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Diethylnitrosamine, ethylnitrosourea, and dimethylbenz(a)anthracene DNA binding studies in the rainbow troutVan Winkle, Samina 11 August 1988 (has links)
Dimethylbenz (a) anthracene (EMBA), a carcinogen that requires
metabolic activation to produce active metabolites capable of
binding to DNA, has been studied in the trout and other fish.
Polycyclic aromatic hydrocarbons (PAH) are of importance as they
are ubiquitous in the environment and their carcinogenic effects
in fish from contaminated waters are an important indication of
the pollution risks to man. Since such pollution risk assessment
presents the involvement of multiple agents, the study of the
modulation of PAH-DNA binding produced by other agents is
important. In this study the effect, of dietary pretreatment at
500 ppm, 100 ppm and 2000 ppn, using BNF, Aroclor 1254, or
indole-3-carbinol (I3C) respectively on DMBA-DNA binding was
examined. To study the effect of age on sensitivity to DMBA-DNA
binding, adult trout and fry were used in two separate studies.
The fish were fed treatment diet for at least two weeks. Fry were then injected with [³H] DMBA, at 22.4 μCi/3.9 x 10⁻² μmole/fish and adult trout at 284 μCi/1.58 μmole/fish. Liver DNA
was isolated, purified and binding of radioactivity to DNA was
examined and computed as the covalent binding index (CBI). Mean
CBI for control dietary group vising adult trout was 1000 fold
lower than for fry. Statistical analysis of covalent binding
index for the treatment groups revealed that a statistically
significant (p < 0.05) inhibition in DNA-DMBA binding response
in adult trout and fry was produced fcy the DNF dietary treatment
only.
Diethylnitrosamine (DENA), a potent hepatocarcinogen in
several animal species belongs also to the class of compounds
that require metabolic activation. Dietary treatment and
continuous exposure of trout to the carcinogen in water, have
produced hepatocellular carcinctnas. The water exposure also
produced a dose related DNA ethylation of the O⁶ position of
guanine, believed to be the promutagenic adduct produced after
DENA exposure. This study examines two other routes of exposure
to DENA, in vitro hepatocyte incubations and i.p. injection.
Adult trout and fry were injected with [³H] DENA. Adult fish
received 3.3, 16.5, and 33 mg/kg DENA, and fry received 10, 50
and 100 mg/kg. Hepatocyte incubation was performed with doses up
to 220 μM [³H] DENA, or 1 mM unlabelled DENA. DNA from fish
livers and from hepatocyte pellets was isolated, purified and
examined for radioactive binding of the DENA metabolites or in
the case of the unlabelled DENA, was analyzed for O⁶ and N7
adduct using an HPIC technique with fluorescence detection. O⁶-EtG adduct after DENA exposure, in DNA of hepatocytes obtained
from trout pretreated with beta-naphthoflavone (BNF, a known
inducer of cytodhrcme P-450 dependent enzyme activities involved
in the activation of xenobiotics) was below the limits of
detection of the HPDC-fluorescenoe detection procedure used. To
examine further if the lack of DNA binding and absence of the
O⁶-EtG adduct was due to rapid repair, the persistence of O⁶-EtG
after exposure to 40 nM ethylnitrosourea (ENU, a direct
ethylating agent) was studied in hepatocytes at 2, 4, and 5
hours after treatment. The activity of the alkyltransferase
protein involved in the repair of alkylguanines also was
determined using liver extracts from adult rainbow trout. The
studies did not reveal a significantly high rate of repair. It
is concluded that i.p. injection and in vitro hepatocyte
incubations are not a good method for studying the kinetics of
activation and DNA binding of DENA in the rainbow trout. The
i.p. route may lead to substantial loss of the dose of the
carcinogen administered and hepatocyte incubations are limited
by the toxic effects of increasing carcinogen concentration. The
reasons mentioned above, coupled with low levels of metabolism
of nitrosamines in trout results in the inability to detect and
study the appearance, persistence and repair of the O⁶-EtG
adduct. / Graduation date: 1989
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Molecular and cellular mechanisms of aromatic hydrocarbon axonopathyKim, Min Sun 28 November 2001 (has links)
Hydrocarbon solvents are widely used in the production of paints,
adhesives, dyes, polymers, plastics, textiles, printing inks, agricultural products and
pharmaceuticals. While the neuropathic potential of aliphatic solvents was shown
in the 1970s, little is known about the neuropathic potential of aromatic solvents.
The present study examines such solvents, 1,2-diethylbenzene (DEB) and
its metabolite 1,2-diacetylbenzene (DAB), to determine (a) the neuropathological
evidence for peripheral neuropathy in rodents treated with 1,2-DAB, (b) the
neurochemical basis for the neurotoxic properties of this compound, and (c) the
structural requirements for nerve fiber damage. The properties of 1,2-DAB and 2,5-
hexanedione (HD) are also compared.
A key finding of this thesis is that 1,2-DAB induces a 2,5-HD-like pattern
of nerve damage of motor and sensory axons with focal swellings containing
neurofilaments. Whereas nerve damage begins distally in 2,5-HD intoxication,
with 1,2-DAB treatment axonal swellings begin intraspinally and in the proximal
ventral roots of motor nerve fibers.
A second key finding is the reactivity of 1,2-DAB with amino acids,
notably lysine, a property that is shared with 2,5-HD. 1,2-DAB and 2,5-HD react
with amino acids and proteins to form blue and yellow chromophores, respectively.
Relative to 2,5-HD, 1,2-DAB is three orders of magnitude more reactive in forming
high-molecular-weight species.
1,2-DAB treatment of spinal cord slices in vitro and intact sciatic nerve
in vivo showed that neurofilament proteins react more readily than beta-tubulin.
The heavy and medium subunits of neurofilament protein were more reactive than
the light subunit. The reactivity of these four axonal proteins was in proportion to
their lysine content. These data are consistent with selective accumulation of
neurofilaments in giant axonal swellings.
In summary, these studies have shown a relationship between the
chromogenic and neuropathic properties of two gamma-diketones, one aliphatic
(2,5-HD) the other aromatic (1,2-DAB). These studies are relevant to occupational
and public health for at least two reasons. First, urinary chromogens generated by
neuropathic aliphatic and aromatic hydrocarbons could serve as biological markers
of exposure to solvents with neuropathic potential, and second, other chromogenic
solvents (such as tetralin) should be considered for neuropathic potential. / Graduation date: 2002
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Adaptive Advantages of Carotenoid Pigments in Alpine and Subalpine Copepod Responses to Polycyclic Aromatic Hydrocarbon Induced PhototoxicityKovach, Matthew James 05 1900 (has links)
Alpine zooplankton are exposed to a variety of stressors in their natural environment including ultraviolet radiation. Physiological coping mechanisms such as the accumulation of photoprotective compounds provide these zooplankton protection from many of these stressors. Elevated levels of carotenoid compounds such as astaxanthin have been shown to help zooplankton survive longer when exposed to ultraviolet radiation presumably due to the strong antioxidant properties of carotenoid compounds. This antioxidant capacity is important because it may ameliorate natural and anthropogenic stressor-induced oxidative stress. While previous researchers have shown carotenoid compounds impart increased resistance to ultraviolet radiation in populations of zooplankton, little work has focused on the toxicological implications of PAH induced phototoxicity on zooplankton containing high levels of carotenoid compounds. This thesis discusses research studying the role that carotenoid compounds play in reducing PAH induced phototoxicity. By sampling different lakes at elevations ranging from 9,500' to 12,700' in the front range of the Colorado Rocky Mountains, copepod populations containing different levels of carotenoid compounds were obtained. These populations were then challenged with fluoranthene and ultraviolet radiation. Results discussed include differences in survival and levels of lipid peroxidation among populations exhibiting different levels of carotenoid compounds, and the toxicological and ecological implications of these results.
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Effects of Deepwater Horizon Crude Oil on Visual Function in Teleost FishesMagnuson, Jason T 08 1900 (has links)
The Deepwater Horizon oil spill released millions of barrels of oil into the Gulf of Mexico, impacting economically and ecologically important fishes. Polycyclic aromatic hydrocarbons (PAHs) present in the oil have been shown to cause developmental impairments in early life stage fishes, such as morphological and behavioral changes related to eye formation and visual processing following PAH exposure. Prior research reported reduced eye growth in open water, pelagic species, as well as reduced photoreceptor-specific transcription factors associated with eye development following exposure to crude oil. Though changes in transcriptomic-level pathways associated with vision and visual processing have been reported, it has yet to be determined how these changes relate to physiological or behavioral-level effects in fish. Therefore, the present studies evaluated the effect of weathered crude oil on eye development and visual function in mahi-mahi, red drum, sheepshead minnow, and zebrafish larvae. Fish were assessed through several visually-mediated behavioral assays, analyzed histologically and immunohistologically, along with subsequent transcriptomic analyses and associated gene expression changes. Larvae exposed to crude oil experienced significantly reduced abilities to exhibit optomotor or optokinetic responses relative to controls, with associated reductions in retinal development. Furthermore, genes associated with eye development and phototransduction were downregulated, with subsequent decreases in the immunofluorescence of neurological connections within the retina and a choroid-specific increase in apoptotic activity. We related oil-induced transcriptomic-level effects to morphological, physiological, and behavioral-level impairments in larval teleost fishes.
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