Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Archives of Toxicology (v.73, #4-5)
CYP2E1-dependent benzene toxicity: the role of extrahepatic benzene metabolism by Ulrike Bernauer; Bärbel Vieth; Rainer Ellrich; Barbara Heinrich-Hirsch; Gerd-Rüdiger Jänig; Ursula Gundert-Remy (pp. 189-196).
Benzene, a ubiquitous environmental pollutant, is haematotoxic and myelotoxic. As has been shown earlier, cytochrome P450 2E1 (CYP2E1)-dependent metabolism is a prerequisite for the cytotoxic and genotoxic effects of benzene, but which of the benzene metabolites produces toxicity is still unknown. The observed differences between the toxicity of benzene and that of phenol, a major metabolite of benzene, could be explained by alternative hypotheses. That is, whether (1) toxic benzene effects are caused by metabolites not derived from phenol (e.g. benzene epoxide, muconaldehyde), which are formed in the liver and are able to reach the target organ(s); or (2) benzene penetrates into the bone marrow, where local metabolism takes place, whereas phenol does not reach the target tissue because of its polarity. To further investigate hypothesis 2, we used various strains of mice (AKR, B6C3F1, CBA/Ca, CD-1 and C57Bl/6), for which different toxic responses have been reported in the haematopoietic system after chronic benzene exposure. In these strains, CYP2E1 expression in bone marrow was investigated and compared with CYP2E1 expression in liver by means of two independent methods. Quantification of CYP2E1-dependent hydroxylation of chlorzoxazone (CLX) by high-performance liquid chromatography (HPLC; functional analysis) was used to characterize specific enzymatic activities. Protein identification was performed by Western blotting using CYP2E1-specific antibodies. In liver microsomes of all strains investigated, considerable amounts of CYP2E1-specific protein and correspondingly high CYP2E1 hydroxylase activities could be detected. No significant differences in CYP2E1-dependent enzyme activities were found between the five strains (range of medians, 4.6–12.0 nmol 6-OH-CLX/[mg protein × min]) in hepatic tissue. In the bone marrow, CYP2E1 could also be detected in all strains investigated. However, chlorzoxazone hydroxylase activities were considerably lower (range of medians, 0.2–0.8 × 10−3 nmol 6-OH-CLX/[mg protein × min]) compared with those obtained from liver microsomes. No significant (P > 0.05) interstrain differences in CYP2E1 expression in liver and/or bone marrow could be observed in the mouse strains investigated. The data obtained thus far from our investigations suggest that strain-specific differences in the tumour response of the haematopoietic system of mice chronically exposed to benzene cannot be explained by differences in either hepatic or in myeloid CYP2E1-dependent metabolism of benzene.
Keywords: Key words Benzene; CYP2E1; Leukaemia; Bone marrow; Extrahepatic metabolism
Haemoglobin adducts of acrylonitrile and ethylene oxide in acrylonitrile workers, dependent on polymorphisms of the glutathione transferases GSTT1 and GSTM1 by Ricarda Thier; Jürgen Lewalter; Manuela Kempkes; Silvia Selinski; Thomas Brüning; Hermann M. Bolt (pp. 197-202).
Fifty-nine persons with industrial handling of low levels of acrylonitrile (AN) were studied. As part of a medical surveillance programme an extended haemoglobin adduct monitoring [N-(cyanoethyl)valine, CEV; N-(methyl)valine, MV; N-(hydroxyethyl)valine, HEV] was performed. Moreover, the genetic states of the polymorphic glutathione transferases GSTM1 and GSTT1 were assayed by polymerase chain reaction (PCR). Repetitive analyses of CEV and MV in subsequent years resulted in comparable values (means, 59.8 and 70.3 μg CEV/l blood; 6.7 and 6.7 μg MV/l blood). Hence, the industrial AN exposures were well below current official standards. Monitoring the haemoglobin adduct CEV appears as a suitable means of biomonitoring and medical surveillance under such exposure conditions. There was also no apparent correlation between the CEV and HEV or CEV and MV adduct levels. The MV and HEV values observed represented background levels, which apparently are not related to any occupational chemical exposure. There was no consistent effect of the genetic GSTM1 or GSTT1 state on CEV adduct levels induced by acrylonitrile exposure. Therefore, neither GSTM1 nor GSTT1 appears as a major AN metabolizing isoenzyme in humans. The low and physiological background levels of MV were also not influenced by the genetic GSTM1 state, but the MV adduct levels tended to be higher in GSTT1− individuals compared to GSTT1+ persons. With respect to the background levels of HEV adducts observed, there was no major influence of the GSTM1 state, but GST− individuals displayed adduct levels that were about 1/3 higher than those of GSTT1+ individuals. The coincidence with known differences in rates of background sister chromatid exchange between GSTT1− and GSTT1+ persons suggests that the lower ethylene oxide (EO) detoxification rate in GSTT1− persons, indicated by elevated blood protein hydroxyethyl adduct levels, leads to an increased genotoxic effect of the physiological EO background.
Keywords: Key words Acrylonitrile; Ethylene oxide; Haemoglobin adducts; Glutathione transferase (GST) polymorphisms
Increase in urinary excretion of 6β-hydroxycortisol in common marmosets as a marker of hepatic CYP3A induction by S. Totsuka; T. Watanabe; F. Koyanagi; K. Tanaka; M. Yasuda; S. Manabe (pp. 203-207).
The ratio of urinary 6β-hydroxycortisol (6β-OHF) to free cortisol (F), i.e., the 6β-OHF/F ratio, has been reported to be a specific marker for human CYP3A induction by in vivo studies of human subjects. In the development of drugs, it is quite beneficial to predict human CYP3A induction in preclinical safety studies using urine samples from experimental animals. We examined the 6β-OHF/F ratio in urine of common marmosets administered with rifampicin, a potent inducer of CYP3A, to evaluate the usefulness of common marmosets for the prediction of CYP3A induction. Rifampicin was orally administered to three groups of four male common marmosets at doses of 0, 10, and 20 mg/kg per day for 4 days. Amounts of 6β-OHF and F in urine samples were determined by means of high-performance liquid chromatography (HPLC) during the experimental period. One day after the 4th dosing, animals were killed, and P450 contents and P450-catalyzed, 7-alkoxycoumarin O-dealkylase (ACD) activities in the liver were measured. Western blot analysis of liver microsomes was also performed using anti-rat P450 (CYP1A1, 2B1/2, 3A, and 4A) antibodies. The results indicated elevations in the 6β-OHF/F ratios that were dependent on both the dosing period and dose levels adopted. The ratios on day 4 reached 4.7- and 5.3-fold the pre-administration values in the 10 and 20 mg/kg per day groups, respectively. P450 contents and ACD activities were also elevated in all of the groups. Western blot analysis showed specific increases in the protein which cross-reacts with anti-rat CYP3A antibody in all of the groups. Furthermore, the 6β-OHF/F ratio was well correlated with the CYP3A contents in liver (r = 0.906). These results indicated that increase in urinary excretion of 6β-OHF is a specific marker of the induction of hepatic CYP3A in common marmosets just as in humans. Consequently, the present study suggested that human CYP3A induction elicited by chemical agents can be predicted in common marmosets by measuring the urinary excretion of 6β-OHF.
Keywords: Key words 6β-Hydroxycortisol; Common marmoset; Rifampicin; CYP3A; HPLC
Constitutive and induced expression by pyridine and β-naphthoflavone of rat CYP1A is sexually dimorphic by Michael M. Iba; Jacqueline Fung; Paul E. Thomas; Yangwon Park (pp. 208-216).
Adult male and female Sprague-Dawley rats were compared in terms of the constitutive levels and inducibility of CYP1A1 and CYP1A2 (CYP1A) in lung, kidney, and liver. CYP1A were induced by i.p. treatment with pyridine (75 mg/kg per day) or β-naphthoflavone (βNF; 25 mg/kg per day) for two consecutive days and analyzed catalytically (via O-dealkylation of resorufin ethers), at the protein level (by Western blot analysis) and at the mRNA level (by Northern blot analysis). In untreated rats, CYP1A1 protein and its mRNA were detectable only in the lung and kidney of females but not males, whereas CYP1A2 protein and its mRNA were detectable only in the liver in either gender. Pyridine treatment upregulated CYP1A1 mRNA and its protein in the lung, kidney and liver in female rats, and upregulated the mRNA but not the protein in the lung and liver in male rats. Conversely, pyridine induced both CYP1A2 mRNA and protein in the liver in female rats, whereas it induced the protein but not its mRNA in the liver in male rats. No gender difference was observed in the plasma elimination rate of administered pyridine. βNF, in contrast to pyridine, induced CYP1A proteins, activities, and mRNA to higher levels in male than in female rats. The results show that the constitutive as well as inducible expression of CYP1A is sexually dimorphic in the Sprague-Dawley rat, with females being more responsive than males to induction by pyridine but with males being more responsive than females to induction by βNF. The findings support the involvement of different mechanisms in CYP1A induction by pyridine and βNF.
Keywords: Key words CYP1A induction; Sexual dimorphism; Pyridine; β-Naphthoflavone
Toxicokinetics of p-tert-octylphenol in female DA/Han rats after single i.v. and oral application by Andreas Upmeier; Gisela H. Degen; Ulrike S. Schuhmacher; Hans Certa; Hermann M. Bolt (pp. 217-222).
Female DA/Han rats were administered p-tert-octylphenol [OP; p-(1,1,3,3-tetramethylbutyl)-phenol], either intravenously (5 mg/kg body wt.) or orally by gavage (50 or 200 mg/kg body wt.). After i.v. administration the blood concentration-time curve of OP was fitted to a tri-exponential model, resulting in a final half-life (γ-phase) of 36.1 h. This contrasts to much more rapid eliminations previously reported in male Wistar rats. The oral bioavailability of 50 mg/kg OP was 12.3% and of 200 mg/kg 8.4%. The higher dose (200 mg/kg) was absorbed slower than the smaller dose, probably due to low solubility of OP in aqueous media. Maximal OP blood levels in female DA/Han rats receiving 50 and 200 mg OP/kg body wt. were 4.5 and 3 times higher than previously reported in male Wistar rats. The blood concentration-time curves after oral administration of OP to female DA/Han rats revealed pronounced interindividual differences, indicating extensive enterohepatic circulation of OP in this rat strain. In contrast to male Wistar rats, after application of high doses of OP to female DA/Han rats the compound was not completely eliminated within 48 h; under these conditions some bioaccumulation might therefore occur. The experimental toxicokinetics of OP appears as a relevant subject to be integrated into extrapolation of toxicological data, from in vitro to in vivo, and into systems of risk assessment of endocrine modulating activity which are currently being developed.
Keywords: Key wordsp-tert-Octylphenol; Nonylphenol; Environmental oestrogens; Toxicokinetics; Enterohepatic circulation
Cadmium-induced calcium release and prostaglandin E2 production in neonatal mouse calvaria are dependent on cox-2 induction and protein kinase C activation by Anna Romare; C. E. Lundholm (pp. 223-228).
The mechanisms by which cadmium (Cd) causes skeletal impairment have not been fully clarified. Release of calcium from neonatal mouse calvaria in organ culture is stimulated by submicromolar concentrations of Cd, an effect that is associated with increased production of prostaglandin E2 (PGE2). The prostaglandin-synthesising enzyme cyclooxygenase (cox) exists in two forms, one constitutive (cox-1) and the other inducible (cox-2). Cox-2 can be induced by mitogenic stimuli and inflammatory cytokines, such as parathyroid hormone (PTH), interleukin-1α and tumour necrosis factor-α. Cd potently activates protein kinase C (PKC), which in turn induces cox-2 production in several cell types. Our aim was to determine whether Cd-induced Ca release and PGE2 production in neonatal mouse calvaria involve induction of cox-2 and, if so, to ascertain whether that effect is mediated by activation of PKC. Cd dose-dependently stimulated Ca release from cultured neonatal mouse calvaria, with a maximal effect at 0.4–0.8 μM. Different sensitivity was observed to Cd-induced Ca release between two breeds of mice suggesting that the susceptibility to Cd may be genetically determined. Dexamethasone (10 μM) added to the culture medium abolished the Ca releasing effect of Cd, an effect not overcome by addition of arachidonic acid (10 μM). The cox-2-selective inhibitors NS-398 and DFU and the less selective inhibitor meloxicam, potently impeded Cd-induced Ca release (IC50 of 1 nM, 41 nM and 7 nM, respectively) and calvarial production of PGE2. Cd-induced and phorbol 12-myristate 13-acetate (PMA; 20 nM)-induced Ca release was inhibited by the PKC inhibitor calphostin C (0.5 μM) and by NS-398. The effects of PMA and Cd on Ca release were not additive, suggesting that both operated via the PKC pathway. We suggest that Cd-induced Ca release from neonatal mouse calvaria in culture depends on induction of cox-2 that occurs via the PKC signalling pathway.
Keywords: Key words Cadmium; Cox-2; Osteoporosis; Prostaglandin E2; Protein kinase C
Rat model for renal effects of 2-alkoxyalcohols and their acetates by J. Liesivuori; J. Laitinen; H. Savolainen (pp. 229-232).
Male Wistar rats were given ethanediol (9.4 g/l), 2-ethoxyethylacetate (5.4 g/l), 2-butoxyethylacetate (2.9 g/l) and 1,2-propanediol (40 g/l) respectively in their drinking water for 2 weeks. Urine was collected during the last 24 h of the exposure. There was a marked increase in the oxalic acid excretion by the rats given ethanediol while rats given the alkoxyacetates excreted large amounts of ethoxyacetic and butoxyacetic acid, respectively. While not increased compared with controls, the excretion of oxalic acid by the latter group of rats was correlated to the excretion of the respective alkoxyacetic acids. The ammonia and glycosaminoglycan excretion was also smaller than that of controls. The urinary activity of succinate dehydrogenase was decreased in rats given the alkoxyacetates but not in animals exposed to ethanediol or propanediol. The data show that oxalic acid is actually a minor metabolite of the alkoxyacetates while the biochemical effects in kidney are associated more with the alkoxyacetic acid load. Alkoxyacetic acids seem to be inhibitors of renal succinate dehydrogenase, which may account for the decreased ammonia and glycosaminoglycan excretion.
Keywords: Key words Rat; Urine; Ethanediol; Alkoxyacetates; Succinate dehydrogenase
Urinary antigens as markers of papillary toxicity. II: Application of monoclonal antibodies for the determination of papillary antigens in rat urine by H. Hildebrand; M. Rinke; G. Schlüter; E. Bomhard; F. W. Falkenberg (pp. 233-245).
We have previously reported the preparation of monoclonal antibodies specific for antigens localized in the rat renal papilla. Three of the monoclonal antibodies reacting with antigens localized in papillary and cortical collecting duct epithelia were selected for the development of enzyme-linked immunosorbent assay (ELISA)-type assays. The papillary antigens (`PapA') determined in these tests were designated PapA1 (applying the monoclonal antibody PapX 5C10), PapA2 (applying the monoclonal antibody PapX 12F6), and PapA3 (applying the monoclonal antibody PapXI 3C7). Using these assays antigen excretion was determined in the urine of rats. Depending on the test compound used, the application route, and the dose, the observed antigen release patterns differed. Whereas after a single intraperitoneal application of 2-bromoethanamine or of propyleneimine an increased release of PapA1 but not of the two other antigens was observed oral application of bromoethanamine had minor effects. In contrast, both a single intraperitoneal application or repeated oral applications of indomethacin resulted in an increased release of all the three antigens. Daily application of ipsapirone in the diet or in drinking water resulted in significantly elevated urinary release of PapA1 which increased incrementally for the duration of the application. Release of PapA2 and PapA3 was not affected and remained in the normal range. These results show that with the tests developed changes in the rat renal papilla caused by xenobiotics can be detected early by urinary analysis and monitored during follow-up studies. Moreover, the different antigen release patterns obtained after application of the different compounds suggest a possible differing mode of action.
Keywords: Key words Rat papillary antigens; Monoclonal antibodies; Papillary toxicity; Urinary markers; ELISA-tests
Glutathione transferase alpha as a marker for tubular damage after trichloroethylene exposure by Thomas Brüning; Anders G. M. Sundberg; Gerhard Birner; Marga Lammert; Hermann M. Bolt; Eeva-Liisa Appelkvist; Robert Nilsson; Gustav Dallner (pp. 246-254).
To investigate possible persistent nephrotoxic effects of trichloroethylene (TRI), a retrospective study was carried out on 39 workers exposed to high levels of TRI from 1956 to 1975. Total protein levels in urine, as well as serum and urine creatinine and serum urea were unchanged in comparison with the control. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) was applied to differentiate between tubular and/or glomerular dysfunction. Urinary excretion of alpha-1-microglobulin and glutathione transferase (GST) alpha, as markers of proximal tubular damage, were correlated with the SDS-PAGE patterns of urinary proteins both in the TRI exposed and the control group. GST alpha was found in elevated concentrations in the urine of the TRI-exposed workers. No increase of urinary GST alpha was observed in the control group, even when alpha-1-microglobulin was elevated as a result of non-toxic damage. Both in the control and exposed groups, GST pi, a marker of distal tubular damage, was in the normal range. The results show that chronic exposure to high doses of TRI causes persistent changes to the proximal tubular system of the kidney and that GST alpha excretion into the urine is a marker well suited for quantitation of the extent of renal damage.
Keywords: Key words Trichloroethylene; Proteinuria; Glutathione transferase; Tubular damage; SDS-PAGE
Glutamine synthetase activity in rat urine as sensitive marker to detect S3 segment-specific injury of proximal tubule induced by xenobiotics by Andrea Trevisan; Patrizia Cristofori; Gianluca Fanelli (pp. 255-262).
The possibility of detecting segment-specific injury of the proximal tubule by means of urinary enzymes was investigated in rats. Urinary glutamine synthetase, an enzyme exclusively localized in the S3 segment, and N-acetyl-β-d-glucosaminidase, prevalently a S1-S2, but S3 enzyme also, were determined after single treatment with 100 mg/kg body wt. of hexachloro-1:3-butadiene (HCBD; i.p.), toxic for the S3 segment, or 25 mg/kg body wt. of potassium dichromate (s.c.), toxic for the S1-S2 segments. Excretion of total urinary proteins was also measured. In addition, a dose-response relationship was determined between three doses (50, 100 and 200 mg/kg body wt.) of HCBD and glutamine synthetase activity in urine. Glutamine synthetase activity, measured according to a new assay for urine based on modification of methods developed for organs, increased in the urine only when the S3 segment of the proximal tubule was damaged, as demonstrated by histological findings of the kidneys. HCBD caused early excretion of the enzyme related to the necrosis of the S3 segment, whereas potassium dichromate caused a slight increase only when the resulting lesion to this segment (vacuolization) began to develop. On the contrary, N-acetyl-β-d-glucosaminidase activity showed the peak of excretion 24 and 34 h after treatment with HCBD or potassium dichromate, respectively, according to the histological findings of necrosis of the S3 segment (the former) and vacuolization of the S1-S2 segments (the latter). Excretion of total urinary proteins reached the peak 24 h (HCBD) and 48 h (potassium dichromate) after treatment. HCBD at 200 mg/kg body wt. caused a peak of glutamine synthetase activity in urine 10 h after injection, whereas the peak caused by doses of 50 and 100 mg/kg body wt. occurred 24 h following treatment. The peak of enzyme activity in urine significantly increased with the dose. The results suggest that the measurement of urinary activity of S3 segment-specific enzyme as glutamine synthetase allows us to detect early S3 segment-specific injury of the proximal tubule. In addition, the method for urinary enzyme activity appears sensitive, simple and fast.
Keywords: Key words Proximal tubule segment-specific injury; Glutamine synthetase; N-acetyl-β-d-glucosaminidase; Hexachloro-1:3-butadiene; Potassium dichromate
Protective effects of capillarisin on tert-butylhydroperoxide-induced oxidative damage in rat primary hepatocytes by Chia-Yih Chu; Tsui-Hwa Tseng; Jin-Ming Hwang; Fen-Pi Chou; Chau-Jong Wang (pp. 263-268).
Capillarisin (Cap), a main constituent of Artemisia capillaris (Compositae), was studied for its antioxidant bioactivity. In the preliminary study, Cap expressed a antioxidant property by its capacity for quenching the free radicals of 1,1-diphenyl-2-picrylhydrazyl (DPPH). This antioxidant bioactivity of Cap was investigated further using a model of t-butylhydroperoxide (t-BHP)-induced cytotoxicity and genotoxicity in rat primary hepatocytes. Results presented here demonstrate that Cap, at concentrations of 0.01–1.00 mg/ml, significantly decreased the leakage of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) and the formation of malondialdehyde (MDA) induced by 30 min treatment of t-BHP (1.5 mM) in primary cultured rat hepatocytes. Cap also attenuated the t-BHP-induced diminution of glutathione (GSH) and high level of DNA repaired synthesis. These results lead to speculation that Cap presents inhibitory effects against t-BHP-caused cytotoxicity and genotoxicity in rat primary hepatocyte cultures at least via two distinct pathways, stabilizing the GSH system and quenching free radicals.
Keywords: Key words Capillarisin; Tert-butylhydroperoxide; Cytotoxicity; Genotoxicity; Hepatocyte
Increased levels of nitrogen oxides and lipid peroxidation in the rat brain after soman-induced seizures by Stig O. P. Jacobsson; Gudrun E. Cassel; Sven-Åke Persson (pp. 269-273).
We have investigated the effect of soman-induced seizures on rat brain levels of nitrogen oxides (NOx) and lipid peroxidation (LPO) 30 min and 24 h after intoxication. Following administration of soman (90 μg/kg s.c.), acetylcholinesterase activity was reduced to <10% of control after 30 min, whereas some de novo synthesis had occurred after 24 h. Significant increases in the LPO products malondialdehyde (MDA) and (E)-4-hydroxy-2-nonenal (4-HNE) were seen in the cortex, hippocampus, striatum, thalamus and medulla-pons 30 min after administration. A significant increase in the brain NOx levels, suggesting an increase in NO production, was seen in the cortex after 30 min and in the hippocampus and the striatum after 24 h. No significant changes were observed in cerebellum. These data suggest the possibility that free radical reactions may be a primary cause of neuronal degeneration after soman intoxication.
Keywords: Key words Soman; Seizures; Brain; Nitric oxide; Lipid peroxidation
Doxorubicin induces male germ cell apoptosis in rats by Kazutoshi Shinoda; Kunitoshi Mitsumori; Kazuo Yasuhara; Chikako Uneyama; Hiroshi Onodera; Masao Hirose; Masato Uehara (pp. 274-281).
To clarify whether apoptosis is involved in doxorubicin (DXR)-induced testicular toxicity and to identify the target germ cell type, adult Sprague-Dawley rats were treated with a single intravenous dose of DXR (8 or 12 mg/kg) and euthanized at 3, 6, 12, 24, and 48 h subsequently. Histologically, germ cell degeneration was first found 6 h after dosing in meiotically dividing spermatocytes and early round spermatids of seminiferous tubules at stage I, and subsequently observed in spermatogonia at stages I–VI showing ultrastructural characteristics of apoptosis. Coincident with the appearance of morphological changes, degenerating germ cells were shown to be undergoing apoptosis as revealed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The frequency of TUNEL-labeled germ cells increased in a stage- and cell type-specific manner, the peak of frequency gradually progressing from stage I of seminiferous tubules to later stages with time after dosing, suggesting that the damaged germ cells, especially spermatogonia, gradually underwent the processes leading to apoptosis. DNA laddering on gel electrophoresis was apparent 24 and 48 h after dosing. The results demonstrate that apoptosis plays an important role in the induction of testicular toxicity caused by DXR with meiotically dividing spermatocytes and type A and intermediate spermatogonia as highly vulnerable target cells.
Keywords: Key words Doxorubicin; Apoptosis; Testicular toxicity
Exposure to epichlorohydrin and dimethylformamide, glutathione S-transferases and sister chromatid exchange frequencies in peripheral lymphocytes by Tsun-Jen Cheng; Shing-Jen Hwang; Hsen-Wen Kuo; Jiin-Chyuan Luo; Ming J. W. Chang (pp. 282-287).
Workers in epoxy resin, synthetic leather, and printed circuit board manufacturing plants are exposed to epichlorohydrin (ECH), or dimethylformamide (DMF), or both. ECH, an alkylating agent, has been shown to cause malignancy in animals, but its genotoxicity in humans is unclear. DMF is a well-known hepatotoxic chemical, although evidence of its genotoxicity in humans is also limited. In this study, we examined the effects of exposure to ECH and DMF on sister chromatid exchange (SCE) in plant workers, in order to examine the genotoxicity of these two agents. Because the genotoxicity of certain agents can be modulated by metabolic traits, we also investigated influence of the glutathione S-transferase (GST) μ (GST M1) and GST θ (GST T1) genes on the genotoxicity of ECH and DMF. A total of 85 male plant workers were included in this study. The subjects were divided into five exposure groups, based on their job titles and the airborne ECH and DMF concentrations in their areas of work. A questionnaire was administered to obtain detailed occupational, smoking, alcohol consumption, and medication histories. Standardized cytogenetic methods were used to determine the frequency of sister chromatid exchange (SCE) in peripheral blood lymphocytes. GST M1 and GST T1 genotypes were identified using polymerase chain reaction (PCR). In analysis, smoking was significantly associated with increased SCE frequency (P < 0.01). Workers with high ECH exposure also had significantly higher SCE frequencies than those with low or no ECH exposure (P < 0.05). However, DMF exposure was not associated with SCE frequency. The GST M1 null genotype was also found to be associated with an increased SCE frequency (P = 0.06). We conclude that ECH exposure may be associated with genetic toxicity and that DMF does not appear to be genotoxic.
Keywords: Key words Sister chromatid exchange; Epichlorohydrin; Dimethylformamide; Glutathione S-transferase (GST) M1; GST T1