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Biomedical subjects

J S Bus

Publications and source records attributed to J S Bus.

At least 37 records · Page 2Linked to original sources
PubMed1986

Inhibition of methyl chloride toxicity in male F-344 rats by the anti-inflammatory agent BW755C.

This study examined the effectiveness of the cyclooxygenase/lipoxygenase inhibitor 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW755C) in preventing the toxicity induced in male F-344 rats by methyl chloride (MeCl). BW755C (10 mg/kg ip, 1 hr pre and postexposure) prevented both lethality (0/6 vs 8/12 in controls) and epididymal granuloma formation (0/6 vs 4/4 in controls) in rats exposed to 7500 ppm MeCl 6 hr/day for 2 days. Additional rats (n = 5 per group) were exposed to 5000 ppm MeCl 6 hr/day for 5 days, with and without BW755C treatment as described above. The rats were killed on Day 5 and tissues processed for light microscopic examination. MeCl-exposed rats showed hepatocellular cloudy swelling, degeneration of renal proximal convoluted tubules, vacuolar degeneration in the adrenal cortex, necrosis of the internal granular layer of the cerebellum, and degenerative changes in the testis and epididymis, including formation of epididymal sperm granulomas. With the exception of the adrenal, tissues examined in rats of the MeCl/BW755C treatment group showed virtually no histologic evidence of lesions. BW755C did not significantly alter metabolism of [14C]MeCl to 14CO2 or 14C in urine, nor did it affect the distribution to various organs of radioactivity derived from [14C]MeCl. Therefore, BW755C protection against MeCl toxicity did not appear to result from altered MeCl metabolism or disposition. Instead, the protection was apparently related to the pharmacologic activity of BW755C as an inhibitor of leukotriene and prostaglandin synthesis.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Inhibition of the acute toxicity of methyl chloride in male B6C3F1 mice by glutathione depletion.

Previous data have demonstrated that methyl chloride (MeCl) is toxic to B6C3F1 mice under both acute and chronic exposure conditions, and that conjugation of MeCl with glutathione (GSH) is a key step in the metabolism of MeCl. This study examined the role of GSH in mediating the acute toxicity of MeCl to liver, kidney, and brain of male B6C3F1 mice. The lethal effects of a single 6-hr inhalation exposure of B6C3F1 males to 2500 ppm MeCl were completely prevented by pretreatment with the GSH synthesis inhibitor, L-buthionine-S,R-sulfoximine (4 mmol L-BSO/kg, ip 1.5 hr prior to MeCl exposure). GSH levels (measured as nonprotein sulfhydryl) in liver and kidney were depleted to 19 and 25% of control values, respectively, at the start of the exposure; the ratio of dead/exposed mice during the 18-hr postexposure declined from 14/15 mice to 0/10. Also, the LC50 for MeCl increased from 2200 to 3200 ppm in male mice pretreated with BSO. The hepatic toxicity of MeCl was detected by increased alanine aminotransferase (ALT) activities in serum 18 hr after a 6-hr exposure to 1500 ppm MeCl (2147 +/- 1327 IU/liter vs 46 +/- 6 in controls). Liver toxicity was inhibited when B6C3F1 males were depleted of GSH prior to MeCl exposure by BSO pretreatment (43 +/- 2), fasting (100 +/- 47), or injection of diethyl maleate (42 +/- 16). The effects of GSH depletion on MeCl toxicity to brain and kidney were determined in B6C3F1 males exposed to 1500 ppm MeCl 6 hr/day, 5 days/week for 2 weeks, with and without daily pretreatment with 2 mmol L-BSO/kg. This dose of BSO depleted hepatic and renal GSH by 28 and 60%, respectively, at the start of MeCl exposure. BSO-pretreated mice were protected from the central nervous system toxicity of MeCl, as assessed by microscopic examination of the granule cell layer of the cerebellum. BSO pretreatment also inhibited the renal toxicity of MeCl as measured by incorporation of [3H]thymidine ([3H]TdR) into renal DNA, an indicator of cell regeneration after cortical necrosis. [3H]TdR incorporation was 105 +/- 10,337 +/- 40, and 60 +/- 15 dpm/microgram DNA in nonexposed controls, MeCl, and MeCl + BSO treatment groups, respectively. These results indicate that GSH is an important component in the toxicity of MeCl to multiple organ systems in B6C3F1 mice. Reaction of MeCl with GSH appears to constitute a mechanism of toxication, contrary to the role usually proposed for GSH in detoxifying xenobiotics.

Animals↗
PubMed1986

Failure of fertilization as a cause of preimplantation loss induced by methyl chloride in Fischer 344 rats.

Methyl chloride (MeCl) is a testicular and epididymal toxicant in the Fischer 344 rat that induces significant decreases in sperm quality in males and significant increases in preimplantation embryonic loss in females mated to exposed males. This study examined the possibility that these losses are due to failure of fertilization and not to preimplantation embryonic death. Groups of males either were exposed to 1000 or 3000 ppm MeCl 6 hr/day for 5 days or received a single ip injection of 0.2 mg/kg triethylenemelamine (TEM) on Day 5 and were bred to two females weekly for up to 8 weeks. Females were killed 12 hr postmating; embryos and ova were isolated and scored as fertilized or unfertilized. Nearly 90% (602/683) of the normal ova recovered from females bred to control males were fertilized, and fertilization rates in the 1000-ppm MeCl and TEM groups were not significantly depressed from that level. The percentage of fertilized ova in the 3000-ppm MeCl group was significantly decreased, ranging from 3 to 72% over the 8 weeks. The frequency of unfertilized ova in this group always equaled or exceeded the frequency of preimplantation loss recorded in an earlier dominant lethal assay. In contrast, only a fraction of the preimplantation losses caused by the genotoxicant TEM could be accounted for by failure of fertilization. After culture of fertilized ova for 24 hr, only the TEM group exhibited a significant decrease in the number of fertilized ova which cleaved (85 vs 96% in the control). We conclude that the preimplantation loss caused by MeCl exposure is due to failure of fertilization and not to a genotoxic effect of MeCl. The methods used here permit a more accurate assessment of the reproductive toxicity of a chemical by discriminating between its cytotoxic and genotoxic effects.

Animals↗
PubMed1986

Role of epididymal inflammation in the induction of dominant lethal mutations in Fischer 344 rat sperm by methyl chloride.

This study assessed the possible relationship between methyl chloride (MeCl)-induced epididymal inflammation and the formation of dominant lethal mutations in sperm of Fischer 344 rats. Groups of 40 males were exposed to MeCl (3000 ppm 6 hr/day for 5 days), with or without concurrent treatment with the anti-inflammatory agent 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C; 10 mg/kg, i.p. 1 hr pre- and postexposure); BW 755C was shown previously to inhibit MeCl-induced epididymal inflammation. Control groups (n = 20) were either untreated, injected as described above with BW 755C, or injected on the afternoon of day 5 with triethylenemelamine (0.2 mg/kg), a known dominant lethal mutagen. Each male was caged with one female weekly for 3 weeks; 12-18 days after mating, females were killed to assess dominant lethal parameters. In females bred to MeCl-exposed males, significant increases were observed in postimplantation loss at postexposure week 1 (0.84 dead implants per female vs. 0.29 in untreated controls) and in dead implants/total implants at both week 1 (0.10 vs. 0.04 control) and week 2 (0.24 vs. 0.06 control). These increases were not observed in females bred to males treated with BW 755C during MeCl exposure. Coadministration of BW 755C to males along with MeCl also reduced the percentage of mated females with two or more postimplantation losses from 31% to 8% (week 1) and 30% to 12% (week 2). Therefore, the dominant lethal mutations induced by MeCl appear to be a consequence of its induction of inflammation in the epididymis. These data demonstrate the potential genotoxicity of inflammatory processes in vivo.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

Reproductive effects of inhaled methyl chloride in the male Fischer 344 rat. I. Mating performance and dominant lethal assay.

Methyl chloride (MeCl) is a direct-acting mutagen in bacteria, induces renal adenocarcinomas in male mice, and is a potent reproductive toxicant in the male Fischer 344 (F-344) rat. A dominant lethal assay was performed to examine the possibility that MeCl may be a germ cell mutagen in the F-344 male rat. Groups of 40 rats each were exposed to 0, 1000, or 3000 ppm MeCl 6 hr/day for 5 consecutive days, or received a single ip injection of 0.2 mg triethylenemelamine (TEM)/kg as a positive control. Each male was bred to a single female weekly for 8 weeks, and the standard criteria of dominant lethal tests were recorded. Exposure to 1000 ppm MeCl caused no consistent change in any parameter relative to control values. TEM caused increases in pre- and postimplantation loss indices in Weeks 1 to 5 postexposure, corresponding to sperm exposed in the epididymis and as early to late stage spermatids in the testis. Exposure to 3000 ppm MeCl caused a slight increase in postimplantation loss at Week 1 postexposure only, i.e., in sperm exposed in the epididymis or vas deferens, and increases in preimplantation loss throughout the 8 weeks postexposure. Fertility of the 3000 ppm MeCl-exposed males was significantly decreased by Week 2 after exposure, and never recovered to control values during the period of observation. It is suggested that the increased preimplantation losses are due, at least in part, to cytotoxic rather than genotoxic effects. High concentrations of inhaled MeCl, however, do induce dominant lethal mutations (reflected as an increased level of postimplantation fetal deaths) in sperm located within the vas deferens and epididymis at the time of exposure.

Animals↗
PubMed1985

Reproductive effects of inhaled methyl chloride in the male Fischer 344 rat. II. Spermatogonial toxicity and sperm quality.

Studies were performed to assess the effects of inhaled methyl chloride (MeCl) on sperm quality and testicular histopathology in the Fischer 344 rat. Adult male F-344 rats were exposed to 1000 or 3000 ppm MeCl 6 hr/day for 5 days, or received an ip injection of 0.2 mg triethylenemelamine (TEM)/kg on the afternoon of Day 5. Five males from a control group and each of the three treatment groups were killed weekly for 8 weeks, and five more from the control and 3000 ppm groups at Week 16 postexposure. Male rats from the 1000 ppm MeCl- and TEM-exposed groups exhibited no consistent difference from control males in any parameter measured. In the 3000 ppm MeCl group, over 50% of the males had uni- or bilateral sperm granulomas in the cauda epididymis. Testes weights were significantly depressed in these males by 3 weeks postexposure, and remained depressed as late as 8 weeks after treatment. Testicular spermatid head counts were significantly lower by 2 weeks postexposure, and the testes showed a characteristic cytotoxic response to MeCl exposure, including a delay in spermiation, chromatin margination in round spermatids, epithelial vacuolation, luminal exfoliation of spermatogenic cells, and multinucleated giant cells. Counts of repopulating seminiferous tubule cross sections and of testicular sperm heads at 7 weeks postexposure indicated that 60 to 70% of the spermatogonial stem cells had been killed by MeCl exposure. Sperm isolated from the vasa deferentia had significantly depressed numbers and an elevated frequency of abnormal sperm head morphology by Week 1 postexposure, and significantly depressed sperm motility and an elevated frequency of headless tails by Week 3 postexposure. All parameters measured in the testes and in vasa deferentia sperm showed varying degrees of recovery, and all were near the normal range by Week 16 postexposure except sperm count. These data suggest that the previously reported high preimplantation loss caused by methyl chloride exposure may be primarily due to cytotoxic effects on the testis and epididymal epithelium, rather than to direct genotoxic effects on the sperm.

Animals↗
PubMed1985

The morphology of carbon disulfide neurotoxicity.

The morphology of carbon disulfide induced peripheral neuropathy was studied in rats exposed to three concentrations of carbon disulfide by inhalation for 90 days. Rats exposed to 800 ppm developed neurofilamentous axonal swellings in the distal portions of long fibers, including the dorsal ascending sensory and corticospinal tracts of the spinal cord. In peripheral nerve the predominant effect was seen at the level of the posterior tibial nerve. Teased fiber preparations of the muscular branch of the posterior tibial nerve showed numerous paranodal and internodal swellings as well as Wallerian degeneration. Ultrastructurally the swellings were characterized by neurofilament accumulations, decreased numbers of microtubules and thin myelin. Other features included segregation of axoplasmic organelles and cytoskeletal components, intrusion of Schwann cell processes into the axoplasm, Schwann cells with increased cytoplasmic contents, and Schwann cell proliferation around many swollen and demyelinated axons. These features draw important parallels between the morphology of carbon disulfide neuropathy and the neurofilamentous neuropathies induced by hexacarbons and beta,beta' iminodipropionitrile (IDPN).

Animals↗
PubMed1985

The relationship of carbon disulfide metabolism to development of toxicity.

The metabolism of CS2 proceeds by two distinct metabolic pathways, direct reaction with amine or thiol functions of cellular constituents, and microsomal oxidation to reactive intermediates that covalently bind to cell macromolecules. Reaction with amines or thiols may alter protein function by two primary mechanisms: formation of dithiocarbamate metabolites capable of inactivating metalloenzymes by chelation of metal ions such as copper and zinc, and direct reaction with such functional groups on proteins. Both of these mechanisms may contribute to CS2-induced neurotoxicity. Formation of reactive intermediates catalyzed by microsomal metabolism is clearly important in mediating CS2-induced hepatotoxicity. Its role in catalyzing neurotoxicity is less certain, however, since the mixed function oxidase activity of the central and peripheral systems has not been well characterized.

Animals↗
PubMed1984

Glutathione depletion by methyl chloride and association with lipid peroxidation in mice and rats.

Inhalation of methyl chloride (CH3Cl) by male B6C3F1 mice resulted in a concentration-dependent depletion of glutathione (GSH) in liver, kidney, and brain. Exposure for 6 hr to 100 ppm CH3Cl decreased the concentration of GSH in mouse liver by 45%, while exposure to 2500 ppm for 6 hr lowered liver GSH to approximately 2% of control levels. For those exposures which decreased liver GSH to less than 20% of control levels, the extent of liver GSH depletion was closely correlated with the capacity of a 9000g supernatant fraction from the liver to undergo lipid peroxidation in vitro. GSH was depleted to a lesser extent in mouse brain and kidney, compared to liver, and no relationship to peroxidation was observed for single exposures to CH3Cl. A dose-dependent decrease in liver GSH was also produced by diethyl maleate, although a nearly lethal amount (2 ml/kg) was required to lower liver GSH to less than 10% of control levels. Under these conditions the amount of lipid peroxidation was 3.5-fold less than in mice exposed to 2000 ppm CH3Cl. Exposure of rats to 2000 ppm CH3Cl reduced liver GSH to 20% of control levels, compared to 4.5% in mice similarly exposed, and under these exposure conditions the amount of lipid peroxidation measured in vitro was 40-fold greater in mouse liver than in rat liver. During exposure of mice to 2500 ppm CH3Cl, ethane expiration increased to an extent comparable to that produced by administration of 2 ml/kg of CCl4. These findings suggest that GSH depletion in liver may be an important component of CH3Cl-induced hepatotoxicity.

Animals↗
PubMed1984

Studies of lesions induced in the testis and epididymis of F-344 rats by inhaled methyl chloride.

Experiments were carried out in rats to characterize the development of the testicular and epididymal lesions and any associated effects on reproductive hormones. Adult F-344 rats were exposed to 3500 ppm methyl chloride (MeCl) 6 hr/day for 5 days, not exposed for 3 days, and exposed again for 4 days. The first consistent testicular lesion was a delay in spermiation which appeared on Day 9. Subsequently, germinal epithelial vacuolation and cellular exfoliation became widespread as exposure continued. All animals killed after 19 days also displayed bilateral epididymal granulomas in regions 5 or 6 of the cauda epididymis. The nature and distribution of inflammatory cells indicated that the primary neutrophilic response may be against the tubular epithelium and not extravasated sperm. After 5 days of exposure, circulating testosterone was below 6 ng/ml (control: 120 +/- 31 ng/ml). Both MeCl exposed and control animals responded similarly to challenge with hCG and LHRH ethylamide, suggesting that Leydig cell and gonadotrope function was unaffected. It is proposed that MeCl acts centrally to lower circulating testosterone. Nonprotein sulfhydryls were depleted in liver, testis, and epididymis after MeCl exposure, but not in whole blood. This finding indicates that sulfhydryl depletion is not due to direct alkylation, but is enzymatically mediated. Sulfhydryl depletion did not correlate with lesion development. It was concluded that the initial testicular effects of MeCl are directed at either the late stage spermatids or the Sertoli cells with a resultant delay in spermiation.

Animals↗
PubMed1984

The effect of buthionine sulfoximine, an inhibitor of glutathione synthesis, on hepatic drug metabolism in the male mouse.

Buthionine sulfoximine significantly reduced the hepatic non-protein sulfhydryl (NPSH) content of male B6C3F1 mice within 2 h after intraperitoneal (i.p.) injection. This treatment did not affect the activity of several hepatic microsomal and cytosolic enzymes responsible for xenobiotic metabolism. Pretreatment of mice with buthionine sulfoximine (2 mmol/kg) increased the hepatotoxicity of chloroform, but did not affect the hepatotoxicity of carbon tetrachloride. These findings suggest that buthionine sulfoximine can be a useful agent for studying the role of glutathione (GSH) in hepatic biotransformation of xenobiotics.

Animals↗
PubMed1984

Paraquat: model for oxidant-initiated toxicity.

Paraquat, a quaternary ammonium bipyridyl herbicide, produces degenerative lesions in the lung after systemic administration to man and animals. The pulmonary toxicity of paraquat resembles in several ways the toxicity of several other lung toxins, including oxygen, nitrofurantoin and bleomycin. Although a definitive mechanism of toxicity of paraquat has not been delineated, a cyclic single electron reduction/oxidation of the parent molecule is a critical mechanistic event. The redox cycling of paraquat has two potentially important consequences relevant to the development of toxicity: generation of "activated oxygen" (e.g., superoxide anion, hydrogen peroxide, hydroxyl radical) which is highly reactive to cellular macromolecules; and/or oxidation of reducing equivalents (e.g., NADPH, reduced glutathione) necessary for normal cell function. Paraquat-induced pulmonary toxicity, therefore, is a potentially useful model for evaluation of oxidant mechanisms of toxicity. Furthermore, characterization of the consequences of intracellular redox cycling of xenobiotics will no doubt provide basic information regarding the role of this phenomena in the development of chemical toxicity.

Animals↗
PubMed1984

A critical review of the literature on hydrogen sulfide toxicity.

The information available on the biological activity of hydrogen sulfide has been examined for present status of critical results pertaining to the toxicity of hydrogen sulfide. This review of the literature is intended as an evaluative report rather than an annotated bibliography of all the source material examined on hydrogen sulfide. The information was selected as it might relate to potential toxic effects of hydrogen sulfide to man and summarized, noting information gaps that may require further investigation. Several recommendations are listed for possible consideration for either toxicological research or additional short- and long-term tests. Two bibliographies have been provided to assist in locating references considered in this report: (1) literature examined but not cited and (2) reference citations. The majority of the references in the first bibliography were considered peripheral information and less appropriate for inclusion in this report.

Abnormalities, Drug-Induced↗
PubMed1983

The morphogenesis of testicular degeneration induced in rats by orally administered 2,5-hexanedione.

The neurotoxic hexacarbon 2,5-hexanedione (2,5-HD) produces testicular atrophy in experimental animals. To examine the morphogenesis of the testicular lesion, 1.0% 2,5-HD was provided in the drinking water of adult F-344 rats for up to 6 weeks. After 3 weeks of administration, there were occasional large vacuoles in the basal region of the germinal epithelium. At 4 weeks, these vacuoles were much larger and more numerous; electron microscopy demonstrated that they were derived from the smooth endoplasmic reticulum. The vacuoles were preferentially associated with stages 12, 13, 14, and 1 of the spermatogenic cycle. Additionally, at 4 weeks there was a significant decrease in the number of tubules in stages 7 and 13, and a concomitant increase in the percentage of tubules in stages 3, 5, and 6. By Week 5, most Golgi-phase and cap-phase spermatids were visibly affected, showing margination of nuclear chromatin, and were becoming dissociated from Sertoli cells. Frequent multinucleated giant cells were seen and electron microscopy of these cells suggested that they were derived from fused spermatocytes or spermatids. After 6 weeks, fewer giant cells were present, most tubules contained cellular debris, and many showed empty lumina encircled by a thin ring of cytoplasm near the basement membrane. Interstitial tissue appeared unaffected. These studies indicate that the Sertoli cell is probably an initial target for 2,5-HD action in the testis.

Animals↗
PubMed1983

The role of glutathione and cytochrome P-450 in the metabolism of methyl chloride.

Rat liver microsomes metabolized methyl chloride to formaldehyde at a rate 15-fold less than the rate of benzamphetamine demethylation. The reaction rate was stimulated approximately 2-fold in microsomes from phenobarbital-pretreated rats and was inhibited by addition of SKF-525A, carbon monoxide, metyrapone, and hexobarbital to the microsomal suspension, indicating dependence on cytochrome P-450. The in vivo incorporation of 14CH3Cl into liver macromolecules, previously shown to reflect metabolism to CH3Cl to formate, was not significantly altered by SKF-525A, Aroclor 1254, or 3-methylcholanthrene pretreatment of rats, although pretreatment with phenobarbital produced a 35 and 28% increase in 14CH3Cl uptake into liver lipid and acid-insoluble material, respectively. Pretreatment with phenobarbital increased the in vivo metabolism of 14CH3Cl to 14CO2 (also derived from a formate intermediate) by 19%, but had no effect on urinary metabolites derived from 14CH3Cl. SKF-525A inhibited 14CO2 production from 14CH3Cl by 30% and also had no effect on urinary excretion of 14C. In contrast, pretreatment with diethylmaleate inhibited 14CH3Cl incorporation into liver macromolecules by 70 to 85%, and lowered 14CO2 expiration and urinary 14C excretion by 52 and 60%, respectively. S-Methylcysteine pretreatment produced a similar inhibition of 14CH3Cl incorporation and metabolism to 14CO2; urinary excretion of 14C, however, was approximately doubled. 14CH3Cl uptake into liver was also stimulated by cysteine pretreatment. These results indicate a strong dependence of CH3Cl metabolism on tissue nonprotein sulfhydryl content and suggest a possible role for cytochrome P-450 in the in vivo metabolism of CH3Cl. A scheme for the metabolism of CH3Cl is postulated which involves initial reaction with glutathione, and sequential metabolism of the conjugate to S-methylcysteine, methanethiol, and formaldehyde.

Animals↗