Evidence that pyrrole formation is a pathogenetic step in γ-diketone neuropathy

Genter, Mary Beth; Szakál-Quin, Gyöngyi; Anderson, C. W.; Anthony, Douglas C.; Graham, Doyle G.

doi:10.1016/0041-008x(87)90296-1

Cited by 74 publications

(34 citation statements)

References 25 publications

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“…The common biologic feature which renders the nervous system and the testis uniquely vulnerable to this toxic injury is unknown. In most instances, the proposed subcellular target for injury is the cytoskeleton (Boekelheide, 1988b;Genter et al, 1987;Gottfried et al, 1985;Miller and Spencer, 1985;Papasozomenos et al, 1981;Seifert and Casida, 1982). Indeed, an effect upon axonal transport is common to many of these toxic agents (Miller and Spencer, 1985;Reichert and AbouDonia, 1980;Weiss and Gorio, 1982).…”

Section: Discussionmentioning

confidence: 99%

Sertoli cell processes have axoplasmic features: an ordered microtubule distribution and an abundant high molecular weight microtubule-associated protein (cytoplasmic dynein).

Neely

Boekelheide

1988

The Journal of Cell Biology

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Abstract. Microtubules in the cytoplasm of rat Sertoli cell stage VI-VIII testicular seminiferous epithelium were studied morphometrically by electron microscopy. The Sertoli cell microtubules demonstrated axonal features, being largely parallel in orientation and predominantly spaced one to two microtubule diameters apart, suggesting the presence of microtubule-bound spacer molecules. Testis microtubule-associated proteins (MAPs) were isolated by a taxol, salt elution procedure. Testis MAPs promoted microtubule assembly, but to a lesser degree than brain MAPs. High molecular weight MAPs, similar in electrophoretic mobilities to brain MAP-1 and MAP-2, were prominent components of total testis MAPs, though no shared immunoreactivity was detected between testis and brain high molecular weight MAPs using both polyclonal and monoclonal antibodies. Unlike brain high molecular weight MAPs, testis high molecular weight MAPs were not heat stable. Testis MAP composition, studied on postnatal days 5, 10, 15, and 24 and in the adult, changed dramatically during ontogeny. However, the expression of the major testis high molecular weight MAP, called HMW-2, was constitutive and independent of the development of mature germ cells. The Sertoli cell origin of HMW-2 was confirmed by identifying this protein as the major MAP found in an enriched Sertoli cell preparation and in two rat models of testicular injury characterized by germ cell depletion. HMW-2 was selectively released from testis microtubules by ATP and co-purified by sucrose density gradient centrifugation with MAP-1C, a neuronal cytoplasmic dynein. The inhibition of the microtubuleactivated ATPase activity of HMW-2 by vanadate and erythro-(2-hydroxy-3-nonyl)adenine and its proteolytic breakdown by vanadate-dependent UV photocleavage confirmed the dynein-like nature of HMW-2. As demonstrated by this study, the neuronal and Sertoli cell cytoskeletons share morphological, structural and functional properties.

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Section: Discussionmentioning

confidence: 99%

Sertoli cell processes have axoplasmic features: an ordered microtubule distribution and an abundant high molecular weight microtubule-associated protein (cytoplasmic dynein).

Neely

Boekelheide

1988

The Journal of Cell Biology

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“…It is now recognized that HD, as a hard diketone electrophile, reacts with hard nucleophilic ε-amine groups on lysine residues to form 2,5-dimethylpyrrole adducts on NF subunits and other proteins (reviewed in 4,10). It is also recognized that pyrrole formation is a necessary step in the production of the γ-diketone neuropathy mediated by lysine adduct formation [37– 39]. However, the levels of protein adducts formed during HD exposure are very low and encompass both neuronal and non-neuronal proteins [18].…”

Section: γ-Diketone Neuropathy – Target Specificity and Tissue Vulnermentioning

confidence: 99%

Toxic neuropathies: Mechanistic insights based on a chemical perspective

LoPachin

Gavin

2015

Neuroscience Letters

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2,5-Hexanedione (HD) and acrylamide (ACR) are considered to be prototypical among chemical toxicants that cause central-peripheral axonopathies characterized by distal axon swelling and degeneration. Because the demise of distal regions was assumed to be causally related to the onset of neurotoxicity, substantial effort was devoted to deciphering the respective mechanisms. Continued research, however, revealed that expression of the presumed hallmark morphological features was dependent upon the daily rate of toxicant exposure. Indeed, many studies reported that the corresponding axonopathic changes were late developing effects that occurred independent of behavioral and/or functional neurotoxicity. This suggested that the toxic axonopathy classification might be based on epiphenomena related to dose-rate. Therefore, the goal of this mini-review is to discuss how quantitative morphometric analyses and the establishment of dose-dependent relationships helped distinguish primary, mechanistically relevant toxicant effects from non-specific consequences. Perhaps more importantly, we will discuss how knowledge of neurotoxicant chemical nature can guide molecular-level research toward a better, more rational understanding of mechanism. Our discussion will focus on HD, the neurotoxic γ-diketone metabolite of the industrial solvents n-hexane and methyl-n-butyl ketone. Early investigations suggested that HD caused giant neurofilamentous axonal swellings and eventual degeneration in CNS and PNS. However, as our review will point out, this interpretation underwent several iterations as the understanding of γ-diketone chemistry improved and more quantitative experimental approaches were implemented. The chemical concepts and design strategies discussed in this mini-review are broadly applicable to the mechanistic studies of other chemicals (e.g., n-propyl bromine, methyl methacrylate) that cause toxic neuropathies.

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“…The reaction of 2,5-hexanedione (and other y-diketones, but not diketones with other than y-spacing) with the lysyl groups of proteins leads via a series of intermediate steps to the formation of Environmental Health Perspectives -Vol 104, Supplement -March 1996 chemical adducts characterized as pyrroles (149,150). Experiments with diastereoisomers of 3,4-dimethyl-2,5-hexanedione have indicated that the formation of the pyrrole is a critical step in the sequence of events that result in the axonopathy (151). Further experiments have also shown that, though formation of pyrrole is a necessary step in neurotoxicity, it is not sufficient because pyrrole oxidation must also occur, leading to neurofilament cross-linking (152).…”

Section: Styrenementioning

confidence: 99%

Biomarker research in neurotoxicology: the role of mechanistic studies to bridge the gap between the laboratory and epidemiological investigations.

Costa

1996

Environ Health Perspect

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There is an increasing interest in the development and validation of biomarkers for use in biochemical/molecular epidemiological studies. Though the area of neurotoxicology has received much attention in the past several years, it still lags behind with regard to the development of biomarkers, particularly those of health effects and susceptibility. This review discusses several aspects of biomarker research as it relates to neurotoxic compounds and focuses on selected agents (organophosphorus insecticides, styrene, n-hexane, carbon disulfide, acrylamide), which have been the subject of a number of investigations in animals and humans. While traditional biomonitoring approaches and novel techniques (e.g., hemoglobin adducts) provide several measurements for monitoring exposure to neurotoxic chemicals, potential markers of genetic susceptibility have been seldom investigated in a neurotoxicology context. Furthermore, the complexity of the nervous system, together with the multiplicity of end points and the limited knowledge of the exact mechanism(s) of action of neurotoxicants, has led to only limited advancements in the development of biomarkers for neurotoxic effects. Significant progress in this area will depend upon an increased understanding of the cellular, biochemical, and molecular targets directly involved in neurotoxicity.

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Evidence that pyrrole formation is a pathogenetic step in γ-diketone neuropathy

Cited by 74 publications

References 25 publications

Sertoli cell processes have axoplasmic features: an ordered microtubule distribution and an abundant high molecular weight microtubule-associated protein (cytoplasmic dynein).

Sertoli cell processes have axoplasmic features: an ordered microtubule distribution and an abundant high molecular weight microtubule-associated protein (cytoplasmic dynein).

Toxic neuropathies: Mechanistic insights based on a chemical perspective

Biomarker research in neurotoxicology: the role of mechanistic studies to bridge the gap between the laboratory and epidemiological investigations.

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