effects of Cd on renal Zn. Renal Cu levels, however, were elevated in the adults. The adult females contained about twice as much MT as the adult males. Cd treatment had no effect on renal MT levels of 8- to 84-day old animals but depressed the levels in 2-day old. Age-related increase in hepatic Cd accumulation was also found; the pattern was more clear cut in females than in males. In addition, in the females the hepatic Cd concentration was significantly higher than in the males. Cd-injection significantly increased hepatic Zn and MT concentrations only in weaned animals. While there were no sex differences in MT levels in the young animals, the weaned females had significantly more MT than the corresponding males. Immunohistochemical staining for MT showed positive staining in both cytoplasm and nuclei of the parenchymal cells. The number of MT-positive nuclei was dependent on the relative MT concentration of the liver. In spite of the intense nuclear staining in 2-day old controls and 84-day old Cd-injected rats, less than 1% of the hepatic MT was present in the nuclear fraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Comparison of cadmium-saturation assay and radioimmunoassay for the determination of metallothionein concentration in tissues.
The more common Cd-saturation method for metallothionein (MT) analysis in tissues is compared with a recently developed radioimmunoassay (RIA). The Cd-saturation assay as described by others is fast, but less specific and accurate than the RIA. The former assay, previously used for MT analysis in urine and plasma, was modified to suit its use in measuring MT concentration in tissues. Liver and kidney from control rats were assayed and values of 7 and 67 micrograms/g were measured in the two tissues, respectively. The detection limit of the assay is 10 ng/g. A modified version of the Cd-saturation assay, which was limited with respect to the number of samples that can be analyzed at one time, gave results which were similar to the ones obtained by the RIA. The advantages and the problems associated with the two assays are discussed.
Animals↗
Occupational exposure to cadmium: effect on metallothionein and other biological indices of exposure and renal function.
The effect of duration of employment at a North American cadmium smelter on urinary metallothionein (MT), total protein, beta 2-microglobulin (beta 2-MG), glucose, cadmium, copper and zinc of 53 men was studied. The levels of all urinary parameters increased with the duration of employment. Smoking history did not affect any of the above parameters studied. Although age was responsible for some of the changes noted in protein, glucose and beta 2-MG levels, its effect on MT and cadmium was insignificant. All urinary parameters were significantly related with each other. The relationship of elevated urinary MT levels with respect to renal dysfunction was also examined. Subjects with abnormal renal function excreted significantly higher amounts of MT than did those with normal renal function. The results confirm not only that occupational exposure to cadmium over long periods results in renal dysfunction but also that urinary MT could be used to monitor exposure and ultimately the appearance of the renal dysfunction.
Adult↗
The vascular endothelium as a target tissue in acute cadmium toxicity.
Sensitivity of tissues to the acute toxicity of cadmium is reviewed. It is concluded that the initial effect of acute cadmium administration is on the integrity and permeability of the vascular endothelium; other necrotic changes occur secondarily to this effect. In a sensitive tissue, not all of the endothelial cells are susceptible to cadmium. Furthermore, after necrosis of the sensitive cells, the resistant cells proliferate and result in regeneration of the vasculature and subsequent acquired resistance to the metal. It is found that sex hormones are probably important in determining susceptibility and response of tissues to cadmium. The role of metallothionein in these phenomena remains to be elucidated.
Animals↗
An evaluation of tissue metallothionein and genetic resistance to cadmium toxicity in mice.
The role of metallothionein or metallothionein-like proteins (MT) in genetic resistance to the testicular and hepatic toxicity of cadmium was examined in inbred strains of mice. Mice of two strains resistant (AJ and C3H/HEJ) or susceptible (129J and DBA/2J) to cadmium-induced testicular necrosis were administered sc 30 mumol CdCl2/kg. The uptake of cadmium and the induction of MT in tissues were determined after 6 hr. The results showed that accumulation of cadmium in liver and kidney tissues of the four strains was very similar. MT levels were elevated up to 20-fold in the liver and up to almost 8-fold in the kidney, resulting in cadmium to MT molar ratios of 6.7 to 10.0 in the liver and 1.2 to 1.9 in the kidney. The greatest increase in hepatic MT as well as the cadmium to MT ratio was in the C3H/HEJ strain which is susceptible to cadmium-induced hepatotoxicity. Testicular cadmium levels were significantly elevated in the two susceptible strains. The basal levels of MT-like protein in the testis were generally higher than those in the kidney. Although, only the testis of 129J (susceptible) showed an increase in this protein after 6 hr, both susceptible strains injected with cadmium had significantly higher levels of the protein as compared to the resistant strains. The 30,000-Da cadmium-binding protein in AJ and CD-1 (susceptible) mouse strains was found to cross-react with the anti-MT-serum. Necrotic changes were visible in the testes of the susceptible strains as a result of cadmium administration. Immunohistochemically, there were no significant differences in the localization of MT in the liver, kidney or testis among the four strains. MT or an MT-like protein was concentrated mainly in the interstitial tissue of the mouse testis, but was also detected in the seminiferous tubules. It is concluded that the strain differences in acute toxicity of cadmium are probably not due to low MT concentration in tissues of the susceptible strains.
Animals↗
Determination of metallothionein in tissues by radioimmunoassay and by cadmium saturation method.
The diversity of reported basal metallothionein (MT) values in animal tissues has made it necessary that the presently available methods be further developed and compared for their accuracy, reproducibility, sensitivity, and specificity. A radioimmunoassay (RIA) to quantitate MT in animal tissues was developed and its performance compared to that of a cadmium saturation method. The procedure is more accurate and reliable but no more time-consuming than other techniques in current use. It offers the advantages of greater specificity and sensitivity thus enabling the determination of basal levels of MT in tissues and the analysis of small samples, for example, biopsies, cultured cells, in vitro protein synthesis, etc. The use of a polyclonal antiserum is advantageous in that total MT can be determined in any tissue from a variety of animal species. Both nonspecific and specific interference in the assay can be eliminated by heat treatment of the sample followed by a short preincubation with cadmium. The sensitivity of the RIA is 10 ng MT/g tissue. The cadmium saturation assay is unsuitable for the measurement of low levels of MT due to its nonspecific nature and its detection limit (10 micrograms MT/g tissue) but it is useful where large amounts of the protein are present in a tissue. Difficulties arising in the analysis of MT by both methods are discussed and solutions are offered. The basal levels of MT in the brain, kidney, liver, lung, muscle, pancreas, small intestine, and spleen of rats are determined by RIA and are shown to be generally lower than the currently accepted values measured by other techniques.
Animals↗