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Biomedical subjects

M S Legator

Publications and source records attributed to M S Legator.

At least 73 records · Page 4Linked to original sources
PubMed1987

The correlation between DNA adducts and chromosomal aberrations in the target organ of benzidine exposed, partially-hepatectomized mice.

An experimental system was developed to test the association between benzidine--DNA adduct levels and chromosome aberrations in the target organ, the liver, of mice. A 2/3 partial hepatectomy was performed (0 h), then the animals were treated with benzidine (0, 7.8, 19.5, 38.2 or 97.8 mg/kg, i.p.) and an agar-coated 50 mg 5-bromodeoxyuridine tablet was implanted subcutaneously (58 h). Colcemid was given at 4 mg/kg i.p. (70 h), and the animals were sacrificed 2 h later. The liver from each animal was divided, with portions allocated for cytogenetics and DNA adduct analysis. DNA adducts were analyzed with the 32P-postlabeling technique. DNA adduct and chromosomal aberration data were available on a total of 43 animals. Benzidine was shown to be a potent clastogen in liver, the target organ, as opposed to its reported weak activity in the bone marrow. A linear dose response was demonstrated for benzidine--DNA adducts found in the liver. The correlation between adduct levels and aberrations in individual animals was 0.43 (P less than 0.05). However, most of the residual variance was due to four outlying cases. When these cases were removed from the data set and the analysis repeated, the linear correlation coefficient increased to 0.74. When the data were analyzed by dose groups, the correlation was 0.91. These data support the hypothesis that carcinogen-DNA adducts are responsible for the induction of chromosomal aberrations, and perhaps other genotoxic events, including neoplasia.

Animals↗
PubMed1986

Correlation between the induction of micronuclei in bone marrow by benzene exposure and the excretion of metabolites in urine of CD-1 mice.

Male and female CD-1 mice received single oral doses of benzene (220, 440, and 880 mg/kg) and were pretreated with modifiers of the mixed-function oxidase enzyme activities. Urinary metabolites (MT) (0-24 and 24-48 hr) were quantified by high-performance liquid chromatography. The micronucleus test was performed at 30 h. The following pretreatments were used to correlate micronucleus formation and the excreted benzene MT: 3-Methylcholanthrene and beta-naphthoflavone led to a marked increase in micronuclei (MN) and MT, whereas phenobarbital caused a slight increase, and SKF-525A had no effect. MN and MT were decreased when benzene was administered by the ip route or toluene was given simultaneously. Females had a lower number of MN and excreted more unconjugated phenol than did males. Muconic acid, hydroquinone, and phenol glucuronide and MN correlated well. They were dependent on both the dose and route of administration of benzene, being most inducible by P-448 inducers, in males more than females. The administration of hydroquinone induced MN, but phenol or catechol (200, 250, and 150 mg/kg, po, respectively) did not, and none of these compounds yielded trans, trans-muconic acid, a benzene MT in urine. This study establishes that benzene myeloclastogenicity is a function of its metabolism and that quantification of urinary metabolites could provide reliable correlates of this effect in vivo.

Animals↗
PubMed1985

Fluorometric assay using high-pressure liquid chromatography for the microsomal metabolism of certain substituted aliphatics to 1,N6-ethenoadenine-forming metabolites.

Monohaloacetaldehydes and monohalooxiranes are early oxidative metabolites of several carcinogenic haloaliphatics. Since monohaloacetaldehydes and supposedly monohalooxiranes react with adenines to form fluorescent 1,N6-ethenoadenines, it was hypothesized that in vitro metabolic systems that produce an ethenoadenine-forming metabolite could be assayed quantitatively by trapping the metabolite in situ with an adenine and identifying it by its characteristic retention and fluorescence during HPLC. Bromoacetaldehyde was chosen as a model haloacetaldehyde to develop an assay based on this concept for measurements in a microsomal system. The optimal trapping reaction requires a postmetabolic step involving acidification and heating. Cyclic AMP was found to be a suitable adenine for the trapping reaction under these conditions. The chromatographic analysis utilizes tetrabutylammonium phosphate and a nonsilica reversed-phase stationary phase (Hamilton PRP-1). The chromatography is isocratic and allows an analysis time of less than 5 min per sample. The titration of bromoacetaldehyde in a microsomal system is affected by typically studied metabolic conditions: incubation time, pH, and protein concentration. Using this assay, the following were found to be metabolized by rat liver microsomes to etheno-adenine-forming products: 1,2-dibromoethane, 1,2-dichloroethane, cyclophosphamide, vinyl chloride, and acrylonitrile. Chloroacetone and 1,3-dichloroacetone also are fluorochromogenic without metabolism but the latter apparently forms a positively charged, nonetheno adduct. The proposed assay should be useful for in vitro metabolic studies of 1,2-dihaloethanes and mustards and has potential application for similar studies of monohalogenated ethanes, ethanols, and ethenes. The positive results with acrylonitrile suggest also that many types of substituted aliphatics may be studied with this proposed assay.

Acetaldehyde↗
PubMed1985

Benzene myeloclastogenicity: a function of its metabolism.

Using the micronucleus test we have found no significant difference between germ-free and conventional (non-germ-free) male CD-1 mice gavaged twice with 440 or 880 mg benzene/kg. Hence, the higher myeloclastogenicity observed previously with the p.o. (4-6 times) than with the i.p. route of benzene administration was ruled out as being due to the involvement of gut flora in benzene biotransformation. Pretreatment of males with 3-methylcholanthrene or beta-naphthoflavone, inducers of P-448 monooxygenase, but not phenobarbital, an inducer of P-450, significantly enhanced the myeloclastogenic effect of a single oral dose of benzene (440 mg/kg). Single oral doses of phenol, catechol, or hydroquinone (250, 150, and 200 mg/kg, respectively) failed to reproduce the potent myeloclastogenic effect of benzene. In fact, only hydroquinone was mildly clastogenic. The relation between benzene's myeloclastogenicity and metabolism is discussed.

Animals↗
PubMed1985

Absence of mutagenicity in the urine of autopsy service workers exposed to formaldehyde: factors influencing mutagenicity testing of urine.

Hospital autopsy service workers and a matched control group were studied using a battery of genetic monitoring tests performed on samples of blood, semen and urine. The results of the analysis of urine for mutagens are described in this report. The participants in the study were matched with the controls for sex, age and their use of alcohol, tobacco and marijuana. Information was collected on general health, usage of medications and any exposure which might affect the outcome of the study. Individuals were sampled three times at approximately two month intervals. Time weighed average exposures to formaldehyde in the work areas were estimated at 0.61 to 1.32 ppm. Additionally, studies were carried out which examined various parameters affecting the testing of human urine samples for mutagenicity. No increase in mutagenicity was seen in the autopsy workers as compared to the control group. One individual who was receiving metronidazole and one control who smoked two packs of cigarettes per day had significantly mutagenic urine. A large proportion of the exposed individuals had toxic urine while only two of the control individuals had similar toxic urine. The material responsible for the toxicity has been isolated and purified but does not appear to be related to the formaldehyde exposure. Studies on the parameters affecting mutagenicity testing of urine with Salmonella typhimurium suggest that in the plate incorporation assay, TA100, but not TA98, can be affected by exogenous histidine. Furthermore, with the conditions employed in this study, 3 to 4% of labeled histidine added to urine samples was retained by the XAD-2 and subsequently eluted in the urine concentrate. Urinary histidine levels of unconcentrated samples ranged from 112 to 2614 nmol per ml (mean 994 nmol per ml) and the amount of histidine present correlated with the corresponding increases in histidine revertants with strain TA100.

Adult↗
PubMed1985

Ethylene dibromide: effects of paternal exposure on the neurotransmitter enzymes in the developing brain of F1 progeny.

The effects of ethylene dibromide (EDB) exposure to male rats on several neurotransmitter enzymes have been examined in various brain regions of the F1 progeny, from 7 to 90 days of age. The choline acetyltransferase activity was significantly increased at 21 days old, in most brain regions studied in the F1 progeny of the EDB-treated males, but not at 7, 14 or 90 days old. The acetylcholinesterase activity was altered in different brain regions of the F1 progeny of the EDB-exposed males at both 14 and 21 days old but not at 7 or 90 days old. Glutamic acid decarboxylase activity was increased in corpus striatum but decreased in frontal cortex only at 21 days of age. These neurochemical changes in the developing brain of F1 progeny of EDB-treated males at low doses may be associated with behavioral abnormalities observed early in their development.

Acetylcholinesterase↗
PubMed1985

Genetic monitoring of aluminum workers exposed to coal tar pitch volatiles.

A group of 50 workers exposed to coal tar pitch volatiles (CTPV) in an aluminum reduction plant and a group of 50 non-exposed workers were selected to evaluate the genotoxic effects of CTPV exposure. A battery of tests was performed on 3 different body fluids; urine, blood and semen. Urine samples were evaluated for mutagenic constituents using the Ames/Salmonella assay. Cultured lymphocytes from blood samples were used to perform cytogenetic analysis. Semen samples were used to measure sperm count, percent abnormal sperm morphology and frequency of sperm carrying double fluorescent bodies (2-F). 14 of 28 (50%) exposed workers and 7 of 36 (19.4%) non-exposed workers had mutagenic urine. This difference was significant (p less than 0.01). Among the non-smokers a significantly higher percentage of workers who were exposed had positive urine (36%) compared to the non-exposed workers (5%) (p less than 0.05). Among the exposed group, more mechanics had mutagenic urine than did other types of workers. Overall chromosome aberration rates were similar in both exposed and non-exposed workers. Among exposed workers a significant inverse correlation (p less than 0.05) between age and chromatid aberration rate was observed. Results of semen analysis failed to detect differences between exposed and non-exposed workers. Results of these tests lend support to a battery approach to genetic monitoring and suggest a link between exposure to CTPV and genotoxic effects. Detection of exposure to mutagens at an early time offers an opportunity for disease prevention by the reduction of exposure.

Adult↗
PubMed1985

trans,trans-Muconic acid, an open-chain urinary metabolite of benzene in mice. Quantification by high-pressure liquid chromatography.

A sensitive h.p.l.c. method is described which separated urinary metabolites from benzene-treated male CD-1 mice. Phenol, trans,trans-muconic acid and quinol in the 48 h urine accounted, respectively, for 12.8-22.8, 1.8-4.7 and 1.5-3.7% of the orally administered single dose of benzene (880, 440 and 220 mg/kg body wt.). Catechol occurred in trace amounts. Ascorbic acid was used to adjust urine pH and increase the extraction efficiency of metabolites, especially muconic acid. It allowed an accurate estimation of quinol by preventing its auto-oxidation. trans,trans-Muconic acid was identified and was unique to benzene as none was detected in urine of mice dosed orally with phenol, catechol or quinol (250, 150 and 200 mg/kg, respectively). The potential existence of a toxic benzene metabolite in the form of an aldehyde precursor of muconic acid in vivo is discussed.

Animals↗
PubMed1984

The influence of simple aromatics on benzene clastogenicity.

The micronucleus test was performed in male ICR Swiss mice following modification of benzene metabolism by co-administration of aniline, pyridine or naphthalene, or by prior injection of alpha-naphthoflavone. HPLC profiles of urinary metabolites were compared to the effects of these compounds on clastogenicity. Pyridine inhibited both benzene clastogenicity and its metabolism. Aniline and naphthalene increased the clastogenicity and slightly altered the metabolism of benzene. alpha-Naphthoflavone inhibited benzene clastogenicity and metabolism only at high doses. Since 3-methylcholanthrene and phenobarbital both increase the metabolism of benzene but only 3-methylcholanthrene increases benzene clastogenicity, specific P450 isozymes may be responsible for different biological effects of benzene, and alterations in these effects might be caused by a shift from one isozyme to another.

Aniline Compounds↗
PubMed1984

Sperm count, morphology and fluorescent body frequency in autopsy service workers exposed to formaldehyde.

A battery of monitoring tests that could indicate genetic damage was used to investigate occupational formaldehyde exposure in a population of a hospital autopsy service workers. 11 exposed individuals and 11 matched controls were evaluated for sperm count, abnormal sperm morphology and 2F-body frequency. Subjects were matched for sex, age and customary use of alcohol, tobacco and marijuana. Additional information was collected on health, medications and other exposures to toxins. 10 subjects were employed for 4.3 months (range 1-11 months) prior to the first sample and 1 was employed for several years. Formaldehyde exposures were episodic but with a time weighed average between 0.61 and 1.32 ppm (weekly exposure range 3-40 ppm X h). Exposed and control subjects were sampled 3 times at 2-3 month intervals. Sperm morphology was also evaluated in B6C3F1 mice after 5 daily oral doses of 100 mg/kg formalin. No increase in abnormal morphology was detected in the treated animals. In humans, no statistically significant differences were observed between the exposed and control groups for the observed variables. Reduced sperm count correlated with increased abnormal morphology and 2F-body frequency in the exposed group but not in the control group. Evaluation of the impact of incidental exposures suggests a reduced count with marijuana use and increased abnormal morphology with medications used by controls. No effects on sperm were seen from formaldehyde or its metabolites in this population after occupational exposure, nor in mice following a high acute exposure. It is possible that minor effects might have occurred. The lack of an effect in this study may be due to a lack of statistical power to detect effects at this exposure level.

Air Pollutants, Occupational↗
PubMed1984

Modifications in the myeloclastogenic effect of benzene in mice with toluene, phenobarbital, 3-methylcholanthrene, Aroclor 1254 and SKF-525A.

Benzene was studied in its target organ of effect, the bone marrow, with the micronucleus test and metaphase analysis. Male and female CD-1 mice were treated with 2 doses of benzene (440 mg/kg) or toluene (860 or 1720 mg/kg) or both 24 h apart, and sacrificed 30 h (or 54 h) after the first dose. Benzene-treated animals were pretreated with phenobarbital (PB), 3-methylcholanthrene (3-MCA), SKF-525A, or Aroclor 1254. Toluene showed no clastogenic activity and reduced the clastogenic effect of benzene when the mixture was given. None of the pretreatments protected against the clastogenic effect of benzene. 3-MCA pretreatment greatly promoted benzene myeloclastogenicity. Females were consistently more resistant to benzene than males. Dose-response curves in benzene-treated mice were much steeper with 3-MCA induction than without. Chromosomal damage was higher with p.o. than i.p. benzene administration.

Animals↗
PubMed1984

Effects of paternal ethylene dibromide exposure on F1 generation behavior in the rat.

The effects of ethylene dibromide (EDB) exposure to the male rat were studied through behavioral assessments of their F1 progeny. Exposed males were bred with untreated female rats at 4 or 9 weeks after 5 daily EDB treatments. Behavioral assessment of motor reflexes and motor coordination were examined up to 21 days of age. Significant differences in the development of motor coordination and motor activity were observed in the F1 progeny of EDB-exposed males. These results support the evidence of EDB genotoxicity and further demonstrates the utility of behavioral end-points of the offspring as a sensitive means of assessing paternal reproductive risk.

Animals↗