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PubMed1998

Towards a biocatalyst for (S)-styrene oxide production: characterization of the styrene degradation pathway of Pseudomonas sp. strain VLB120.

In order to design a biocatalyst for the production of optically pure styrene oxide, an important building block in organic synthesis, the metabolic pathway and molecular biology of styrene degradation in Pseudomonas sp. strain VLB120 was investigated. A 5.7-kb XhoI fragment, which contained on the same strand of DNA six genes involved in styrene degradation, was isolated from a gene library of this organism in Escherichia coli by screening for indigo formation. T7 RNA polymerase expression experiments indicated that this fragment coded for at least five complete polypeptides, StyRABCD, corresponding to five of the six genes. The first two genes encoded the potential carboxy-terminal part of a sensor, named StySc, and the complete response regulator StyR. Fusion of the putative styAp promoter to a lacZ reporter indicated that StySc and StyR together regulate expression of the structural genes at the transcriptional level. Expression of styScR also alleviated a block that prevented translation of styA mRNA when a heterologous promoter was used. The structural genes styA and styB produced a styrene monooxygenase that converted styrene to styrene oxide, which was then converted to phenylacetaldehyde by StyC. Sequence homology analysis of StyD indicated a probable function as a phenylacetaldehyde dehydrogenase. To assess the usefulness of the enzymes for the production of enantiomerically pure styrene oxide, we investigated the enantiospecificities of the reactions involved. Kinetic resolution of racemic styrene oxide by styrene oxide isomerase was studied with E. coli recombinants carrying styC, which converted styrene oxide at a very high rate but with only a slight preference for the S enantiomer. However, recombinants producing styrene monooxygenase catalyzed the formation of (S)-styrene oxide from inexpensive styrene with an excellent enantiomeric excess of more than 99% at rates up to 180 U g (dry weight) of cells-1.

Base Sequence↗
PubMed1994

Evidence for DNA and protein binding by styrene and styrene oxide.

Styrene is metabolized to styrene oxide, a direct-acting mutagen and carcinogen. Styrene oxide reacts with DNA mainly at the N-7 position in guanine, but also at other sites and with other bases. Substitution occurs at both the alpha- and beta-positions of the styrene molecule. Experiments with radiolabeled styrene and styrene oxide demonstrate that both have a low level of DNA binding activity in experimental animals. 32P-Postlabeling studies have demonstrated the potential of the technique to detect styrene-DNA adducts. Styrene oxide alkylates several nucleophilic sites in proteins, particularly cysteine sulfydryl, histidine imidazole, lysine amino, aspartic, and glutamic carboxylic groups, and the N-terminal position. In experimental animals, styrene oxide treatment results in cysteine adducts in hemoglobin and albumin, valine adducts in hemoglobin, and carboxylic acid adducts in hemoglobin. The extent of alkylation is low compared with that produced by ethylene oxide. The available evidence indicates, therefore, that styrene and styrene oxide have low DNA and protein binding activities in vivo. There is preliminary evidence for the presence of DNA adducts and for adducts in hemoglobin and albumin in blood cells of styrene-exposed workers. Nevertheless, the applicability and sensitivity of DNA and protein adduct detection methods for monitoring human exposure to styrene remain to be determined.

Animals↗
PubMed2005

Comparison of the depletion of glutathione in mouse liver and lung following administration of styrene and its metabolites styrene oxide and 4-vinylphenol.

Styrene is hepatotoxic and pneumotoxic in mice. Its major metabolite styrene oxide and its minor, but potent, metabolite 4-vinylphenol cause similar toxicities. Styrene and styrene oxide cause decreases in reduced glutathione levels in tissues. The current studies examined styrene and styrene oxide in a time and dose-dependent manner and 4-vinylphenol in a time dependent fashion. Styrene (600 mg/kg, 5.8 mmol/kg ip) caused decreased GSH levels in both liver and lung within one hour. A maximum was seen at three hours with return to control levels by 12 h. Lower doses also caused changes in a dose-dependent fashion. For styrene oxide, similar findings were observed with a dose of 300 mg/kg (2.5 mmol/kg). GSH levels in liver, but not lung, returned to control by 6 h. Again a dose response was found for both tissues. While 4-vinylphenol (100 mg/kg, 0.83 mmol/kg) was administered at a dose known to be more hepatotoxic and more pneumotoxic than styrene or styrene oxide and it caused decreased GSH levels, the degree of depletion was less compared to styrene and styrene oxide. In general the lung was more affected by these agents than was liver. The decreases in GSH suggest the possibility that the toxicity of styrene in lung and liver may be related to a profound but reversible oxidative stress in these tissues.

Animals↗
PubMed1998

Metabolism of styrene oxide to styrene glycol by mouse liver and lung.

Styrene is a widely used chemical that causes both liver and lung damage in mice. Strain and sex differences in susceptibility to styrene-induced toxicity have been reported. Understanding the relationship of the metabolism of styrene to its toxicity depends upon knowing the balance between the bioactivation of styrene to the epoxide by cytochromes P-450 and the detoxication of the oxide to the glycol by microsomal epoxide hydrolase. When hepatic and pulmonary microsomal preparations from non-Swiss albino (NSA) and Swiss (CD-1) mice were compared for their abilities to metabolize racemic, S- and R-styrene oxide to styrene glycol, enzymic activities were higher in liver than in lung. R-Styrene glycol formation was favored with racemic styrene oxide as the substrate. Only minor strain differences were found that could not account for the differences in reported susceptibility to styrene-induced toxicity. While the oxidation of styrene to styrene oxide was similar in male and female NSA mice, male hepatic microsomes were more active in the metabolism of the oxide to the glycol. Hepatic metabolism of styrene oxide to styrene glycol was inducible by butylated hydroxyanisole, whereas pulmonary metabolism was not. The data indicate that strain differences in susceptibility cannot be accounted for by this detoxication step, and there are sex differences in this reaction.

Animals↗
PubMed1988

[Inhibition of delta-aminolevulinic acid dehydratase by styrene and styrene oxide].

Effects of styrene and styrene oxide on delta-aminolevulinic acid dehydratase in rats were investigated, in vivo and in vitro. In the in vivo study, rats were exposed to styrene or styrene oxide intraperitoneally for seven days. delta-Aminolevulinic acid dehydratase in the erythrocyte was inhibited by both styrene and styrene oxide. The inhibition by styrene oxide had a clear dose-response relationship, but that by styrene did not. In the liver, however, these substances did not inhibit delta-aminolevulinic acid dehydratase. In the in vitro study, styrene oxide inhibited delta-aminolevulinic acid dehydratase both in the erythrocyte and in the liver, but styrene failed to inhibit it. These results suggest that styrene is metabolized to styrene oxide, and this metabolite inhibits delta-aminolevulinic acid dehydratase. It is also thought that the discrepancy of inhibition between the erythrocyte and the liver is due to a difference of distribution and metabolism of the substances.

Animals↗
PubMed2000

Metabolism of styrene oxide to styrene glycol in enriched mouse clara-cell preparations.

Styrene is a widely used chemical that has been shown to cause lung tumors in mice but not in rats. Styrene toxicity appears to be related to its bioactivation to styrene oxide, and this occurs almost exclusively in Clara cells. An important pathway in the detoxification of styrene oxide is via epoxide hydrolase to yield styrene glycol. When mouse Clara cells were incubated with racemic styrene oxide, R-styrene glycol was the predominant metabolite, giving an R/S ratio of 3.6. When the pure styrene oxide enantiomers were used as substrates, the corresponding styrene glycols were the predominant but not exclusive metabolites. Activity was slightly higher with the S-styrene oxide than with the R-styrene oxide. Addition of reduced glutathione to the incubation medium resulted in an increase in epoxide hydrolase activity, perhaps by decreasing oxidative stress. Mouse Clara cells thus show the capacity for detoxifying styrene oxide.

Animals↗
PubMed1985

In vitro transformation and tumor promotion studies of styrene and styrene oxide.

The carcinogenic properties of styrene and styrene oxide were investigated using C3H/10T1/2C18 cells as a test system. In vitro transformation was not observed for either of the two chemicals; however, styrene oxide at three different concentrations enhanced the morphological transformation in the two-stage transformation assay. 0.1, 1 and 10 microM styrene oxide added twice weekly resulted in 32.4, 26.8 and 31.4 per cent of the dishes with one or more type III foci. Styrene and styrene oxide were only slightly toxic to the cells at the concentrations used. Styrene oxide did not affect the growth rate of the C3H/10T1/2 cells at 10 microM. However, 100 microM styrene oxide added to logarithmically growing cells caused a significant decrease in growth rate within 24 to 48 h. The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate inhibited DNA synthesis approximately 60% 8 h after initiation of treatment. When styrene oxide at concentrations up to 100 microM was tested in a similar experiment, however, no significant effect was observed. Total RNA synthesis increased by 70% 1.5 h after initiation of treatment at 1 microM styrene oxide; this effect was not seen after 24 h. Styrene oxide at concentrations of 1 and 0.1 microM stimulated the incorporation of [3H]choline into cells by approximately 20% during a 2 h incubation, the major site of incorporation being the nuclear-associated endoplasmic reticulum.

Animals↗
PubMedDate not supplied

Modulation of different stress pathways after styrene and styrene-7,8-oxide exposure in HepG2 cell line and normal human hepatocytes.

Styrene is one of the most important monomers produced worldwide. IARC classified styrene as a possible carcinogen to humans (group 2B). Styrene-7,8-oxide (SO) is the main reactive metabolite of styrene, and it is found to be genotoxic in several in vitro test systems. Styrene and styrene-7,8-oxide (SO) toxicity to HepG2 cells was investigated by evaluating end-points such as heat shock proteins (Hsps), metallothioneins (MT), apoptosis-related proteins, accumulation of styrene within the cells and expression of two isoforms of cytochrome P450. The potential activity of styrene and styrene-7,8-oxide in modulating gene expression was also investigated. The results showed induction of Hsp70, metallothioneins, BclX(S/L) and c-myc expression and a decrease in Bax expression in HepG2 after treatments, confirming that these compounds activated protective mechanisms. Moreover, up-regulation of TGFbeta2 and TGFbetaRIII in HepG2 cells was found after exposure to styrene, while in human primary hepatocytes these genes were down-regulated after both treatments. Finally, it was found that styrene and SO treatments did not induce CYP1A2 and CYP2E1 protein expression. In conclusion, both compounds caused toxic stress in HepG2 cells, with SO being more toxic; in the meantime, a different effect of the two compounds in HepG2 cells and primary human hepatocytes was observed regarding their activity in gene modulation.

Carcinogens↗
PubMed2000

Measurement of styrene-7,8-oxide and other oxidation products of styrene in air.

Styrene-7,8-oxide (SO) is generated at low concentrations from the oxidation of styrene during the processing of reinforced plastics. Since exposure to SO has important health implications, we developed air sampling and analytical methods to measure low levels of airborne SO in the presence of styrene and its other oxidation products, namely phenylacetaldehyde (PAA) and acetophenone (AP). Both active and passive air monitors were used. The active sampling method, which employed adsorption on Tenax, was suitable for measuring SO, PAA and AP but had limited capacity for styrene due to breakthrough. The passive monitor employed a carbon adsorbent and was suitable for measurement of styrene and SO but not PAA and AP due to poor recovery. After sampling, the analytes were extracted from the adsorbents with ethyl acetate and measured by gas chromatography with flame ionization detection or mass spectrometry. By maintaining the injection port at 70 degrees C, the thermal rearrangement of SO to PAA was minimized. Recovery of styrene and SO from the passive monitor depended upon loading and was corrected by linearization of the Freundlich isotherm. The limits of detection for SO, PAA, and AP were 0.2 ppb using the active monitor, and for SO was 1 ppb using the passive monitor. The sampling precision for SO (RSD from personal measurements) was 5.0% for the passive monitor and was 13.4% for the active monitor over a range of exposures from 5-150 ppb. The corresponding precision for styrene was 5.3% for the passive monitor for levels ranging from 1.2 to 104 ppm. Measurements of 235 personal exposures with the active monitor in 12 facilities manufacturing fiberglass-reinforced plastics (FRP) showed that levels of AP and PAA were below 7.8 ppb and 5 ppb, respectively. In contrast, SO averaged 30.4 ppb (SE=2.4) in these FRP facilities, ranging from below 0.2 ppb to 190 ppb. The active monitor was also used to detect airborne SO at levels of approximately equals 1 ppb in one facility manufacturing styrene butadiene rubber, suggesting that SO is generally present during the polymerization of styrene. Personal passive monitoring in the 12 FRP facilities (n = 657) revealed mean concentrations of styrene ranging between 1.8 and 55.4 ppm, and for SO between 1.7 and 62.6 ppb. The ratio of the mean styrene level to the mean SO level varied between 449:1 and 1,635:1 among the 12 FRP facilities.

Air Pollutants↗
PubMed2003

Ototoxic effects of occupational exposure to styrene and co-exposure to styrene and noise.

Ototoxicity of styrene and the synergistic action of styrene and noise have been shown in rats. The respective data in humans are scarce and equivocal. This study evaluated the effects of occupational exposure to styrene and combined exposures to styrene and noise on hearing. The study group, comprised of 290-yacht yard and plastic factory workers, was exposed to a mixture of organic solvents, having styrene as its main compound. The reference group, totaling 223 subjects, included (1) white-collar workers, exposed neither to solvents nor noise and (2) metal factory workers, exposed exclusively to noise. All subjects were assessed by means of a detailed questionnaire and underwent otorhinolaryngological and audiometric examinations. Multiple logistic regression analysis revealed almost a 4-fold (or 3.9; 95% CI = 2.4-6.2) increase in the odds of developing hearing loss related to styrene exposure. The factors adjusted for were: age, gender, current occupational exposure to noise, and exposure to noise in the past. In cases of the combined exposures to styrene and noise, the odds ratios were two to three times higher than the respective values for styrene-only and noise-only exposed subjects. The mean hearing thresholds--adjusted for age, gender, and exposure to noise--were significantly higher in the solvent-exposed group than in the unexposed reference group at all frequencies tested. A positive linear relationship existed between an averaged working life exposure to styrene concentration and a hearing threshold at the frequencies of 6 and 8 kHz. This study provides the epidemiological evidence that occupational exposure to styrene is related to an increased risk of hearing loss. Combined exposures to noise and styrene seem to be more ototoxic than exposure to noise alone.

Adult↗
PubMed2001

Investigation of protein-styrene oxide adducts as a molecular biomarker of human exposed to styrene.

Hemoglobin-styrene oxide adducts in blood have been studied as a molecular biomarker of worker exposed to styrene. Determination of protein-styrene oxide adducts in different biological samples with modified Raney-Ni procedure is described in this paper. The following biological samples have been investigated: fresh rat blood reacted with styrene oxide in vitro; rat blood reacted with styrene or styrene oxide in vivo; vein blood from workers exposed to styrene in two factories. The data showed that there was a good linear dose-response relationship between reacting dose of styrene oxide or styrene and amount of protein-styrene oxide adducts in both in vitro and in vivo experiments. For human samples, a dose-response relationship between protein adducts and styrene exposure can be found in glass fiber factory, but not in piano manufacture plant.

Animals↗
PubMed1989

Sub-chronic effects of styrene and styrene oxide on lipid peroxidation and the metabolism of glutathione in rat liver and brain.

Sub-chronic effects of styrene and styrene oxide on lipid peroxidation, glutathione contents and glutathione reductase activities in the liver and brain were examined after intraperitoneal administration to rats 3 times a week for 7 weeks. Styrene (300, 400 and 500 mg/kg) and styrene oxide (200 and 300 mg/kg) increased lipid peroxidation in the liver after 7 weeks of treatment. Hepatic lipid peroxidation in the rats treated with a higher dose of styrene oxide (400 mg/kg) was significantly enhanced even after 2 weeks of treatment. On the other hand, no change in lipid peroxidation was observed in the brain under the above conditions. Neither glutathione contents nor glutathione reductase activities in the liver and brain were altered at 40 h after the last of these sub-chronic treatments. To elucidate the cause of lipid peroxidation, the time courses of glutathione content after treatment with either styrene or styrene oxide (300 mg/kg) were studied in more detail. Significant decreases in both the GSH and GSSG contents were detected shortly after these treatments and the levels recovered to the control values at 40 h in these organs, although the changes were less significant in the brain of rats treated with styrene. These results suggest that enhancement of lipid peroxidation in the liver after treatment with styrene or styrene oxide was a consequence of repeated depletions of glutathione to certain critical levels and delayed recovery of lipid peroxides.

Animals↗
PubMed1996

An investigation of multiple biomarkers among workers exposed to styrene and styrene-7,8-oxide.

Investigations of cancer and cytogenetic damage among reinforced-plastics workers have produced contradictory results. In all studies, the focus has been on styrene rather than the carcinogen, styrene-7,8-oxide (SO), traces of which are generated during the manufacturing process. Because styrene is present at very high levels and is metabolized almost exclusively through SO, coexposures to SO have been discounted. This study investigated the relative contributions of airborne styrene and SO and of smoking toward several SO-specific biomarkers (DNA and albumin adducts) and sister chromatid exchanges in the blood of 48 reinforced-plastics workers. Among individual subjects, albumin and DNA adducts as well as sister chromatid exchanges were significantly correlated with styrene exposure. However, among the 20 subjects with measurements to both styrene and SO, albumin adducts were significantly correlated with exposure to SO but not to styrene. Finally, among the 10 job groups, surprisingly strong correlations (0.709 < or = r < or = 0.966) were found between all SO biomarkers and exposure to SO but not to styrene. Calculations suggest that SO was about 2000 times more effective than styrene in producing SO biomarkers. After accounting for the disparate exposures to the two chemicals, a typical worker received 71% of the systemic dose of SO via inhalation; nonetheless, 5 of the 20 subjects received the majority of the SO dose from styrene. Cigarette smoking increased levels of SO-albumin and SO-DNA adducts, suggesting that SO was a constituent of tobacco smoke. We conclude that inhalation of SO should be considered in any interventions to reduce health risks.

Adult↗
PubMed2001

Determination of styrene and styrene-7,8-oxide in human blood by gas chromatography-mass spectrometry.

Methods of isotope-dilution gas chromatography-mass spectrometry (GC-MS) are described for the determination of styrene and styrene-7,8-oxide (SO) in blood. Styrene and SO were directly measured in pentane extracts of blood from 35 reinforced plastics workers exposed to 4.7-97 ppm styrene. Using positive ion chemical ionization, styrene could be detected at levels greater than 2.5 microg/l blood and SO at levels greater than 0.05 microg/l blood. An alternative method for measurement of SO employed reaction with valine followed by derivatization with pentafluorophenyl isothiocyanate and analysis via negative ion chemical ionization GC-MS-MS (SO detection limit=0.025 microg/l blood). The detection limits for SO by these two methods were 10-20-fold lower than gas chromatographic assays reported earlier, based upon either electron impact MS or flame ionization detection. Excellent agreement between the two SO methods was observed for standard calibration curves while moderate to good agreement was observed among selected reinforced plastics workers (n = 10). Levels of styrene in blood were found to be proportional to the corresponding air exposures to styrene, in line with other published relationships. Although levels of SO in blood, measured by the direct method, were significantly correlated with air levels of either styrene or SO among the reinforced plastics workers, blood concentrations were much lower than previously reported at a given exposure to styrene. The two assays for SO in blood appear to be unbiased and to have sufficient sensitivity and specificity for applications involving workers exposed to styrene and SO during the manufacture of reinforced plastics.

Air↗
PubMed2003

In vitro metabolism of styrene to styrene oxide in liver and lung of Cyp2E1 knockout mice.

Styrene is a widely used chemical. In mice it is both hepatotoxic and pneumotoxic, and this toxicity is thought to be associated with its metabolism to styrene oxide. In vitro studies by several investigators suggest that this bioactivation in mice is primarily due to CYP2E1 and CYP2F2. However, in vivo studies demonstrate that CYP2E1 knockout mice can metabolize styrene to a similar extent as the wild-type mice. The current studies compared the in vitro metabolism of styrene by hepatic and pulmonary microsomes from CYP2E1 knockout and wild-type mice. There was no difference in the hepatic microsomal metabolism of styrene to styrene oxide between the two strains. The metabolism of styrene was lower in the lungs of the knockout mice than in the wild-type. Chemical inhibitors were used to ascertain the contributions made by various cytochromes P-450: imipramine for CYP2C, alpha -methylbenzylaminobenzotriazole for CYP2B, alpha -naphthoflavone for CYP1A, 5-phenyl-1-pentyne for CYP2F2, and diethyldithiocar-bamate for CYP2E1. The data indicate that CYP2E1 and CYP2F2 may be important in wild-type mice, but they do not clearly indicate what cytochromes P-450 are responsible for the metab-olism in the knockout mice. Inhibition of styrene metabolism in the knockout mice by diethyl-dithiocarbamate indicates this inhibitor is not completely selective for CYP2E1. These in vitro data support the in vivo finding of styrene metabolism in CYP2E1 knockout mice and indicate that other enzymes are contributing to styrene metabolism in these mice.

Animals↗
PubMed1999

An investigation of factors contributing to styrene and styrene-7,8-oxide exposures in the reinforced-plastics industry.

During the manufacturing of reinforced plastics, large amounts of styrene and trace quantities of styrene-7,8-oxide (SO) are released. Since previous work suggests that inhalation of even small amounts of SO might be an important health risk, we investigated several possible factors contributing to styrene and SO exposure during the manufacture of reinforced plastics. Factors related to job type, worker and the type and quantity of styrene-containing resins were investigated using mixed-effects multiple linear regression models. Overall, SO exposure levels were positively correlated with styrene exposure levels. However, this correlation was statistically significant only among hand laminators who had the highest exposures to both styrene and SO. An important factor for predicting both styrene and SO concentrations was the type of resin used, while the quantity of resin consumed was predictive of styrene but not of SO exposure. Since So exposure appears to be associated with factors other than coexposure to styrene, more effort should be placed on investigating emissions of SO per se. The type of mixed-models regression analysis employed in this study can be used for clarifying the underlying patterns for exposures to styrene and SO as well as for evaluating preventive measures.

Carcinogens↗
PubMed1978

Biological indicators of exposure in styrene polymerization workers. Styrene in blood and adipose tissue and mandelic and phenylglyoxylic acids in urine.

The concentrations of mandelic and phenylglyoxylic acids, urinary metabolites of styrene, and styrene in blood were determined for 491 styrene polymerization workers. Styrene in subcutaneous fat was determined for 25 workers. The levels of styrene exposure were estimated to be less than 10 ppm, and urinary metabolite and blood styrene concentrations indicated that significant recent exposure (within 4 h) had occurred among workers in areas of styrene polymerization and styrene monomer production. Styrene analysis of subcutaneous fat suggested that the monomer may have been present for as long as 3 d after exposure, a time when urinary metabolites and blood styrene were almost invariably undetectable. All three biological parameters were correlated with recency of exposure and estimated intensity of exposure within job categories.

Adipose Tissue↗
PubMed2004

Bimetallic catalysis for styrene homopolymerization and ethylene-styrene copolymerization. Exceptional comonomer selectivity and insertion regiochemistry.

This communication reports the styrene homopolymerization behavior and ethylene-styrene copolymerization behavior of the covalently linked bimetallic constrained geometry catalyst (mu-CH2CH2-3,3'){(eta5-indenyl)[1-Me2Si(tBuN)](TiMe2)}2 (Ti2), which is the first single-site catalyst that effects not only styrene homopolymerization with high activity, but also efficient ethylene-styrene copolymerization over a broad styrene composition range (0-76% at 20 degrees C, 1.0 atm ethylene pressure). In styrene homopolymerization, a 50x increase in polymerization activity is achieved with Ti2 vs the mononuclear analogue, Ti1, using an identical trityl borate cocatalyst and polymerization conditions. In ethylene + styrene copolymerization, Ti2 enchains approximately 20% more styrene than Ti1 under identical reaction conditions. 13C NMR spectroscopy indicates that greater than two consecutive styrene units are enchained in the copolymer backbone produced by Ti2 + Ph3C+B(C6F5)4-. End group analysis of the styrene homopolymer produced by Ti2 + Ph3C+B(C6F5)4- suggests that 1,2-regiochemistry is installed in approximately 50% of the initiation steps. This unusual microstructure is believed to be related to the bimetallic catalyst structure.

Journal Article↗