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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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