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Michael P Stone - One of the best experts on this subject based on the ideXlab platform.
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structure of the 1 4 bis 2 deoxyadenosin n 6 yl 2s 3s butanediol intrastrand dna cross link arising from Butadiene Diepoxide in the human n ras codon 61 sequence
Chemical Research in Toxicology, 2007Co-Authors: Keither W Merritt, Lubomir V Nechev, Thomas M Harris, Constance M Harris, Stephen R Lloyd, Michael P StoneAbstract:The 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S-butanediol intra-strand DNA cross-link arises from bis-alkylation of tandem N6-dA sites in DNA by R,R-Butadiene Diepoxide (BDO2). The oligodeoxynucleotide 5′-d(C1G2G3A4C5X6Y7G8A9A10G11)-3′·5′-d(C12T13T14C15T16T17G18T19C20C21G22)-3′ contains the BDO2 cross-link between the second and third adenines of the codon 61 sequence (underlined) of the human N-ras protooncogene and is named the (S,S)-BD-(61-2,3) cross-link (X,Y = cross-linked adenines). NMR analysis reveals that the cross-link is oriented in the major groove of duplex DNA. Watson-Crick base pairing is perturbed at base pair X6·T17, whereas base pairing is intact at base pair Y7·T16. The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the β-OH is predicted to form a hydrogen bond with T16 O4, whereas in the second, the β-OH is predicted to form a hydrogen bond with T17 O4. In contrast to the (R,R)-BD-(61-2,3) cross-link in the same sequence [Merritt, W.K., Nechev, L.V., Scholdberg, T.A., Dean, S.M., Kiehna, S.E., Chang, J.C., Harris, T.M., Harris, C.M., Lloyd, R.S., and Stone, M.P. (2005) Biochemistry 44, 10081–10092], the anti conformation of the two hydroxyl groups at Cβ and Cγ with respect to the Cβ-Cγ bond results in a decreased twist between base pairs X6·T17 and Y7·T16, and an approximate 10° bending of the duplex. These conformational differences may account for the differential mutagenicity of the (S,S)- and (R,R)-BD-(61-2,3) cross-links, and suggest that stereochemistry plays a role in modulating biological responses to these cross-links [Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572–1580].
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structure of the 1 4 bis 2 deoxyadenosin n6 yl 2r 3r butanediol cross link arising from alkylation of the human n ras codon 61 by Butadiene Diepoxide
Biochemistry, 2005Co-Authors: Keither W Merritt, Lubomir V Nechev, Thomas M Harris, Constance M Harris, Stephen R Lloyd, Tandace A Scholdberg, Stephen M Dean, Sarah E Kiehna, Johanna C Chang, Michael P StoneAbstract:The solution structure of the l,4-bis(2'-deoxyadenosin-N 6 -yl)-2R,3R-butanediol cross-link arising from N 6 -dA alkylation of nearest-neighbor adenines by Butadiene Diepoxide (BDO 2 ) was determined in the oligodeoxynucleotide 5'-d(CGGACXYGAAG)-3'.5'-d(CTTCTTGTCCG)-3'. This oligodeoxynucleotide contained codon 61 (underlined) of the human N-ras protooncogene. The cross-link was accommodated in the major groove of duplex DNA. At the 5'-side of the cross-link there was a break in Watson-Crick base pairing at base pair X 6 .T 1 7 , whereas at the 3'-side of the cross-link at base pair Y 7 .T 1 6 , base pairing was intact. Molecular dynamics calculations carried out using a simulated annealing protocol, and restrained by a combination of 338 interproton distance restraints obtained from 'H NOESY data and 151 torsion angle restraints obtained from 1 H and 3 1 P COSY data, yielded ensembles of structures with good convergence. Helicoidal analysis indicated an increase in base pair opening at base pair X 6 .T 1 7 , accompanied by a shift in the phosphodiester backbone torsion angle β P5'-05'-C5'-C4' at nucleotide X 6 . The rMD calculations predicted that the DNA helix was not significantly bent by the presence of the four-carbon cross-link. This was corroborated by gel mobility assays of multimers containing nonhydroxylated four-carbon N 6 ,N 6 -dA cross-links, which did not predict DNA bending. The rMD calculations suggested the presence of hydrogen bonding between the hydroxyl group located on the β-carbon of the four-carbon cross-link and T 1 7 O 4 , which perhaps stabilized the base pair opening at X 6 .T 1 7 and protected the T 1 7 imino proton from solvent exchange. The opening of base pair X 6 .T 1 7 altered base stacking patterns at the cross-link site and induced slight unwinding of the DNA duplex. The structural data are interpreted in terms of biochemical data suggesting that this cross-link is bypassed by a variety of DNA polymerases, yet is significantly mutagenic [Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580].
Vernon E Walker - One of the best experts on this subject based on the ideXlab platform.
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1 3 Butadiene metabolite 1 2 3 4 diepoxybutane induces dna adducts and micronuclei but not t 9 22 translocations in human cells
Chemico-Biological Interactions, 2019Co-Authors: Vernon E Walker, Amanda Degner, Elizabeth W Carter, Janice A Nicklas, Dale M Walker, Natalia Y Tretyakova, Richard J AlbertiniAbstract:Abstract Epidemiological studies of 1,3-Butadiene (BD) exposures have reported a possible association with chronic myelogenous leukemia (CML), which is defined by the presence of the t(9;22) translocation (Philadelphia chromosome) creating an oncogenic BCR-ABL fusion gene. Butadiene Diepoxide (DEB), the most mutagenic of three epoxides resulting from BD, forms DNA-DNA crosslink adducts that can lead to DNA double-strand breaks (DSBs). Thus, a study was designed to determine if (±)-DEB exposure of HL60 cells, a promyelocytic leukemia cell line lacking the Philadelphia chromosome, can produce t(9;22) translocations. In HL60 cells exposed for 3 h to 0–10 μM DEB, overlapping dose-response curves suggested a direct relationship between 1,4-bis-(guan-7-yl)-2,3-butanediol crosslink adduct formation (R = 0.977, P = 0.03) and cytotoxicity (R = 0.961, P = 0.002). Experiments to define the relationships between cytotoxicity and the induction of micronuclei (MN), a dosimeter of DNA DSBs, showed that 24 h exposures of HL60 cells to 0–5.0 μM DEB caused significant positive correlations between the concentration and (i) the degree of cytotoxicity (R = 0.998, p = 0.002) and (ii) the frequency of MN (R = 0.984, p = 0.016) at 48 h post exposure. To determine the relative induction of MN and t(9;22) translocations following exposures to DEB, or x-rays as a positive control for formation of t(9;22) translocations, HL60 cells were exposed for 24 h to 0, 1, 2.5, or 5 μM DEB or to 0, 2.0, 3.5, or 5.0 Gy x-rays, or treatments demonstrated to yield 0, 20%, 50%, or 80% cytotoxicity. Treatments between 0 and 3.5 Gy x-rays caused significant dose-related increases in both MN (p
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mutagenicity of the racemic mixtures of Butadiene monoepoxide and Butadiene Diepoxide at the hprt locus of t lymphocytes following inhalation exposures of female mice and rats
Mutation Research, 1999Co-Authors: Quanxin Meng, R F Henderson, Vernon E Walker, Dale M Walker, Michael J Bauer, Andrew A ReillyAbstract:Abstract The purpose of this study was to determine if Hprt mutant frequency (M f ) data from rodents exposed directly to individual epoxy metabolites of 1,3-Butadiene (BD) can be used to identify the relative significance of each intermediate in the mutagenicity of BD in mice vs. rats. To this end, the relative contributions of the racemic mixtures of BD monoepoxide (BDO) and BD Diepoxide (BDO 2 ) to BD-induced mutagenicity was investigated by exposing mice and rats to selected concentrations of BDO and BDO 2 (i.e., 2.5 and 4.0 ppm, respectively) and comparing the mutagenic potency of each intermediate to that of BD (at 62.5 ppm) when comparable blood levels of metabolites are achieved (in the mouse). Female B6C3F1 mice and F344 rats (4–5 weeks old) were exposed to rac -BDO (0, 2.5, or 25 ppm) or (±)-BDO 2 (0, 2, 4 ppm) by inhalation for 4 weeks (6 h/day, 5 days/week), and then groups of control and exposed animals ( n =3–12/group) were necropsied at multiple time points post-exposure for measuring Hprt M f s in splenic lymphocytes (via the T-cell cloning assay) and estimating mutagenic potencies (represented by the difference in the areas under the mutant T-cell `manifestation' curves of treated vs. control animals). The resulting M f data, along with the extant metabolism data, suggest that at lower BD exposures (≤62.5 ppm) (±)-BDO 2 is a major contributor to the mutagenicity of BD in mice, whereas other metabolites and stereochemical configurations are responsible for mutations in BD-exposed rats and for the incremental mutagenic effects at higher BD exposures in mice. These studies indicate that additional work is needed to determine more definitively the relative contributions of these and other metabolites and stereochemical forms to BD-induced mutagenicity. Also, the novel approach of measuring mutagenic potencies as the change in Hprt M f s over time in T-cells of exposed vs. control animals, as used in this study, can be valuable for predicting the potential role of these intermediates in each species.
A R Dahl - One of the best experts on this subject based on the ideXlab platform.
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urinary Butadiene Diepoxide a potential biomarker of blood Diepoxide
Toxicology, 2001Co-Authors: R F Henderson, J R Thorntonmanning, W E Bechtold, A R DahlAbstract:The carcinogenicity of 1,3-Butadiene (BD) varies greatly in the rodent species in which 2-year bioassay studies were completed. This raises the question of whether the risk of BD exposure in humans is more like that of the sensitive species, the mouse, or more like that of the resistant species, the rat. Numerous studies have indicated that one reason for the species differences in response to BD is that the blood and tissues of BD-exposed mice contain high levels of both the mono- and the Diepoxide metabolite, while the tissue and blood of exposed rats contain very little of the Diepoxide. The Diepoxide is far more mutagenic than the monoepoxide, and so it is reasonable that the Diepoxide plays a major role in tumor induction in the mouse. If the Diepoxide is the primary carcinogen, the presence of the Diepoxide in the blood of exposed individuals should be an indicator of risk from BD exposure. In this study, we report that the Diepoxide is sufficiently stable to be excreted into the urine of exposed rodents and that the urinary levels of the Diepoxide reflect the relative levels of the compound in the blood of the two species. The conclusion is that urinary Diepoxide should be investigated as a potential biomarker of the formation of the Diepoxide in humans exposed to BD.
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dosimetry and acute toxicity of inhaled Butadiene Diepoxide in rats and mice
Toxicological Sciences, 1999Co-Authors: R F Henderson, W E Bechtold, F F Hahn, Janet M Benson, Edward B Barr, D G Burt, A R DahlAbstract:Butadiene Diepoxide (BDO2), a metabolite of 1,3-Butadiene (BD) and potent mutagen, is suspected to be a proximate carcinogen in the multisite tumorigenesis in B6C3F1 mice exposed to BD. Rats, in contrast to mice, do not form much BDO2 when exposed to BD, and they do not form cancers after exposure to the low levels of BD at which mice develop lung and heart tumors. Tests were planned to determine the direct carcinogenic potential of BDO2 in similarly exposed rats and mice, to see if they would develop tumors of the lung (the most sensitive target organ in BD-exposed mice) or other target tissues. The objective of the current series of studies was to assess the acute toxicity and dosimetry to blood and lung of BDO2 administered by various routes to B6C3F1 mice and Sprague-Dawley rats. The studies were needed to aid in the design of the carcinogenesis study. Initial studies using intraperitoneal injection of BDO2 were designed to determine the rate at which each of the species cleared the compound from the body; the clearance was equally fast in both species. A second study was designed to determine if the highly reactive BDO2, when deposited in the lung, would enter the bloodstream from the lung; intratracheally instilled BDO2 did enter the bloodstream, indicating that exposure via the lungs would result in BDO2 reaching other organs of the body. In a third study, rats and mice were exposed by inhalation for 6 h to 12 ppm BDO2 to determine blood and lung levels of the compound. Concentrations of BDO2 in the lung immediately after the exposure were 2 to 3 times higher than in the blood in both species (approximately 500 and 1000 pmol/g blood in the rat and mouse, respectively). As expected, mice received a higher dose/g tissue than did rats, consistent with the higher minute volume/kg body weight of the mice. The inhalation dosimetry study was followed by a histopathology study to determine the acute toxicity to rodents following a single, 6-h exposure to 18 ppm BDO2. No clinical signs of toxicity were observed; lesions were confined to the olfactory epithelium where areas of necrosis were observed. Analysis of bronchoalveolar lavage fluid did not indicate pulmonary inflammation. Based on these findings, an attempt was made to expose rats and mice repeatedly (for 7 days) to 10 and 20 ppm BDO2, but these exposure concentrations proved too toxic, due to inflammation of the nasal mucosa and occlusion of the nasal airway, a lesion that cannot be tolerated by obligate nose breathers. Finally, the toxicity of rats and mice exposed 6 h/day for 5 days to 0, 2.5, or 5.0 ppm BDO2 was determined. The repeated exposures caused no clinical signs of toxicity, nor were any lesions observed in the respiratory tract or other major organs. Therefore, the final design selected for the carcinogenesis study comprised exposing the rats and mice for 6 h/day, 5 days/week for 6 weeks to 0, 2.5, or 5.0 ppm BDO2.
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gender and species differences in the metabolism of 1 3 Butadiene to Butadiene monoepoxide and Butadiene Diepoxide in rodents following low level inhalation exposures
Toxicology, 1996Co-Authors: J R Thorntonmanning, A R Dahl, W E Bechtold, Rogene F HendersonAbstract:Abstract Levels of Butadiene monoepoxide (BDO) and Butadiene Diepoxide (BDO2) were compared in tissues of male Sprague-Dawley rats and male B6C3F1 mice and in tissues of male and female Sprague-Dawley rats following inhalation exposures to 62.5 ppm 1,3-Butadiene (BD). In male rats, BDO2 levels were highest in blood and were present at a concentration of only 5 ± 1 pmol/g. Following a 6-h exposure, the concentration of BDO2 in the blood, femurs, lung and fat of female rats was 3 to 7-fold that of male rats. Levels of BDO were similar in tissues of female and male rats. Generally, levels of BDO were approximately 3 to 8-fold greater in mouse tissues as compared with rat tissues following 4-h exposures to BD. In blood, 204 ± 15 pmol/g BDO2 was detected in male mice, while in rats, blood BDO2 levels were 5 ± 1 pmol/g. This study shows marked species differences in tissue levels of BD epoxides, particularly BDO2, in rats and mice, and is the first to show gender differences in BD metabolism.
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gender differences in the metabolism of 1 3 Butadiene to Butadiene Diepoxide in sprague dawley rats
1995Co-Authors: J R Thorntonmanning, A R Dahl, W E BechtoldAbstract:1,3-Butadiene (BD), a gaseous compound used in the production of rubber, is a potent carcinogen in mice and a weak carcinogen in rats. The mechanism of BD-induced carcinogenicity is thought to involve genotoxic effects of its reactive epoxide metabolites Butadiene monoepoxide (BDO) and Butadiene Diepoxide (BDO{sub 2}). Studies in our laboratory have shown that levels of the epoxides, particularly BDO{sub 2}, are greater in mice-the more sensitive species-than rats. While both epoxides are genotoxic in a number of assays, BDO{sub 2} is mutagenic in TK6 human lymphoblastoid cells at concentrations approximately 100-fold lower than BDO. Species differences in carcinogenicity of BD have posed a dilemma to investigators deciding which animal model is most appropriate for BD risk assessment.
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disposition of Butadiene monoepoxide and Butadiene Diepoxide in various tissues of rats and mice following a low level inhalation exposure to 1 3 Butadiene
Carcinogenesis, 1995Co-Authors: J R Thorntonmanning, A R Dahl, W E Bechtold, William C Griffith, Rogene F HedersonAbstract:1,3-Butadiene (BD), a chemical used extensively in the production of styrene-Butadiene rubber, is carcinogenic in Sprague-Dawley rats and B6C3F 1 mice. Chronic inhalation studies revealed profound species differences in the potency and organ-site specificity of BD carcinogenesis between rats and mice. BD is a potent carcinogen in mice and a weak carcinogen in rats. Previous studies from our laboratory and others have shown marked differences between rats and mice in the metabolism of BD, which may account for species differences in carcinogenicity. The purpose of the present study was to examine the production and disposition of two mutagenic BD metabolites, Butadiene monoepoxide (BDO) and Butadiene Diepoxide (BDO 2 ), in blood and other tissues of rats and mice during and following inhalation exposures to a target concentration of 62.5 p.p.m. BD. BDO was increased above background in blood, bone marrow, heart, lung, fat, spleen and thymus tissues of mice after 2 h and 4 h exposures to BD. In rats, levels of BDO were increased in blood, fat, spleen and thymus tissues. No increases in BDO were observed in rat lungs. BDO 2 , the more mutagenic of the two epoxides, was increased in the blood of rats and mice at 2 and 4 h after initiation of exposure to BD. In mice, BDO 2 was detected in all tissues examined immediately following the 4 h exposure. This metabolite was detected in heart, lung, fat, spleen and thymus of rats, but at levels 40- to 160-fold lower than those seen in mice. Immediately after the 4 h exposure, blood levels of BDO 2 were 204 ± 15 pmol/g for mice but were 41-fold lower for rats. In the sensitive mouse target organs, heart and lungs, levels of BDO 2 exceeded BDO levels immediately after the exposure. This study shows that the levels of BD epoxides are markedly greater in the mouse BD target organs. The high concentrations of BDO 2 in these organs suggest that this compound may be particularly important in BD-induced carcinogenesis. Thus, although BD is oxidatively metabolized by similar metabolic pathways in rats and mice, the substantial quantitative differences in tissue levels of mutagenic epoxides between species may be responsible for the increased sensitivity of mice to BD-induced carcinogenicity.
Keither W Merritt - One of the best experts on this subject based on the ideXlab platform.
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structure of the 1 4 bis 2 deoxyadenosin n 6 yl 2s 3s butanediol intrastrand dna cross link arising from Butadiene Diepoxide in the human n ras codon 61 sequence
Chemical Research in Toxicology, 2007Co-Authors: Keither W Merritt, Lubomir V Nechev, Thomas M Harris, Constance M Harris, Stephen R Lloyd, Michael P StoneAbstract:The 1,4-bis(2′-deoxyadenosin-N6-yl)-2S,3S-butanediol intra-strand DNA cross-link arises from bis-alkylation of tandem N6-dA sites in DNA by R,R-Butadiene Diepoxide (BDO2). The oligodeoxynucleotide 5′-d(C1G2G3A4C5X6Y7G8A9A10G11)-3′·5′-d(C12T13T14C15T16T17G18T19C20C21G22)-3′ contains the BDO2 cross-link between the second and third adenines of the codon 61 sequence (underlined) of the human N-ras protooncogene and is named the (S,S)-BD-(61-2,3) cross-link (X,Y = cross-linked adenines). NMR analysis reveals that the cross-link is oriented in the major groove of duplex DNA. Watson-Crick base pairing is perturbed at base pair X6·T17, whereas base pairing is intact at base pair Y7·T16. The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the β-OH is predicted to form a hydrogen bond with T16 O4, whereas in the second, the β-OH is predicted to form a hydrogen bond with T17 O4. In contrast to the (R,R)-BD-(61-2,3) cross-link in the same sequence [Merritt, W.K., Nechev, L.V., Scholdberg, T.A., Dean, S.M., Kiehna, S.E., Chang, J.C., Harris, T.M., Harris, C.M., Lloyd, R.S., and Stone, M.P. (2005) Biochemistry 44, 10081–10092], the anti conformation of the two hydroxyl groups at Cβ and Cγ with respect to the Cβ-Cγ bond results in a decreased twist between base pairs X6·T17 and Y7·T16, and an approximate 10° bending of the duplex. These conformational differences may account for the differential mutagenicity of the (S,S)- and (R,R)-BD-(61-2,3) cross-links, and suggest that stereochemistry plays a role in modulating biological responses to these cross-links [Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572–1580].
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structure of the 1 4 bis 2 deoxyadenosin n6 yl 2r 3r butanediol cross link arising from alkylation of the human n ras codon 61 by Butadiene Diepoxide
Biochemistry, 2005Co-Authors: Keither W Merritt, Lubomir V Nechev, Thomas M Harris, Constance M Harris, Stephen R Lloyd, Tandace A Scholdberg, Stephen M Dean, Sarah E Kiehna, Johanna C Chang, Michael P StoneAbstract:The solution structure of the l,4-bis(2'-deoxyadenosin-N 6 -yl)-2R,3R-butanediol cross-link arising from N 6 -dA alkylation of nearest-neighbor adenines by Butadiene Diepoxide (BDO 2 ) was determined in the oligodeoxynucleotide 5'-d(CGGACXYGAAG)-3'.5'-d(CTTCTTGTCCG)-3'. This oligodeoxynucleotide contained codon 61 (underlined) of the human N-ras protooncogene. The cross-link was accommodated in the major groove of duplex DNA. At the 5'-side of the cross-link there was a break in Watson-Crick base pairing at base pair X 6 .T 1 7 , whereas at the 3'-side of the cross-link at base pair Y 7 .T 1 6 , base pairing was intact. Molecular dynamics calculations carried out using a simulated annealing protocol, and restrained by a combination of 338 interproton distance restraints obtained from 'H NOESY data and 151 torsion angle restraints obtained from 1 H and 3 1 P COSY data, yielded ensembles of structures with good convergence. Helicoidal analysis indicated an increase in base pair opening at base pair X 6 .T 1 7 , accompanied by a shift in the phosphodiester backbone torsion angle β P5'-05'-C5'-C4' at nucleotide X 6 . The rMD calculations predicted that the DNA helix was not significantly bent by the presence of the four-carbon cross-link. This was corroborated by gel mobility assays of multimers containing nonhydroxylated four-carbon N 6 ,N 6 -dA cross-links, which did not predict DNA bending. The rMD calculations suggested the presence of hydrogen bonding between the hydroxyl group located on the β-carbon of the four-carbon cross-link and T 1 7 O 4 , which perhaps stabilized the base pair opening at X 6 .T 1 7 and protected the T 1 7 imino proton from solvent exchange. The opening of base pair X 6 .T 1 7 altered base stacking patterns at the cross-link site and induced slight unwinding of the DNA duplex. The structural data are interpreted in terms of biochemical data suggesting that this cross-link is bypassed by a variety of DNA polymerases, yet is significantly mutagenic [Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580].
W E Bechtold - One of the best experts on this subject based on the ideXlab platform.
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urinary Butadiene Diepoxide a potential biomarker of blood Diepoxide
Toxicology, 2001Co-Authors: R F Henderson, J R Thorntonmanning, W E Bechtold, A R DahlAbstract:The carcinogenicity of 1,3-Butadiene (BD) varies greatly in the rodent species in which 2-year bioassay studies were completed. This raises the question of whether the risk of BD exposure in humans is more like that of the sensitive species, the mouse, or more like that of the resistant species, the rat. Numerous studies have indicated that one reason for the species differences in response to BD is that the blood and tissues of BD-exposed mice contain high levels of both the mono- and the Diepoxide metabolite, while the tissue and blood of exposed rats contain very little of the Diepoxide. The Diepoxide is far more mutagenic than the monoepoxide, and so it is reasonable that the Diepoxide plays a major role in tumor induction in the mouse. If the Diepoxide is the primary carcinogen, the presence of the Diepoxide in the blood of exposed individuals should be an indicator of risk from BD exposure. In this study, we report that the Diepoxide is sufficiently stable to be excreted into the urine of exposed rodents and that the urinary levels of the Diepoxide reflect the relative levels of the compound in the blood of the two species. The conclusion is that urinary Diepoxide should be investigated as a potential biomarker of the formation of the Diepoxide in humans exposed to BD.
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dosimetry and acute toxicity of inhaled Butadiene Diepoxide in rats and mice
Toxicological Sciences, 1999Co-Authors: R F Henderson, W E Bechtold, F F Hahn, Janet M Benson, Edward B Barr, D G Burt, A R DahlAbstract:Butadiene Diepoxide (BDO2), a metabolite of 1,3-Butadiene (BD) and potent mutagen, is suspected to be a proximate carcinogen in the multisite tumorigenesis in B6C3F1 mice exposed to BD. Rats, in contrast to mice, do not form much BDO2 when exposed to BD, and they do not form cancers after exposure to the low levels of BD at which mice develop lung and heart tumors. Tests were planned to determine the direct carcinogenic potential of BDO2 in similarly exposed rats and mice, to see if they would develop tumors of the lung (the most sensitive target organ in BD-exposed mice) or other target tissues. The objective of the current series of studies was to assess the acute toxicity and dosimetry to blood and lung of BDO2 administered by various routes to B6C3F1 mice and Sprague-Dawley rats. The studies were needed to aid in the design of the carcinogenesis study. Initial studies using intraperitoneal injection of BDO2 were designed to determine the rate at which each of the species cleared the compound from the body; the clearance was equally fast in both species. A second study was designed to determine if the highly reactive BDO2, when deposited in the lung, would enter the bloodstream from the lung; intratracheally instilled BDO2 did enter the bloodstream, indicating that exposure via the lungs would result in BDO2 reaching other organs of the body. In a third study, rats and mice were exposed by inhalation for 6 h to 12 ppm BDO2 to determine blood and lung levels of the compound. Concentrations of BDO2 in the lung immediately after the exposure were 2 to 3 times higher than in the blood in both species (approximately 500 and 1000 pmol/g blood in the rat and mouse, respectively). As expected, mice received a higher dose/g tissue than did rats, consistent with the higher minute volume/kg body weight of the mice. The inhalation dosimetry study was followed by a histopathology study to determine the acute toxicity to rodents following a single, 6-h exposure to 18 ppm BDO2. No clinical signs of toxicity were observed; lesions were confined to the olfactory epithelium where areas of necrosis were observed. Analysis of bronchoalveolar lavage fluid did not indicate pulmonary inflammation. Based on these findings, an attempt was made to expose rats and mice repeatedly (for 7 days) to 10 and 20 ppm BDO2, but these exposure concentrations proved too toxic, due to inflammation of the nasal mucosa and occlusion of the nasal airway, a lesion that cannot be tolerated by obligate nose breathers. Finally, the toxicity of rats and mice exposed 6 h/day for 5 days to 0, 2.5, or 5.0 ppm BDO2 was determined. The repeated exposures caused no clinical signs of toxicity, nor were any lesions observed in the respiratory tract or other major organs. Therefore, the final design selected for the carcinogenesis study comprised exposing the rats and mice for 6 h/day, 5 days/week for 6 weeks to 0, 2.5, or 5.0 ppm BDO2.
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gender and species differences in the metabolism of 1 3 Butadiene to Butadiene monoepoxide and Butadiene Diepoxide in rodents following low level inhalation exposures
Toxicology, 1996Co-Authors: J R Thorntonmanning, A R Dahl, W E Bechtold, Rogene F HendersonAbstract:Abstract Levels of Butadiene monoepoxide (BDO) and Butadiene Diepoxide (BDO2) were compared in tissues of male Sprague-Dawley rats and male B6C3F1 mice and in tissues of male and female Sprague-Dawley rats following inhalation exposures to 62.5 ppm 1,3-Butadiene (BD). In male rats, BDO2 levels were highest in blood and were present at a concentration of only 5 ± 1 pmol/g. Following a 6-h exposure, the concentration of BDO2 in the blood, femurs, lung and fat of female rats was 3 to 7-fold that of male rats. Levels of BDO were similar in tissues of female and male rats. Generally, levels of BDO were approximately 3 to 8-fold greater in mouse tissues as compared with rat tissues following 4-h exposures to BD. In blood, 204 ± 15 pmol/g BDO2 was detected in male mice, while in rats, blood BDO2 levels were 5 ± 1 pmol/g. This study shows marked species differences in tissue levels of BD epoxides, particularly BDO2, in rats and mice, and is the first to show gender differences in BD metabolism.
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gender differences in the metabolism of 1 3 Butadiene to Butadiene Diepoxide in sprague dawley rats
1995Co-Authors: J R Thorntonmanning, A R Dahl, W E BechtoldAbstract:1,3-Butadiene (BD), a gaseous compound used in the production of rubber, is a potent carcinogen in mice and a weak carcinogen in rats. The mechanism of BD-induced carcinogenicity is thought to involve genotoxic effects of its reactive epoxide metabolites Butadiene monoepoxide (BDO) and Butadiene Diepoxide (BDO{sub 2}). Studies in our laboratory have shown that levels of the epoxides, particularly BDO{sub 2}, are greater in mice-the more sensitive species-than rats. While both epoxides are genotoxic in a number of assays, BDO{sub 2} is mutagenic in TK6 human lymphoblastoid cells at concentrations approximately 100-fold lower than BDO. Species differences in carcinogenicity of BD have posed a dilemma to investigators deciding which animal model is most appropriate for BD risk assessment.
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disposition of Butadiene monoepoxide and Butadiene Diepoxide in various tissues of rats and mice following a low level inhalation exposure to 1 3 Butadiene
Carcinogenesis, 1995Co-Authors: J R Thorntonmanning, A R Dahl, W E Bechtold, William C Griffith, Rogene F HedersonAbstract:1,3-Butadiene (BD), a chemical used extensively in the production of styrene-Butadiene rubber, is carcinogenic in Sprague-Dawley rats and B6C3F 1 mice. Chronic inhalation studies revealed profound species differences in the potency and organ-site specificity of BD carcinogenesis between rats and mice. BD is a potent carcinogen in mice and a weak carcinogen in rats. Previous studies from our laboratory and others have shown marked differences between rats and mice in the metabolism of BD, which may account for species differences in carcinogenicity. The purpose of the present study was to examine the production and disposition of two mutagenic BD metabolites, Butadiene monoepoxide (BDO) and Butadiene Diepoxide (BDO 2 ), in blood and other tissues of rats and mice during and following inhalation exposures to a target concentration of 62.5 p.p.m. BD. BDO was increased above background in blood, bone marrow, heart, lung, fat, spleen and thymus tissues of mice after 2 h and 4 h exposures to BD. In rats, levels of BDO were increased in blood, fat, spleen and thymus tissues. No increases in BDO were observed in rat lungs. BDO 2 , the more mutagenic of the two epoxides, was increased in the blood of rats and mice at 2 and 4 h after initiation of exposure to BD. In mice, BDO 2 was detected in all tissues examined immediately following the 4 h exposure. This metabolite was detected in heart, lung, fat, spleen and thymus of rats, but at levels 40- to 160-fold lower than those seen in mice. Immediately after the 4 h exposure, blood levels of BDO 2 were 204 ± 15 pmol/g for mice but were 41-fold lower for rats. In the sensitive mouse target organs, heart and lungs, levels of BDO 2 exceeded BDO levels immediately after the exposure. This study shows that the levels of BD epoxides are markedly greater in the mouse BD target organs. The high concentrations of BDO 2 in these organs suggest that this compound may be particularly important in BD-induced carcinogenesis. Thus, although BD is oxidatively metabolized by similar metabolic pathways in rats and mice, the substantial quantitative differences in tissue levels of mutagenic epoxides between species may be responsible for the increased sensitivity of mice to BD-induced carcinogenicity.
