Begell House Inc.
Journal of Environmental Pathology, Toxicology and Oncology
JEP(T)
0731-8898
20
2
2001
Oxidative Mechanisms in the Toxicity of Chromium and Cadmium Ions
12
10.1615/JEnvironPatholToxicolOncol.v20.i2.10
Sidney J.
Stohs
Departments of Pharmaceutical and Administrative Sciences, Creighton University School of Pharmacy and Allied Health Professions, 2500 California Plaza, Omaha, NE 68178
Debasis
Bagchi
Departments of Pharmaceutical and Administrative Sciences, Creighton University School of Pharmacy and Allied Health Professions, 2500 California Plaza, Omaha, NE 68178
Ezdihar
Hassoun
College of Pharmacy, University of Toledo, Toledo, Ohio 43606-3390
Manashi
Bagchi
Departments of Pharmaceutical and Administrative Sciences, Creighton University School of Pharmacy and Allied Health Professions, 2500 California Plaza, Omaha, NE 68178
Chromium and cadmium are widely used industrial chemicals. The toxicities associated with both metal ions are well known. However, less information is available concerning the mechanisms of toxicity. The results of in vitro and in vivo studies demonstrate that both cations induce an oxidative stress that results in oxidative deterioration of biological macromolecules. However, different mechanisms are involved in the production of oxidative stress by chromium and cadmium. Chromium undergoes redox cycling, while cadmium depletes glutathione and protein-bound sulfhydryl groups, resulting in enhanced production of reactive oxygen species such as superoxide ion, hydroxyl radicals, and hydrogen peroxide. These reactive oxygen species result in increased lipid peroxidation, enhanced excretion of urinary lipid metabolites, modulation of intracellular oxidized states, DNA damage, membrane damage, altered gene expression, and apoptosis. Enhanced production of nuclear factor-кВ and activation of protein kinase С occur. Furthermore, the p53 tumor suppressor gene is involved in the cascade of events associated with the toxicities of these cations. In summary, the results clearly indicate that although different mechanisms lead to the production of reactive oxygen species by chromium and cadmium, similar subsequent mechanisms and types of oxidative tissue damage are involved in the overall toxicities.
Bioactive Anthocyanins Detected in Human Urine after Ingestion of Blackcurrant Juice
7
10.1615/JEnvironPatholToxicolOncol.v20.i2.20
Michael
Netzel
Institute of Nutritional Science, Justus-Liebig-University Giessen, Giessen, Germany; Institute of Nutritional Sciences, Friedrich-Schiller-University Jena, Jena, Germany
Gabriele
Strass
Institute of Nutritional Science, Justus-Liebig-University Giessen, Giessen, Germany
Marlies
Janssen
Institute of Nutritional Science, Justus-Liebig-University Giessen, Giessen, Germany
Irmgard
Bitsch
Institute of Nutritional Science, Justus-Liebig-University Giessen, Giessen, Germany
Roland
Bitsch
Institute of Nutritional Sciences, Friedrich-Schiller-University Jena, Jena, Germany
Anthocyanins are a group of very efficient bioactive compounds that are widely distributed in plant food. Several fruits (blackcurrant, blackberry, red grape) and some vegetables (eggplant, onion, red radish) are rich sources of these natural pigments. Extracts of some of them are used as food colorants as well as components of pharmaceutical preparations and functional foods. Anthocyanins, through their ability to inhibit radical reactions, are considered to exert several protective effects in the human body. Until now there has been only a small amount of data available on their capability, in intact or metabolized form, to reach the systemic circulation of humans. The present study was designed to determine the potential bioavailability in humans of the most important anthocyanins of blackcurrants: delphinidine-3-glucoside, delphinidine-3-rutinoside, cyanidine-3-glucoside, and cyanidine-3-rutinoside.Urinary samples from 4 healthy volunteers (2 women and 2 men) were collected before (baseline) and over a period of 5 hours with intervals of 30 minutes after the ingestion of 200 mL of blackcurrant juice (containing 153 mg of anthocyanins). Using high-performance liquid chromatography (HPLC), it was possible to quantify the 4 main anthocyanins of blackcurrants, excreted unchanged in the urine (0.020–0.050% of the oral doses). We present data on the bioavailability in humans of blackcurrant anthocyanins, which are dietary antioxidants with possible biological effects.
Increased TGF-b1* in the Lungs of Asbestos-Exposed Rats and Mice: Reduced Expression in TNF-a Receptor Knockout Mice
12
10.1615/JEnvironPatholToxicolOncol.v20.i2.30
Jing-Yao
Liu
Tulane University Health Sciences, New Orleans, Louisiana
Inhalation of numerous fibrogenic agents causes interstitial pulmonary fibrosis (IPF) in humans and in a number of animal models. Several of these models provide evidence that certain peptide growth factors (GF) are playing a role in the disease process.Transforming growth factor beta 1 (TGF-b1) is a potent inducer of extracellular matrix production by mesenchymal cells, and we have shown that this peptide is produced in the lung after asbestos exposure. We used in situ hybridization to demonstrate that the mRNA for TGF-b1 is rapidly expressed postexposure at sites of initial asbestos-induced lung injury in both rats and mice. The TGF-b1 is expressed by bronchiolar-alveolar epithelial cells as well as by mesenchymal cells and lung macrophages in exposed animals. Normal rats and mice express little TGF-b1, as we have demonstrated previously for PDGF-A and -B, TGF-a, and TNF-a. TGF-b1 expression is accompanied by collagen and fibronectin production in asbestos-exposed animals. Most interesting, TGF-b1 expression is largely absent in the lungs of TNF-a receptor knockout mice that fail to develop asbestos-induced IPF.We have shown previously that the mRNAs and cognate peptides of PDGF-A and -B and TGF-a, but not TNF-a, are reduced in the fibrosis-resistant knockout mice. In this article, we show that TGF-b1 is included in this group of cytokines, supporting the postulate that TNF-a is necessary for the expression of other, more downstream growth factors, and the consequent development of idiopathic pulmonary fibrosis (IPF).
Optical Visualization of Microsomal Degranulation by a Carcinogen
3
10.1615/JEnvironPatholToxicolOncol.v20.i2.40
Parminder
Kaur
Department of Biochemistry, Panjab University, Chandigarh-160014, India
Harinder M.
Dani
Department of Biochemistry, Panjab University, Chandigarh, 160014, India
We report here for the first time the optical visualization of microsomal degranulation induced by a carcinogen (p-dimethylaminoazobenzene), employing analytical ultracentrifugation.Our observations demonstrate that electrophiles of a carcinogen can disrupt ribosome-membrane interaction in rough microsomes by their attacks on nucleophilic components of the reticular membrane-ribosome complex involved in protein synthesis for export from the cytosol. Lack of exported proteins can adversely affect signal transduction across plasma membrane, possibly leading to carcinogenesis.
Prevalence of Human Papillomavirus Infection Among Prostitutes in Calcutta
5
10.1615/JEnvironPatholToxicolOncol.v20.i2.50
Ramdas
Chatterjee
Dept. of Viral Associated Human Cancer, Chittaranjan National Cancer Institute, Calcutta, India
Debnath
Mukhopadhyay
Dept. of Viral Associated Human Cancer, Chittaranjan National Cancer Institute, Calcutta, India
Nabendu
Murmu
Chittaranjan National Cancer Institute
Smarajit
Jana
Institute of Hygiene and Public Health, Calcutta, India
We investigated the presence of human papilloma virus (HPV) 16/18 and herpes simplex virus-1,-2 (HSV-1,-2) infections in buccal mucosal cells of prostitutes of Calcutta, India, by in situ DNA hybridization and immunocytochemical technique. In some of them, we also examined the prevalence of viral infections in uterine cervical cells. The women were also tested for venereal disease research laboratory antigen (VDRL) positivity. Oral infections with HSV-1,-2 and HPV 16/18 were detected in 24.6%, 11.6%, and 29%, respectively. Similar cervical infections were found in 0%, 44%, and 62.9% of the cases studied. HPV coinfection was significantly higher (p p > 0.05). The HPV or HSV infection rates showed no remarkable variation between the two age groups of the prostitutes studied (p > 0.05). Cytological abnormalities were more pronounced in the cervix of women having concurrent infection with HPV and HSV-2 rather than in the presence of infection with either of the two. This preliminary investigation, the first of its kind in India, requires a larger study to understand the significance of the association of different sexually transmitted agents including HPV (apart from HIV) as risk factors for pathologic lesions.
Sister Chromatid Exchanges and Micronuclei in Lymphocytes of Operating Room Personnel Occupationally Exposed to Enfluorane and Nitrous Oxide
8
10.1615/JEnvironPatholToxicolOncol.v20.i2.60
Rossana
Pasquini
Department of Hygiene, University of Perugia, Perugia, Italy
Giuseppina
Scassellati-Sforzolini
Department of Hygiene, University of Perugia, Perugia, Italy
Cristina
Fatigoni
Department of Hygiene, University of Perugia, Perugia, Italy
Massimiliano
Marcarelli
Department of Hygiene, University of Perugia, Perugia, Italy
Silvano
Monarca
Department of Experimental and Applied Medicine, Section of Hygiene, University of Brescia, Brescia, Italy
Francesco
Donato
Department of Experimental and Applied Medicine, Section of Hygiene, University of Brescia, Brescia, Italy
Stefano
Cencetti
Azienda Ospedaliera, Perugia, Italy
Francesco Maria
Cerami
Azienda Ospedaliera, Perugia, Italy
The objective of this article is to assess whether occupational exposure to anesthetics increases genotoxic risk.We investigated two cytogenetic biomarkers, sister chromatid exchanges (SCE) and micronuclei (MN), in the peripheral blood lymphocytes of 46 anesthesiologists (24 men), working in operating rooms and mostly exposed to enfluorane and nitrous oxide, and 66 controls (35 men), not exposed to chemicals and living in the same area. Contrary to what was expected, a lower frequency of SCE was found in male anesthesiologists than in controls. Smoking status was found to be positively associated with SCE frequency in each group, while no relation to age was evident. On the contrary, MN frequency was significantly higher in female, but not male, anesthesiologists than in controls. Age and smoking status did not modify the association.No relationship between MN frequency and duration of employment was found in anesthesiologists. Smoking status and mean number of cigarettes smoked per day in smokers were not associated with MN frequency in either anesthesiologists or in controls. MN analysis seems to be a sensitive index of possible genotoxic effects of occupational exposure to anesthesiologists, and women appear to be more susceptible to these effects than men.
Transplacental Carcinogenic Potential of the Carbamate Fungicide Mancozeb
5
10.1615/JEnvironPatholToxicolOncol.v20.i2.70
Yogeshwer
Shukla
Environmental Carcinogenesis Division, Industrial Toxicology Research Centre,Lucknow, India
We evaluated the effects of mancozeb (Dithane M4-5™), a protective carbamate fungicide, on transplacental carcinogenesis in Swiss albino mice. Mancozeb, a polymeric complex of ethylene bis (dithiocarbamate) manganese with zinc salt, is reported to possess carcinogenic and cocarcinogenic activity in various tumor models. In the present study, pregnant Swiss albino mice were administered mancozeb intraperitoneally on the 14th day of gestation. The first filial generation (F1 progeny) was promoted with a well-known tumor promoter 12-o-tetradecanoyl phorbol-13-acetate (TPA). The results revealed a significantly high tumor incidence (72%) in the F1 progeny of the animals initiated with mancozeb or a well known carcinogen 7,12-dimethyl benzanthracene (DMBA) and promoted with TPA in comparison to animals that were either from mothers given only the vehicle (DMSO) and promoted with TPA in F1 progeny or not promoted with TPA in F1 progeny.No significantly higher tumor incidence was observed in any other experimental groups. These results suggest that mancozeb or its metabolites are capable of crossing the placental barrier and can exert DNA damage and tumor initiating consequences in the fetal cells that, after promotion with TPA, get converted into neoplastic cells.
The Effect of Coenzyme Q10 on Blood Ascorbic Acid, Vitamin E, and Lipid Peroxide in Chronic Cadmium Intoxication
8
10.1615/JEnvironPatholToxicolOncol.v20.i2.80
Sladjan Z.
Pavlovic
Department of Physiology, Institute for Biological Research Sinis.a Stankovic., Belgrade,Yugoslavia
Branka I.
Ognjanovic
Institute of Biology, Faculty of Sciences, University of Kragujevac, Kragujevac, Yugoslavia
Andras S.
Stajn
Institute of Biology, Faculty of Sciences, University of Kragujevac, Kragujevac, Yugoslavia
Radoslav V.
Zikic
Institute of Biology, Faculty of Sciences, University of Kragujevac, Kragujevac, Yugoslavia
Zorica S.
Saicic
Department of Physiology, Institute for Biological Research Sinis.a Stankovic., Belgrade,Yugoslavia
Vojislav M.
Petrovic
Department of Physiology, Institute for Biological Research Sinis.a Stankovic., Belgrade,Yugoslavia
The aim of our study was to investigate the possible protective role of coenzyme Q10 (CoQ10) administration on ascorbic acid (AsA), vitamin E (vit E), and lipid peroxide (LP) concentrations in the blood of rats chronically treated with cadmium. Results were compared to those obtained in control animals, as well as to those obtained in animals treated with olive oil. Compared to that of the control animals, the AsA concentration was significantly increased in rats treated with CoQ10 and olive oil, whereas vit E concentration was significantly increased in animals treated with cadmium, CoQ10, or cadmium + CoQ10. A significant decrease in LP concentration was noted in animals treated with cadmium or with cadmium + CoQ10, whereas a significant increase was seen in animals treated with olive oil. Compared to that of the animals treated with olive oil, the ascorbic acid concentration was significantly decreased in rats treated with cadmium or with cadmium + CoQ10, whereas vit E concentration was significantly increased in animals treated with cadmium,CoQ10, or cadmium + CoQ10. LP concentration was significantly decreased in rats treated with cadmium,CoQ10, or cadmium + CoQ10. Our study showed that CoQ10 administration in rats chronically exposed to exogenous cadmium exerts beneficial effects on the nonenzymatic components of the antioxidant defense system, such as AsA and vit E, resulting in a decreased concentration of LP in the blood.
Influence of Caffeine on Allyl Alcohol-Induced Hepatotoxicity in Rats* I. In Vivo Study
14
10.1615/JEnvironPatholToxicolOncol.v20.i2.90
Maria
Karas
Hopital du Sacre-Coeur de Montreal, 5400 Gouin Blvd.West Montreal,Quebec, H4J 1C5 Canada
Saroj K.
Chakrabarti
Departement de Medecine du Travail et Hygiene du Milieu, Faculte de Medecine, Universite de Montreal, Montreal,Quebec, Canada
Cotreatment of rats with a low hepatotoxic dose (30.7 mg/kg, ip) of allyl alcohol (AA) and a higher, but nontoxic, dose (150 mg/kg, oral) of caffeine (CF) potentiated the hepatotoxicity of AA. This was verified by significantly higher levels of plasma alanine aminotransferase (ALT) activity and histopathologically greater severity of lesions in the periportal hepatocytes than those due to AA alone. Treatment of rats with 4-methylpyrazole (4-MP) (0.5 mmol/kg, ip) (an inhibitor liver alcohol dehydrogenase) for 30 minutes, followed by similar cotreatment with AA and CF, completely prevented the elevation of plasma levels of ALT and histological damage induced by cotreatment with CF and AA 24 hours following their administration. Severe liver damage induced by cotreatment with CF and AA was further, markedly enhanced by phenobarbital pretreatment (80 mg/kg, ip, 3 days). Thus, extensive necrosis of periportal hepatocytes was noted, as well as edema and accumulation of inflammatory cells in the necrotic foci caused by such pretreatment. The depression of hepatic nonprotein sulfhydryls resulting from CF plus AA was much more severe than that caused by AA or CF alone and appeared as early as 30 minutes after administration. However, much less marked depletion of protein thiols was observed following similar treatments. Significant increase in lipid peroxidation (as measured by melondialdehyde [MDA] formation) was also observed in rat liver but only 24 hours after administration.The production of MDA in the rat liver was significantly higher after administration of AA plus CF than after administration of AA alone. Pretreatment of rats with phenobarbital further significantly enhanced the formation of 2,4-dinitrophenylhydrazine (DNP)-reactive metabolite(s) (measured as DNP-acrolein adduct equivalents) in rat liver induced by AA (30.7 mg/kg) plus CF (150 mg/kg) within 1 hour following such treatment. Cotreatment with AA and a higher dose of CF resulted in significantly higher excretion of urinary thioethers or mercapturic acids than in rats treated with AA alone. Thus, these data suggest that an increased bioactivation pathway of acrolein involving a P450 mixed-function oxidase system caused by CF may be involved in such potentiating effects of CF on AA-induced hepatotoxicity in rats.
Caffeine Potentiation of Allyl Alcohol-Induced Hepatotoxicity. II. In Vitro Study*
10
10.1615/JEnvironPatholToxicolOncol.v20.i2.100
Maria
Karas
Hopital du Sacre-Coeur de Montreal, 5400 Gouin Blvd.West Montreal,Quebec, H4J 1C5 Canada
Saroj K.
Chakrabarti
Departement de Medecine du Travail et Hygiene du Milieu, Faculte de Medecine, Universite de Montreal, Montreal,Quebec, Canada
We examined the effects of caffeine (C) on allyl alcohol (AA)- and acrolein (A)-induced hepatotoxicity on freshly-isolated, rat hepatocytes obtained from livers of adult, male, Sprague-Dawley rats. Isolated rat hepatocytes in suspension were incubated in each test with one of the following: 0, 1.0, or 2.5 mM of AA alone; or with 0, 2.5, or 5 mM of C alone; or a combination of AA and C at the same range of concentrations as used alone, for 15, 30, 60, 90, and 120 minutes at 37 °C.A dose- and time-dependent potentiation of cytotoxicity as measured by cellular viability (using trypan blue exclusion) were observed. The AA (2.5 mM)-induced lactate dehydrogenase (LDH) leakage observed after 60 minutes incubation was completely prevented when pretreated for 15 minutes with 4-methylpyrazole (MP) (0.5 mM). Such pretreatment, even with a double dose of 4-MP, only partially, and not significantly, prevented LDH leakage when the hepatocytes were incubated with a mixture of 2.5 mM AA and 5 mM C. The depletion of hepatocyte nonprotein sulfhydryl (NPSH) content caused by AA was further enhanced in the presence of C, as early as 15 minutes after their exposure. The AA-induced increase in lipid peroxidation was also potentiated by C; however, potentiation started later, and only after sufficient depletion of NPSH (mostly glutathione) occurred resulting from the presence of AA plus C. A significant loss of protein sulfhydryls in rat hepatocytes could be noted following a 60-minute incubation period with either AA (1 mM) or AA (1 mM) plus C (5 mM). Similarly, C produced a dose-and time-dependent potentiation of A-induced liver cytotoxicity, which was preceded by severe loss of NPSH content within 15 minutes of exposure, whereas the potentiation of lipid peroxidation (LPO) resulting from A plus C was found to be a relatively late event, as with AA plus C. Furthermore, combined treatment with AA and C produced a significantly higher cytotoxicity (as measured by cellular viability) than that due to the combined treatment with A plus C based on equimolar concentration. These results suggest that two increased bioactivation pathways of AA involving the P-450 mixed-function oxidase system resulting from C may be involved in the potentiation of AA hepatotoxicity.