Publications

 Dieguez-Acuna FJ., Ellis ME., Kushleika J., Woods JS* (Department of Environmental Health, University of Washington, 4225 Roosevelt Way NE, Suite 100, Seattle, WA 98105, USA): Mercuric ion attenuates nuclear factor-kB activation and DNA binding in normal rat kidney epithelial cells: implications for mercury-induced nephrotoxicity. Toxicol Appl Pharmacol, 173(3), 2001, 176-187. [60 Ref]

Mercuric ion (Hg2+), one of strongest thiol-binding agents known, mediates the toxicity associated with elemental, inorganic, and organic mercurial compounds. Studies of cellular events associated with Hg2+ toxicity have focused largely on disruption of cell membranes and impairment of mitochondrial functions. In contrast, few studies have sought to define the specific molecular mechanisms through which Hg2+ might affect toxicity via alteration of thiol-dependent signal transduction pathways that regulate cell proliferation and survival. Of particular interest in this regard is the effect of Hg2+ on nuclear factor-kB (NF-kB), a pleiotropic transcriptional factor that is known to reqire reduced cysteine moieteis at critical steps of activation and DNA binding. Here, we evaluated the effects of Hg2+ on the expression of NF-kB in normal rat kidney epithelial (NRK52E) cells, a principal target of Hg2+ toxicity. The lipopolysaccharide (LPS)-inducible form of NF-kB was readily detected in kidney cells and has been characterized as the p50p65 heterodimer. NF-kB-DNA binding was prevented in a dose-related manner by Hg2+ (0-55 uM) in vitro when added to DNA binding reactions containing the nonthiol reducing agent Trist (2-carboxyethyl) phosphine hydrochloride (TCEP). Similarly, Hg2+ at the same concentrations prevented DNA binding of a human recombinant wild-type p50p50 homodimer in binding reactions, and this effect was attenuated using a mutant form of the p50 protein containing a cys62 ser 62 mutation. The inhibition of p50-DNA binding by Hg2+ was reversible in a dose-related manner in vitro by competitive thiols DTT, GSH, and L-cysteine in binding reactins. In contrast, competitive thiols added to nuclear binding reactions were unable to reverse attenuation of LPS-mediated NF-kB-DNA binding affinity when cells were pretreated in vivo with Hg2+ at concentrations as low as 2 uM prior to LPS administration. Immunoblot analyses indicated that Hg2+ pretreatment of kidney cells substantially diminished, in a dose-related manner, the concentration of p65 translocated into the nucles following LPS administration. Additionally, Hg2+ pretreatment impaired both the phosphorylation and degradation of IkBa, suggesting a specific effect on NF-kB activation at the level of IkBa proteolysis. Finally, Hg2+ at concentrations as low as 5 uM significantly diminished NF-kB-mediated transcriptional activity when administered to kidney cells transiently transfected with an NF-kB-driven luciferase reporter gene (pLuc-4xNF-kB) prior to LPS treatment. These findings demonstrate that Hg2+, at low cellular concentrations, attenuates NF-kB activation at sites associated with IkBa phosphorylation and degradation, nuclear translocation of the p50p65 heterodimer, and association of p50-cys62 with the DNA kB binding site. Attenuation of NF-kB activation by Hg2+ through these mechanisms may underlie apoptotic or other cytoxic responses that are known to be associated with low level Hg2+ exposure in kindney epithelial cells.


Magos L (TNO BIBRA International Ltd. Woodmansterne Rd, Carshalton, Surrey SM5 4DS, UK): Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products. J Appl Toxicol, 21(1), 2001, 1-5.

The interest in ethylmercury has been raised lately by a letter sent to The Lancet suggesting that ethyl-mercurythiosalicylate preservative (product names: Thimerosal, Thiomersal, Merthiolate) in hepatitis B immunoglobulin (HBIG) caused severe ethylmercury intoxication. Most likely as a reverberation of this letter, the Public Health Service, US Department of Health and Human Services and the American Academy of Pediatrics published a joint statement on thimerosal in vaccines. As the nature of this statement has not required documentation on the toxicity of ethylmercury and the authors of the letter sent to The Lancet made the diagnosis without the prudent evaluation of published data, this survey attempts to fill up the gap. It is not concerned with contact allergy or with acrudynia (Pink disease). The only reported case of acrodynia was the result of regular injection of gamma-globulin was the result of regular injection of gamm-globulin with ethylmercury preservative to a 20-year-old man who had a history of chronic skin rash and sensitivity to sulfonamide drugs.


Raizada RB., Srivastava MK., Kausal RA., Singh RP., Gupta KP (Pesticide Toxicology Laboratory, Industrial Toxicology Research Centre, PO Box 80, M.G. Marg, Lucknow 226001, India): Subcronic oral toxicity of a combination of insecticide (HCH) and herbicide (ISP) in male rats. J Appl Toxicol, 21(1), 2001, 75-79. [29 Ref]

Rats were treated orally with technical hexachlorocyclohexane (HCH, 12.5, 25 and 50 mg/kg/day) and technical isoproturon (ISP 22.5 45 and 90 mg/kg/day) daily for a period of 90 days alone and in combination. Treatment with HCH alone showed mild to severe toxicity and death. Significantl changes occurred in liver weight, clinical enzyme profiles, haematological parameters and pathomorphological changes. Treatment with ISP alone did not produce such changes. The combination of HCH and ISP produced changes not suggestive of synergism.


Aoki Y., Sato H., Nishimura N., Takahashi S., Itoh K., Yamamoto M (Environmental Health Sciences Division, National Institute for Environmental Studies, Onogawa, Tsukuba 305-0053, Japan): Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust. Toxicol Appl Pharmacol, 173(3), 2001, 154-160. [45 Ref]

Diesel exhaust (DE) has been recognized as a noxious mutagen and/or carcinogen, because its components can form DNA adducts. Machanisms governing the susceptibility to DE and the efficiency of such DNA adduct formation require clarification. The transcription factor Nrf2 is essential for inducible and/or constitutive expression of a group of detoxificatin and antioxidant enzymes, and we hypothesized that the nrf2 gene knockout mouse might serve as an excellent model system for analyzing DE toxicity. To address this hypothesis, lungs from nrf2(-/-)and nrf2(+/-) mice were examined for the production of xenobiotic DNA adducts after exposure to DE(3 mg/m3 suspended particulate matter) for 4 weeks. Whereas the relative adduct levels (RAL) were significantly increased in the lungs of both nrf2(+/-) and nrf2(-/-) mice upon exposure to DE, the increase of RAL in the lungs from nrf2(-/-) mice exposed to DE were approximately 2.3-fold higher than that of nrf2(+/-) mice exposed to DE. In contrast, cytochrome P4501A1 mRNA levels in the nrf2(-/-) mouse lungs were similar to those in the nrf2(+/-) mouse lungs even after exposure to DE, suggesting that suppressed activity of phase II drug-metabolizing enzymes is important in giving rise to the increased level of DNA adducts in the Nrf2-null mutant mouse subjected to DE. Importantly, severe hyper plasia and accumulation of the oxidative DNA adduct 8-hydroxydeoxyguanosine were observed in the bronchial epidermis of nrf2(-/-) mice following DE exposure. These results demonstrate the increased susceptibility of the nrf2 germ line mutant mouse to DE exposure and indicate the nrf2 gene knockout mouse may represent a valuable model for the assessment of respiratory DE toxicity.


Hesterberg TW., Hart GA (Johns Manville Corporation, P.O. Box 625005, Littleton, CO 80162-5005, USA): Synthetic Vitreous Fibers: A review of toxicology research and its impact on hazard classification. Crit Rev Toxicol, 31(1), 2001, 1-53. [113 Ref]

Because the inhalation of asbestos, naturally, occurring inorgnic fibrous materials, is associated with lung fibrosis and thoracic cancers, concerns have been raised about the possible health effects of synthetic vitreous fibers (SVFs). SVFs include a very broad variety of inorganic fibrous materials with an amorphous molecular structure. Traditionally, SVFs have been divided into three subcatagories based on composition: fiberglass, mineral wool (rock, stone, and slag wools), and refractory ceramic fiber. For more than 50 years, the toxicologic potential of SVFs has been researched extensively using human epidemiology and a variety of laboratory studies. Here we review the research and its impact on hazard classification and regulation of SVFs. Large, ongoing epidemilogy studies of SVF manufacturing workers have provided very little evidence of harmful effects in humans. Several decades of research using rodents exposed by inhalation have confirmed that SVF pulmonary effects are determined by the "Three D's", fibre dose (lung), demention, and durability. Lung dose over time is determined by fiber deposition and biopersistence in the lung. Deposition is inversely related to fiber diameter. Biopersistence is directly related to fiber length and inversely related to fiber dissolution and fragmentation rates. Inhlaled short fibers are cleared from the lung relatively quickly by mobile phagocytic cells, but long fibers persist until they dissolve or fragment. In contrast to asbestos, most of the SVFs tested in rodent inhalation studies cleared rapidly from the lung (were nonbiopersistent) and were innocuous. However, several relatively biopersistent SVFs induced chronic inflammation, lung scarring (fibrosis), and thoracic neoplasms. Thus, biopersistence of fibers is now generally recognized as key determinant of the toxicologic potential of SVFs. In vitro dissolution of fibers in simulated extracellular fluid correlates fairly well with fiber biopersistence in the lung and pulmonary toxicity, but several exceptions suggest that biopersistence involves more than dissolution rate.


Rasmussen EB., Newland MC* (Department of Psychology, 228 Tach Hall, Auburn University, Auburn, Al 36830, USA): Developmental exposure to methylmercury alters behavioral sensitivity to d-amphetamine and pentobarbital in adult rats. Neurotoxicol Teratol, 23(1), 2001, 45-55. [39 Ref]

Female rats were exposed to 0,0.5, or 6.4 ppm methylmercury in their drinking water before mating, and throughout gestation and lactation. When the female offspring were 4-6 months old, they were trained to respond under a multiple differential reinforcement of high rate (DRH) 9:4-Extinction schedule of reinforcement. No differences among exposure groups were apparent in steady-state behavior. Drug challenges were conducted with multiple doses of d-amphetamine, scopolamine, pentobarbital, haloperidol, and dizocilpine, drugs selected for their different pharmacological effects. The ED50 values for amphetamine's reinformcement rate-reducing effects for the control, 0.5 and 6.4-ppm groups were 3.1, 1.9 and 0.9 mg amphetamine/kg body weight, respectively, demonstrating an increased sensitivity to d-amphetamine in methylmercury-exposed rats. Rats in the 6.4 ppm group also demonstrated a relative insensivity to pentobarbital. Further, these exposed rats exhibited an inverted U-shaped dose-effect curve under the pentobarbital dose-effect determination, while controls showed only a declining curve. Exposed rats did not respond differentially to haloperidol, scopolamine, or dizocilpine, suggesting specificity. The present data suggest an involvement of catecholaminergic and GABAergic activity in methylmercury's neurotoxicity.



Narotsky MG., Best DS., Guidici DL., Cooper RL (Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory US Environmental Protection Agency, Research Triangle Park NC27711, USA): Strain comparisons of atrazine-induced pregnancy loss in the rat. Rep Toxicol, 15(1), 2001, 61-69. [40 Ref]

Atrazine was administered by gavage, in 1% methylcellulose, to F344 Sprague-Dawley (SD), and Long Evans (LE) rat at 0, 25, 50, or 200 mg/kg/day on gestation days 6 through 10. The dams were allowed to deliver and litters were examined postnatally. The F344 was the most sensitive to atrazine's effects on pregnancy, showing full-litter resorption (FLR) at >= mg/kg. In surviving F344 litters prenatal loss was increased at 200 mg/kg. In SD and LE rats, FLR occurred only at 200 mg/kg. Delayed parturition was seen at >= 100 mg/kg in F344 and SD rats. Regarding maternal toxicity, the SD dams were the most sensitive, with weight loss at >= 25 mg/kg. When 200 mg/kg was administered to F344 rats on days 11 through 15 (after the LH-dependent period of pregnancy), no FLR was seen. These find suggest that atrazine-induced FLR is maternally mediated, and consistent with loss of LH support of the corpora lutea.



Kurinczuk JJ., Clarke M (Department of Epidemiology and Public Health, University of Leicester, 22-8 Princess Road West, Leicester LE1 6TP, UK): Case-control study of leatherwork and male infertility. Occup Environ Med, 58(4), 2001, 217-224. [44 Ref]

To test the hypothesis that leatherwork is associated with male infertility mediated through the development of oligozoospermia. The basis of any association was postulated, at the outset, to be with exposure to the solvents used in leatherwork. There was little evidence to support the hypothesis that leatherwork is associated with an increased risk of presenting with infertility or oligozoospermia. There was limited evidence that leatherwork is a risk factor for teratozoospermia. Workers with solvents were at an increased risk of presenting with infertility, although this was not mediated through effects on standards measures of semen quality; this finding merits further investigation.


Vartia MA (Finnish Institute of Occupational Health, Department of Pychology, Laajaniityntie 1, FIN-01620 Vantaa, Finland): Consequences of workplace bullying with respect to the well-being of its targets and the observers of bullying. Scand J Work Environ Hlth, 27(1), 2001, 63-69. [27 Ref]

This study investigated the effects of workplace bullying and the psychological work environment on the well-bing and subjective stress of the targets and observers of bullying. In a questionnaire study, stress and psychological ill-health were measured, and the causes of reported stress were analyzed for municipal employees (N=949, 85% women, 15% men mean age 41 years for the men and 40 years for the women). Both the tergets of bullying and the observed reported more ganeral stress and mental stress reactions than did respodents from the workplace with no bullying. The targets also expressed feeling of low self confidence more often than did those who had not been subjected to bullying. Being bullied, but also features of one's work, especially haste, excessively difficult tasks and poor goal clarity, predicted the stress reactions reported. Of the single forms of bullying, judging a person's work unjustly or in an offending manner, restricting a person's possibilities to express his or her opinions, and assaulting one's private life were the most clearly connected with all the stress reactions measured, Victim history was assocaited with feelings of low selfconfidence. The target of bullying used sleep-inducing drugs and sedative more often than did the respondents who were not bullied. The study shows that not only the targets of bullying, but also bystanders, suffer when someone is bullied in the workplace. Bullying must therefore be regarded as a problem for the entire work until and not merely as a problem of the target.



Hassan MQ., Hadi RA., Al-Rawi ZS., Padron VA., Stohs SJ* (School of Pharmacy and Allied Health Profession, Creighton University, Omaha, Nebraska, USA):The glutathione defense system in the pathogenesis of rheumatoid arthritis. J Appl Toxicol, 21(1), 2001, 69-73. [34 Ref]

In order to assess a possible role of the natural glutathione defense system in the pathogenesis of rheumatoid arthritis (RA). serum reduced glutathione levels (GSH), glutathione reductase (GSR), glutathione S-transferase (GST), glutathione peroxidase (GSH-Px) and alkaline phosphatase (ALP) activities, lipid peroxidation (MDA content) and indexes of inflammation were evaluated in58 rheumatic patients. Rheumatoid athritis was associated with significant depletion (ca. 50 percent) in GSH levels compared with normal control subjects. Serum levels of the detoxifying enzymes GSR and GSH-Px decreased by ca. 50% and 45 percent, respectively, whereas a threefold increase in the activity of GST was observed. A 1.2-fold increase in ALP was observed in patients with RA. These effects were accompanied by a 3.1-fold increase in serum MDA content. The MdA content was higher in RA patients who were seropositive for rheumatoid factor as well as positive for C-reactive proteins. The erythrocyte sedimentation rate for all patients with RA was approximately 13.8-fold higher than for the control group, and was higher among RA patients with RA receiving gold therapy exhibited significantly lower MDA levels whereas all other factors that were measured were not effected. The results support a hypothesis that defense mechanisms against reactive oxygen species are impaired in RA.
 

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