Amino Acid and Protein Targets of 1,2-Diacetylbenzene, a Potent Aromatic γ-Diketone That Induces Proximal Neurofilamentous Axonopathy

Kim, Min Sun; Hashemi, Seyed B.; Spencer, Peter S.; Sabri, Mohammad I.

doi:10.1006/taap.2002.9456

Cited by 31 publications

(36 citation statements)

References 29 publications

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“…These data suggest that 1,2-DAB targets many neural proteins including motor and cytoskeletal proteins. An earlier communication from our laboratory showed that the neuroprotein reactivity of 1,2-DAB correlates directly with total lysine content [16]. Thus NF-H (13-16% lysine) and NF-M (11-12%) reacted more readily than NF-L (6-7%) or tubulin (3-4%) with 1,2-DAB.…”

Section: Discussionmentioning

confidence: 94%

“…Eight-microgram protein from spinal cord or sciatic nerve was separated on 4-12% or 4-15% gradient polyacrylamide gels [16]. Proteins were visualized by immunoblotting using monoclonal mouse antibodies for neurofilament M (NF-M), kinesin, dynein, or tau.…”

Section: Western Blottingmentioning

confidence: 99%

“…The in vitro reactivity of DAB isomers with motor and cytoskeletal proteins was studied as described earlier [16]. Briefly, rats were anesthetized with an isofluorane/oxygen mixture, decapitated by guillotine, and the spinal cord (SC) expelled with ice-cold 0.1 M phosphate-buffered saline by the method of deSousa and Horrocks [5].…”

Section: In Vitro Studies Of Dab Isomers With Rat Spinal Cordmentioning

confidence: 99%

“…Unlike the other isomers, 1,2-diethylbenzene (1,2-DEB) [8,27,37], is metabolized to a proteinreactive neurotoxic metabolite 1,2-diacetylbenzene (1,2-DAB) [3]. We have shown that 1,2-DAB reacts with amino acids and proteins to form a blue pigment both in vitro and in vivo [16,18]. Rats treated with 1,2-DEB or 1,2-DAB, but not with the corresponding meta or para isomers, develop a bluish tissue and urine, limb weakness accompanied by electrophysiological deficits, altered brain stem auditory evoked potentials [6][7][8][9], and neuropathological evidence of a central-peripheral proximal axonopathy characterized by islands of segregated mitochondria and microtubules and focal axonal swellings filled with 10 nm neurofilaments (NF) [17,18,39].…”

Section: Introductionmentioning

confidence: 99%

“…Neurofilaments are composed of triplet proteins that move anterogradely in a slow phase of axonal transport from their site of synthesis in the nerve cell body along the axon to the nerve terminal [14]. Both aromatic (1,2-DAB) and aliphatic (2,5-hexanedione) c-diketones react with lysine moieties of proteins, cross-link NF and other proteins and form protein adducts [4,11,16]. It is, however, unclear whether NF adduction is responsible for their accumulation in axonal swellings or other neuronal (axonal) proteins are also involved in the genesis of c-diketone axonopathy.…”

Section: Introductionmentioning

confidence: 99%

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Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

et al. 2007

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The aromatic hydrocarbon 1,2-diacetylbenzene (1,2-DAB) is a protein-reactive gamma-diketone metabolite of the neurotoxic solvent 1,2-diethylbenzene (1,2-DEB). The effect of neurotoxic 1,2-DAB and its non-neurotoxic isomer 1,3-DAB has been studied on motor proteins and cytoskeletal proteins of rat spinal cord (SC). For in vitro studies, SC slices were incubated with 1, 2, 5, 10 mM of DAB isomers for 30 min at 37 degrees C. For in vivo studies, rats received (i.p.) 20 mg/kg/day of 1,2-DAB or 1,3-DAB, or vehicle (2% acetone in saline), 5 days a week for 2 weeks. Spinal cord and sciatic nerve proteins were subjected to Western blotting using monoclonal mouse antibodies to NF-M, kinesin, dynein, and tau. Proteins were quantified and paired mean comparisons performed to assess concentration-dependent changes in native protein bands. In vitro, 1,2-DAB produced a concentration-dependent decrease of motor and cytoskeletal proteins. While dynein and tau appeared similarly affected by 1,2-DAB, kinesin was most affected by the toxicant. In vivo, 1,2-DAB affected motor and cytoskeletal proteins of sciatic nerves and spinal cord differentially. In general, sciatic nerve proteins were much more affected than spinal cord proteins. The results show that motor proteins that drive axonal transport anterogradely (kinesin) and retrogradely (dynein), cytoskeletal protein NF-M, which is slowly transported in the anterograde direction, and microtubule-associated protein, tau, which is involved in axonal transport, are differentially impacted by 1,2-DAB. By contrast, non-neurotoxic isomer 1,3-diacetylbenzene (1,3-DAB), had no adverse effect on neural proteins either in vitro or in vivo. 2D-Differential in gel electrophoresis (2D-DIGE) of sciatic nerves from neurotoxic 1,2-DAB and non-neurotoxic 1,3-DAB treated rats revealed 197 and 304 protein spots, respectively.

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Section: Discussionmentioning

confidence: 94%

Section: Western Blottingmentioning

confidence: 99%

Section: In Vitro Studies Of Dab Isomers With Rat Spinal Cordmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

et al. 2007

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Diethylbenzol (alle Isomere) [MAK Value Documentation in German language, 2018]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated diethylbenzene as mixture of isomers [ 25340‐17‐4 ], as well as the individual isomers 1,2‐diethylbenzene [ 135‐01‐3 ], 1,3‐diethylbenzene [ 141‐93‐5 ] and 1,4‐diethylbenzene [ 105‐05‐5 ] considering all toxicological endpoints. Available publications and unpublished studies are described in detail. 1,2‐Diethylbenzene is the most toxic of the isomers, the critical effect being peripheral neurotoxicity which is due to a gamma‐diketone formed metabolically. In subchronic inhalation and oral studies in rats with diethylbenzene mixtures containing 1,2‐diethylbenzene, subclinical neurotoxicity is observed at all concentrations and doses used. From these studies a maximum concentration at the workplace (MAK value) of 1 ml/m 3 is set for 1,2‐diethylbenzene. For a diethylbenzene mixture containing 10 % 1,2‐diethylbenzene, the critical effect in rats is leuco‐ and lymphopenia. A MAK value of 5 ml/m 3 is set for diethylbenzene mixtures and the MAK value for 1,2‐diethylbenzene has to be observed additionally. In rats, critical endpoints for 1,3‐diethylbenzene are increased liver and thyroid weight and for 1,4‐diethylbenzene altered clinical chemical parameters and increased kidney weight. A MAK value of 5 ml/m 3 for both isomers is derived. Since systemic effects are critical, Peak Limitation Category II is designated for all isomers. As peripheral neurotoxicity is a cumulative effect, an excursion factor of 8 is set for 1,2‐diethylbenzene. The default excursion factor of 2 for systemically acting substances is set for diethylbenzene mixtures as well as 1,3‐ diethylbenzene and 1,4‐diethylbenzene as their half‐lives are not known. Thus, the allowable peak exposures are lower than those of other alkyl benzenes and also prevent from irritation. By analogy with acrylamide it is deduced that rats exposed in utero to 1,2‐diethylbenzene are not more susceptible to peripheral neurotoxicity than adult animals. The oral NOAEL for developmental toxicity of 1,2‐diethylbenzene in rats is scaled to a concentration of 17 ml/m 3 at the workplace. Therefore, damage to the embryo or foetus is unlikely when the MAK value is observed and 1,2‐diethylbenzene is assigned to Pregnancy Risk Group C. The oral NOAEL for developmental toxicity of a diethylbenzene mixture in rats is scaled to a concentration of 94 ml/m 3 at the workplace. Developmental toxicity studies with 1,3‐diethylbenzene and 1,4‐diethylbenzene are lacking, however, these isomers are contained in the diethylbenzene mixture to about 60 % and 30 %, respectively. Therefore, damage to the embryo or foetus is unlikely when the MAK value is observed and diethylbenzene mixtures as well as 1,3‐diethylbenzene and 1,4‐diethylbenzene are assigned to Pregnancy Risk Group C. Diethylbenzenes are not genotoxic in vitro and in vivo. In a carcinogenicity study dermal application of a diethylbenzene mixture induced a single squamous carcinoma in mice, which is judged not sufficient for classification as a carcinogen. According to skin absorption models, percutaneous absorption can contribute significantly to systemic toxicity and all diethylbenzene isomers are designated with an “H” notation. Limited data show no sensitization.

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Diethylbenzene (all isomers) [MAK value documentation, 2018]

Hartwig

Arand²

2019

The MAK‐Collection for Occupational Health and Safety

View full text Add to dashboard Cite

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated diethylbenzene as mixture of isomers [ 25340‐17‐4 ], as well as the individual isomers 1,2‐diethylbenzene [ 135‐01‐3 ], 1,3‐diethylbenzene [ 141‐93‐5 ] and 1,4‐diethylbenzene [ 105‐05‐5 ] considering all toxicological end points. Available publications and unpublished studies are described in detail. 1,2‐Diethylbenzene is the most toxic of the isomers, the critical effect being peripheral neurotoxicity which is due to a gamma‐diketone formed metabolically. In subchronic inhalation and oral studies in rats with diethylbenzene mixtures containing 1,2‐diethylbenzene, subclinical neurotoxicity is observed at all concentrations and doses used. From these studies a maximum concentration at the workplace (MAK value) of 1 ml/m 3 is set for 1,2‐diethylbenzene. For a diethylbenzene mixture containing 10% 1,2‐diethylbenzene, the critical effect in rats is leuco‐ and lymphopenia. A MAK value of 5 ml/m 3 is set for diethylbenzene mixtures and the MAK value for 1,2‐diethylbenzene has to be observed additionally. In rats, critical end points for 1,3‐diethylbenzene are increased liver and thyroid weight and for 1,4‐diethylbenzene altered clinical chemical parameters and increased kidney weight. A MAK value of 5 ml/m 3 for both isomers is derived. Since systemic effects are critical, Peak Limitation Category II is designated for all isomers. As peripheral neurotoxicity is a cumulative effect, an excursion factor of 8 is set for 1,2‐diethylbenzene. The default excursion factor of 2 for systemically acting substances is set for diethylbenzene mixtures as well as 1,3‐ diethylbenzene and 1,4‐diethylbenzene as their half‐lives are not known. Thus, the allowable peak exposures are lower than those of other alkyl benzenes and also prevent from irritation. By analogy with acrylamide it is deduced that rats exposed in utero to 1,2‐diethylbenzene are not more susceptible to peripheral neurotoxicity than adult animals. The oral NOAEL for developmental toxicity of 1,2‐diethylbenzene in rats is scaled to a concentration of 17 ml/m 3 at the workplace. Therefore, damage to the embryo or foetus is unlikely when the MAK value is observed and 1,2‐diethylbenzene is assigned to Pregnancy Risk Group C. The oral NOAEL for developmental toxicity of a diethylbenzene mixture in rats is scaled to a concentration of 94 ml/m 3 at the workplace. Developmental toxicity studies with 1,3‐diethylbenzene and 1,4‐diethylbenzene are lacking, however, these isomers are contained in the diethylbenzene mixture to about 60% and 30%, respectively. Therefore, damage to the embryo or foetus is unlikely when the MAK value is observed and diethylbenzene mixtures as well as 1,3‐diethylbenzene and 1,4‐diethylbenzene are assigned to Pregnancy Risk Group C. Diethylbenzenes are not genotoxic in vitro and in vivo. In a carcinogenicity study dermal application of a diethylbenzene mixture induced a single squamous carcinoma in mice, which is judged not sufficient for classification as a carcinogen. According to skin absorption models, percutaneous absorption can contribute significantly to systemic toxicity and all diethylbenzene isomers are designated with an “H” notation. Limited data show no sensitization.

show abstract

Amino Acid and Protein Targets of 1,2-Diacetylbenzene, a Potent Aromatic γ-Diketone That Induces Proximal Neurofilamentous Axonopathy

Cited by 31 publications

References 29 publications

Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

Diethylbenzol (alle Isomere) [MAK Value Documentation in German language, 2018]

Diethylbenzene (all isomers) [MAK value documentation, 2018]

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