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Biomedical subjects

R A Goyer

Publications and source records attributed to R A Goyer.

At least 19 recordsLinked to original sources
PubMed1996

Down-regulation of metallothionein expression in human and murine hepatocellular tumors: association with the tumor-necrotizing and antineoplastic effects of cadmium in mice.

Previously, we found that oral cadmium (Cd) treatment either prevented or substantially reduced N-nitrosodiethylamine (NDEA)-induced tumor formation in B6C3F1 mouse liver or lung regardless of exposure interval and even when the Cd was given well after tumors were formed. Because Cd salts are powerful emetics, oral exposure would probably be impractical in humans. Thus, we studied suppression of NDEA-initiated tumors in male B6C3F1 mice by a single i.v. dose of Cd. NDEA (776 mumol/kg i.p.) was given at time 0 followed by CdCl2 (16 mumol/kg i.v.) 40 weeks later. This dose of Cd had no effect on body weights through the conclusion of the study at 52 weeks. The NDEA-induced increase in hepatic tumor incidence (19 tumor-bearing mice/22 mice at risk, 86%) over control (5/24, 21%) was remarkably reduced by Cd treatment (13/27, 48%, P < or = .05). Multiplicity and size of liver tumors induced by NDEA (2.18 tumors/liver; 31.6 mm3 mean volume) were also substantially reduced by the Cd exposure (0.96 tumors/liver; 17.1 mm3 mean volume). NDEA-induced lung tumor incidence (22/22, 100%) and multiplicity (5.09 tumors/lung) were modestly, but significantly, reduced by Cd treatment (21/27, 78%; 3.89 tumors/lung). Clear evidence of tumor-specific cytotoxicity was observed as Cd treatment induced a necrotizing effect that was localized only within the hepatic tumors. Metallothionein (MT), an inducible metal-binding protein associated with tolerance to many metal including Cd, was not detected immunohistochemically in mouse liver tumors, even those undergoing Cd-induced necrosis, whereas the surrounding normal liver cells expressed high levels of MT after Cd exposure. Likewise, in human hepatocellular carcinomas MT was only poorly or erratically expressed relative to normal tissue. These results indicate that a single, nontoxic dose of Cd dramatically reduces liver tumor burden through tumor cell-specific necrosis due to a down-regulation of MT expression in hepatic tumors of murine origin and furthermore indicate that a similar down-regulation of MT occurs in human hepatocellular carcinomas.

Animals↗
PubMed1995

Renal tubular tumors and atypical hyperplasias in B6C3F1 mice exposed to lead acetate during gestation and lactation occur with minimal chronic nephropathy.

Lead is a high-priority hazardous substance in humans and a renal carcinogen in adult rodents. This study assessed the carcinogenic potential and toxicity of gestational and lactational lead exposure in (C57BL/6NCr x C3H/HeN)F1 (hereafter called B6C3F1) mice. Effects of a renal tumor promoter [barbital sodium (BB)] on lead-initiated lesions were also studied. Pregnant female C57BL/6NCr mice (10-15/group) previously bred with C3H/HeN males were given lead acetate (0, 500, 750 and 1000 ppm lead) ad libitum in their drinking water, starting on gestation day 12 and continuing to 4 weeks postpartum. Offspring were then weaned and divided into same-sex groups of 23-25 and observed for a maximum of 112 weeks. Other groups received lead and then continuous BB (500 ppm) ad libitum in their drinking water from weaning onward. In control male offspring (0 lead/0 BB), renal proliferative lesions [(RPLs); defined as atypical tubular hyperplasia or tumor] occurred rarely (1 lesion-bearing mouse/23 mice examined, 4%) and did not include tumors. RPLs increased in a dose-related fashion with lead exposure (500 lead/0 BB, 4/25, 16%; 750 lead/0 BB, 6/25, 24%; 1000 lead/0 BB, 12/25, 48%) in male offspring and were often multiple. All lead-treated groups had renal tumors, including carcinoma, but these were most common at the highest dose (1000 lead/0 BB, 5/25). Lead-induced renal tumors arose in the absence of the extensive chronic nephropathy and lead inclusion bodies typically seen with lead carcinogenesis in rodents exposed chronically as adults. Postnatal BB exposure had no effect on RPL incidence (e.g., 1000 lead/500 BB, 8/25, 32%). Lead-treated female offspring also developed RPLs, including adenoma and carcinoma, but at a much lower rate than males. Thus, short-term lead exposure during the gestational/lactational period has carcinogenic potential in the mouse kidney.

Animals↗
PubMed1995

Nutrition and metal toxicity.

Lead, cadmium, and mercury are toxic metals that are not essential for nutrition. However, the toxic effects of these metals may be mediated or enhanced by interactions or deficiencies of nutritionally essential metals. Lead competes with calcium, inhibiting the release of neurotransmitters, and interferes with the regulation of cell metabolism by binding to second-messenger calcium receptors, blocking calcium transport by calcium channels and calcium-sodium ATP pumps, and by competing for calcium-binding protein sites and uptake by mitochondria. Dietary deficiencies of calcium, iron, and zinc enhance the effects of lead on cognitive and behavioral development. Iron deficiency increases the gastrointestinal absorption of cadmium, and cadmium competes with zinc for binding sites on metallothionein, which is important in the storage and transport of zinc during development. Selenium protects from mercury and methyl mercury toxicity by preventing damage from free radicals or by forming inactive selenium mercury complexes.

Animals↗
PubMed1994

Immunomodulation by metals.

A symposium entitled Immunomodulation by Metals was held at the 32nd Annual Meeting of the Society of Toxicology (SOT) in New Orleans, Louisiana. The symposium was co-sponsored by the Immunotoxicology and Metals Specialty Sections of SOT and was designed to describe the types of adverse immunological reactions which occur in response to environmental and/or occupational exposure to metals. Epidemiological evidence and underlying mechanisms responsible for the observed alterations were also discussed. The following is a summary of each of the individual presentations.

Animals↗
PubMed1993

Nephrotoxicity of repeated injections of cadmium-metallothionein in rats.

Cadmium-metallothionein (Cd-MT) may have a role in the pathogenesis and irreversibility of Cd nephrotoxicity. In the present study, rats were injected with 0.3 mg Cd/kg body wt per week as Cd-MT for 5 consecutive weeks and a group of rats (n = 3) was killed 24 hr after each injection. A group of three rats was kept for an additional week after the 5 weeks of Cd-MT injection for recovery. After the first injection, urinary Cd and protein levels and kidney/body wt ratio were increased. The electrophoretic pattern of urinary protein showed increased excretion of low-molecular-weight proteins, especially after the first injection of Cd-MT. Tubular cell necrosis occurred after the first week with renal Cd levels of only 10 micrograms/g and gradually progressed to severe necrosis with inflammation in 3 weeks and then to interstitial fibrosis in 5 weeks. The levels of Cd and MT in kidney increased with repeated injection of Cd-MT, but renal Cd was about 40 micrograms/g after 5 weeks of injection. Urinary Cd and MT levels progressively increased during the Cd exposure period, but returned to pretreatment levels during the sixth week (recovery period). Renal cell necrosis and inflammation were absent at the sixth week, but interstitial fibrosis persisted. This study indicates that nephrotoxicity of Cd in this model is related to urinary excretion of Cd-MT and that renal cell injury may be independent of Cd in the renal cortex. Nephrotoxicity occurs at levels much lower than the proposed critical concentration for Cd (200 micrograms Cd/g) following long-term exposure to CdCl2. However, in the absence of continued Cd exposure from liver or circulation, the Cd-MT-induced renal damage is reversible.

Analysis of Variance↗
PubMed1993

Nephrotoxicity in rats following liver transplantation from cadmium-exposed rats.

Although kidney is considered as the critical organ for cadmium (Cd) toxicity, little is known about the transport of Cd to kidney after chronic exposure. In order to study this transfer, male Lewis rats (150-200 g) were given eight injections (sc) of CdCl2 (3 mg Cd/kg) over 2 weeks which resulted in increases of tissue Cd and metallothionein (MT) concentrations (223 and 1850 micrograms/g, respectively, in the liver and 118 and 873 micrograms/g, respectively, in the kidney). Livers from Cd-injected rats were transplanted to age-matched control healthy Lewis rats and the recipient rats were killed at 2 to 47 days after transplantation. The levels of Cd and MT in the liver of recipient rats were decreased (106 and 1503 micrograms/g, respectively) with time after surgery. On the other hand, renal Cd and MT levels were markedly increased (195 and 1468 micrograms/g, respectively) and most of the Cd in the kidney was bound to MT. About 100 ng/ml of Cd and MT were detected in the plasma of recipient rats by ELISA. There was some periportal fibrosis in the liver due to transplant procedure which did not anastomose hepatic arteries. There was an increase in blood urea nitrogen levels in rats transplanted with Cd-containing liver. In addition, both necrosis and inflammation were observed in the epithelial cells in the proximal tubules in the kidney which typically occurs in chronic Cd toxicity. These results suggest that the major source of renal Cd in chronic Cd exposure may be derived from hepatic Cd which is transported in the form of Cd-MT in blood plasma.

Animals↗
PubMed1993

Lead toxicity: current concerns.

Over the 20-year period since the first issue of Environmental Health Perspectives was published, there has been considerable progress in the understanding of the potential toxicity of exposure to lead. Many of these advances have been reviewed in published symposia, conferences, and review papers in EHP. This brief review identifies major advances as well as a number of current concerns that present opportunities for prevention and intervention strategies. The major scientific advance has been the demonstration that blood lead (PbB) levels of 10-15 micrograms/dL in newborn and very young infants result in cognitive and behavioral deficits. Further support for this observation is being obtained by prospective or longitudinal studies presently in progress. The mechanism(s) for the central nervous system effects of lead is unclear but involve lead interactions within calcium-mediated intracellular messenger systems and neurotransmission. Effects of low-level lead exposure on blood pressure, particularly in adult men, may be related to the effect of lead on calcium-mediated control of vascular smooth muscle contraction and on the renin-angiotensin system. Reproductive effects of lead have long been suspected, but low-level effects have not been well studied. Whether lead is a carcinogen or its association with renal adenocarcinoma is a consequence of cystic nephropathy is uncertain. Major risk factors for lead toxicity in children in the United States include nutrition, particularly deficiencies of essential metals, calcium, iron, and zinc, and housing and socioeconomic status. A goal for the year 2000 is to reduce prevalence of blood lead levels exceeding 15 micrograms/dL.

Animals↗
PubMed1993

Pregnancy-associated changes in plasma metallothionein concentration and renal cadmium accumulation in rats.

Pregnancy-associated changes in metallothionein (MT) concentrations in blood plasma were examined using a competitive enzyme-linked immunosorbent assay with a rabbit polyclonal antibody to rat liver MT. Plasma MT of pregnant rats significantly increased after 8 days of gestation and remained high during pregnancy and for 7 days after delivery. Gel filtration showed that both Cu and Zn were associated with the plasma MT of pregnant rats. These results suggest that plasma MT may play a role in the transport of essential metals such as Cu and Zn to fetus during pregnancy, but the source of plasma MT is unknown. Injections of cadmium chloride and cadmium-metallothionein to pregnant rats further increased the plasma MT concentrations. After injection of CdCl2, both MT and Cd concentrations in the liver of the pregnant rats were significantly lower than those of the nonpregnant rats, whereas renal Cd and MT levels were higher in pregnant rats. This increased accumulation of Cd in the kidney of pregnant rats may be related to the increase of plasma MT during pregnancy. About 5% of 6 pg of in vitro added Cd (20 pg/ml) was bound to the MT in the plasma. Therefore, Cd may be transported by the circulating MT to the kidney, leading to an increase in renal accumulation of Cd in pregnant rats.

Animals↗
PubMed1993

Further evidence of the tumor-suppressive effects of cadmium in the B6C3F1 mouse liver and lung: late stage vulnerability of tumors to cadmium and the role of metallothionein.

Previously, we studied the ability of cadmium to initiate or promote tumors in B6C3F1 mice and, contrary to expectation, found that cadmium inhibited development of N-nitrosodiethylamine (NDEA)-initiated and sodium barbital-promoted liver tumors. In this study, the time course of cadmium inhibition of NDEA-initiated tumor formation was studied. A single dose of NDEA (90 mg/kg i.p.) was given at 5 weeks of age (time 0) followed by cadmium (1000 ppm) in drinking water from 2 to 48, 4 to 48, 8 to 48, 16 to 48 and 32 to 48 weeks. The study ended at 48 weeks. NDEA-induced elevations in liver tumor incidence (22 tumor-bearing mice/25 total) over control (5/25) were prevented by cadmium regardless of the period of administration (NDEA + cadmium: 2-48 weeks, 2/25; 4-48 weeks, 1/25; 8-48 weeks, 1/25; 16-48 weeks, 2/25; 32-48 weeks, 6/24). Cadmium alone (2-48 weeks) eliminated (0/25) spontaneously occurring liver tumors (5/25). NDEA-induced lung tumor incidence (25/25) and multiplicity (7.28 tumors/lung) were also reduced by cadmium (maximal decreases 28% and 80%, respectively). Some evidence of a specific deficiency of metallothionein in tumor cells was seen immunohistologically in NDEA-induced hepatic lesions and pulmonary lesions. These results indicate that cadmium prevents or reduces tumor formation in the B6C3F1 mouse liver and lung regardless of the exposure interval and apparently by cell-specific cytotoxicity. Auxiliary studies indicated that in mice bearing multiple liver foci resulting from NDEA treatment there was a marked reduction in basal metallothionein levels and in response to zinc induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Immunohistochemical evidence of high concentrations of metallothionein in pancreatic hepatocytes induced by cadmium in rats.

A recent study from our laboratory has shown that cadmium, a toxic heavy metal, is one of the most effective agents known for inducing hepatocytic transdifferentiation of the rat pancreas. With repeated injections of cadmium, the incidence of rats with pancreatic hepatocytic foci can be as high as 93%. Cadmium is also well known as a very potent inducer of metallothionein, a metal-binding protein that appears to be important in the biologic response to several toxic heavy metals in most tissues, including the pancreas. Therefore, the present study sought to determine if metallothionein was associated with cadmium-induced transdifferentiation of pancreatic cells. Expression of metallothionein was studied immunohistochemically by the peroxidase-antiperoxidase method in tissue sections of the pancreas of rats with pancreatic hepatocytes. High levels of metallothionein were localized primarily within the pancreatic hepatocytes. Surrounding normal pancreatic islet and acinar cells were not immunoreactive. Thus, metallothionein is expressed actively in cells transdifferentiated to hepatocytes by cadmium within the pancreas.

Animals↗
PubMed1992

Role of metallothionein in human placenta and rats exposed to cadmium.

A strong positive relationship between zinc and copper and metallothionein (MT) in placentas has been found, but a negative one between cadmium and MT. In rats given cadmium i.p. as the chloride, liver cadmium is lower and kidney cadmium higher than in cadmium-treated non-pregnant rats, suggesting that pregnancy enhances mobilization of cadmium from liver to kidney. The cadmium concentration of digested whole fetuses is not significantly increased in offspring of dams given cadmium i.p. as the chloride or CdMT, but the placental levels of cadmium and MT are increased. The placenta therefore acts as a barrier to maternal-fetal cadmium transfer. The way in which cadmium is retained in the placenta but zinc and copper are transferred to the fetus is not understood, since all are bound to MT. Focal renal tubular necrosis and placental necrosis occur at the same level of cadmium exposure, suggesting a similar threshold to cadmium toxicity for the two organs.

Adolescent↗
PubMed1990

Environmentally related diseases of the urinary tract.

Nephrotoxicity from exposure to therapeutic agents and chemicals in the environment and workplace results in a broad spectrum of clinical renal disease that may mimic disorders from other causes. Nephrotoxic agents may, in fact, be responsible for some fraction of renal disease of undetermined etiology. Specific diagnosis and treatment by removal from exposure to the toxic agent is more likely in the early phase of the disorder. Measurement and characterization of proteinuria provides the most sensitive and reliable method of early detection. Increased urinary excretion of serum proteins with molecular weight in excess of 50,000, such as albumin and transferrin, is an early indicator of glomerular injury. Low-molecular-weight proteinuria (beta 2-microglobulin or retinol-binding protein) and enzymuria, particularly excretion of NAG, are sensitive indicators of renal tubular cell injury. Tests that reflect hypersensitivity reactions are often indicative of immunologically mediated nephrotoxicity but are not specific for the kidney. Cancers of the kidney and urinary bladder appear to be increasing and are most common among the socially active and affluent. Susceptibility of the urinary tract to toxicity and carcinogenicity reflect contact of excreted toxins with the epithelial cells of nephrons and urinary bladder.

Aminoglycosides↗
PubMed1990

Lead toxicity: from overt to subclinical to subtle health effects.

Although the toxicity of lead was recognized centuries ago, concern was restricted to overt symptoms: colic, encephalopathy, anemia, or renal disease. Two major reasons for lack of progress in restricting toxicity were that interest was limited to occupational exposures and there was lack of awareness of specific biochemical or metabolic effects. Identification of subclinical effects has been possible the last 15 or 20 years because of the development of sensitive measures to detect cognitive and behavioral changes that are not apparent clinically and because of methods to measure the reduced activity of heme enzymes. This progress was driven by basic and clinical research that resulted in a better understanding of cellular toxicology. The new awareness prompted the lowering of acceptable occupational exposures, as measured by blood lead from 80 to 40 to 60 micrograms/dL range, and the establishment of maximum recommended exposures in children to a blood lead level of 25 micrograms/dL. Lowering the lead content in gasoline has been accomplished by a nearly 50% decrease in average blood levels of persons in the United States (NHANES II data). Current research implicates lead as a contributing etiologic factor in a number of common diseases affecting large portions of the population such as subtle cognitive and neurological deficits, hypertension, congenital malformations, immunotoxicity, and deficits in growth and development. For each of these disorders there may be multiple etiologic factors; the scientific challenge is to develop sensitive methodology to detect the specific role of lead. Other potential subtle health effects include the influence of small amounts of lead on cell proliferation and lead as a cofactor in carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Transplacental transport of lead.

Neurotoxicity is the major health effect from exposure to lead for infants and young children, and there is current concern regarding possible toxic effects of lead on the child while in utero. There is no placental-fetal barrier to lead transport. Maternal and fetal blood lead levels are nearly identical, so lead passes through the placenta unencumbered. Lead has been measured in the fetal brain as early as the end of the first trimester (13 weeks). There is a similar rate of increase in brain size and lead content throughout pregnancy in the fetus of mothers in the general population, so concentration of lead probably does not differ greatly during gestation unless exposure of the mother changes. Cell-specific sensitivity to the toxic effects of lead, however, may be greater the younger the fetus. Lead toxicity to the nervous system is characterized by edema or swelling of the brain due to altered permeability of capillary endothelial cells. Experimental studies suggest that immature endothelial cells forming the capillaries of the developing brain are less resistant to the effects of lead, permitting fluid and cations including lead to reach newly formed components of the brain, particularly astrocytes and neurons. Also, the ability of astrocytes and neurons to sequester lead in the form of lead protein complexes occurs only in the later stages of fetal development, permitting lead in maturing brain cells to interact with vital subcellular organelles, particularly mitochondria, which are the major cellular energy source. Intracellular lead also affects binding sites for calcium which, in turn, may affect numerous cell functions including neurotransmitter release.

Animals↗