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Biomedical subjects

G J Harry

Publications and source records attributed to G J Harry.

At least 19 recordsLinked to original sources
PubMed2001

Neurotoxicant-induced elevation of adrenomedullin expression in hippocampus and glia cultures.

Adrenomedullin (AM), a vasoactive peptide first isolated from pheochromocytoma, has been reported to be present in neurons in the central nervous system and in tumors of neural and glial origin. In this study, we investigated AM expression both in the hippocampus and in glial cell cultures using a chemical-induced model of injury. An acute intraperitoneal injection of the organometal trimethyltin (TMT) results in neurodegeneration of the hippocampal CA3-4 pyramidal cell layer. Within 4 days of injection, sparse, punctate staining for AM and lectin was evident in the CA3-4 region; by 10 days, a minimal level of CA3-4 neuronal degeneration was evident, with an increase in glial fibrillary acidic protein (GFAP)-positive astrocytes throughout the hippocampus. Degeneration progressed in severity until 30 days post-TMT, with distinct positive immunoreactivity for AM in the CA4 region. mRNA levels for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, GFAP, and AM in the hippocampus were increased over control levels within 4 days following TMT. In cultured glial cells, a 6 hr exposure to TMT (10 microM) produced a morphological response of the cells and increased immunoreactivity for vimentin, GFAP, and AM. mRNA levels for TNFalpha, IL-1alpha, GFAP, vimentin, and AM were elevated within 3-6 hr of exposure. In culture, neutralizing antibodies to IL-1alpha and TNFalpha were effective in inhibiting the TMT-induced elevation of AM mRNA. These data suggest an interaction between the proinflammatory cytokines and glia response in the regulation of AM in response to injury.

Adrenomedullin↗
PubMed2001

Cytochrome P450 CYP2J9, a new mouse arachidonic acid omega-1 hydroxylase predominantly expressed in brain.

A cDNA encoding a new cytochrome P450 was isolated from a mouse brain library. Sequence analysis reveals that this 1,958-base pair cDNA encodes a 57-58-kDa 502-amino acid polypeptide that is 70-91% identical to CYP2J subfamily P450s and is designated CYP2J9. Recombinant CYP2J9 was co-expressed with NADPH-cytochrome P450 oxidoreductase (CYPOR) in Sf9 cells using a baculovirus system. Microsomes of CYP2J9/CYPOR-transfected cells metabolize arachidonic acid to 19-hydroxyeicosatetraenoic acid (HETE) thus CYP2J9 is enzymologically distinct from other P450s. Northern analysis reveals that CYP2J9 transcripts are present at high levels in mouse brain. Mouse brain microsomes biosynthesize 19-HETE. RNA polymerase chain reaction analysis demonstrates that CYP2J9 mRNAs are widely distributed in brain and most abundant in the cerebellum. Immunoblotting using an antibody raised against human CYP2J2 that cross-reacts with CYP2J9 detects a 56-kDa protein band that is expressed in cerebellum and other brain segments and is regulated during postnatal development. In situ hybridization of mouse brain sections with a CYP2J9-specific riboprobe and immunohistochemical staining with the anti-human CYP2J2 IgG reveals abundant CYP2J9 mRNA and protein in cerebellar Purkinje cells. Importantly, 19-HETE inhibits the activity of recombinant P/Q-type Ca(2+) channels that are known to be expressed preferentially in cerebellar Purkinje cells and are involved in triggering neurotransmitter release. Based on these data, we conclude that CYP2J9 is a developmentally regulated P450 that is abundant in brain, localized to cerebellar Purkinje cells, and active in the biosynthesis of 19-HETE, an eicosanoid that inhibits activity of P/Q-type Ca(2+) channels. We postulate that CYP2J9 arachidonic acid products play important functional roles in the brain.

Amino Acid Sequence↗
PubMed2001

Neurodegeneration and glia response in rat hippocampus following nitro-L-arginine methyl ester (L-NAME).

Hippocampal neurodegeneration and glia response was examined following administration of the nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME). Male Long-Evans rats received L-NAME (50 mg/kg, ip) either once or twice a day for 4 days. Both dosing schedules decreased NOS-activity by approximately 90%. At 10 and 30 days following cessation of L-NAME (2x/day), moderate neuronal death was evident in CA1-2 pyramidal cells and dentate granule cells. Neurodegeneration was accompanied by increased astrocyte glial fibrillary acidic protein (GFAP) immunoreactivity yet, minimal astrocyte hypertrophy. Microglia response was limited to an increase in ramified microglia at 10 days, returning to normal by 30 days. As early as 4 days post-dosing (2x/day), GFAP mRNA levels were significantly elevated as were mRNA levels for tumor necrosis factor-alpha (TNFalpha), interleukin-1alpha (IL-1alpha), and interleukin 6 (IL-6). No alterations were seen with L-NAME dosing limited to once a day. The co-administration of a hippocampal neurotoxicant, trimethyltin (TMT), with the last dose of L-NAME (2x/day), produced an additive response pattern of neuronal degeneration including both CA1-2 and CA3-4 pyramidal neurons accompanied by TMT-induced astrocyte hypertrophy and prominent microglia reactivity. This was preceded by elevations in mRNA levels for GFAP, TNFalpha, IL-1alpha, and IL-6 similar to those seen with each substance alone. These data suggest that high levels of L-NAME can produce a pro-inflammatory environment in the brain and that neurodegeneration and neuroglia responses in the hippocampus can be induced by an alteration in the balance and regulation of local nitric oxide levels.

Journal Article↗
PubMed2001

Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain.

The present studies were undertaken to characterize the regional and temporal patterns of neurotrophin messenger RNA and protein levels for beta-nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the developing CNS. We have examined the levels of these neurotrophin messenger RNAs with ribonuclease protection assays and corresponding protein levels with enzyme-linked immunosorbent assays in the developing Long-Evans rat hippocampus, neocortex and cerebellum on postnatal days 1, 7, 14, 21, and 92. In addition, immunohistochemistry was used to localize the neurotrophins in these developing brain regions. Results indicated that in neocortex and hippocampus, messenger RNA for both nerve growth factor and brain-derived neurotrophic factor increased in an age-dependent manner, reaching a plateau by postnatal day 14. In the neocortex, nerve growth factor and brain-derived neurotrophic factor protein levels both peaked at postnatal day 14. In hippocampus, nerve growth factor protein peaked at postnatal day 7 while brain-derived neurotrophic factor peaked at postnatal day 14. In cerebellum, nerve growth factor messenger RNA levels were flat, while nerve growth factor protein peaked at postnatal day 7. Brain-derived neurotrophic factor messenger RNA increased in an age-dependent manner while the pattern for its protein levels was mixed. Neurotrophin-3 messeger RNA levels increased in an age-dependent manner in hippocampus, peaked at postnatal day14 in cerebellum, and no changes occurred in neocortex. Neurotrophin-3 protein was at its peak at postnatal day 1 and thereafter decreased at other postnatal days in all three brain regions. Results of neurotrophin immunohistochemistry often paralleled and complemented enzyme-linked immunosorbent assay data, demonstrating specific cell groups containing neurotrophin proteins in these regions. Within each region, patterns with regard to messenger RNA and respective protein levels for each neurotrophin were unique. No consistent relationship between patterns of neurotrophin messenger RNAs and their cognate proteins was observed between regions. The different regional patterns for neurotrophin messengerRNA and protein levels in each brain region indicate that messenger RNA studies of neurotrophin messenger RNA must be augmented by protein determination to fully characterize spatial and temporal neurotrophin distribution.

Aging↗
PubMed2001

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

Animals↗
PubMed2000

Chemical-induced hippocampal neurodegeneration and elevations in TNFalpha, TNFbeta, IL-1alpha, IP-10, and MCP-1 mRNA in osteopetrotic (op/op) mice.

The osteopetrotic (op/op) mouse, deficient in biologically active colony stimulating factor 1 (CSF-1), was used to examine the role of microglia in chemical-induced trauma. Op/op mice and normal phenotype littermates (non-op/op) received an acute i.p. injection of the hippocampal toxicant, trimethyltin hydroxide (TMT; 1.5 or 2.0 mg/kg). At 2.0 mg/kg, both mice displayed severe degeneration of dentate granule neurons. At 1.5 mg/kg, non-op/op mice showed a limited punctate pattern of neuronal death while op/op mice showed prominent neuronal death. TMT-induced astrocyte reactivity was similar in both groups. RNase protection assays were conducted on hippocampal tissue at 24 hr post-TMT. Elevations were seen in mRNA levels for the host response genes: intercellular cell adhesion molecule (ICAM-1; non-op/op 80%, op/op 85%), the protease inhibitor EB22 (non-op/op 60%, op/op 300%), and glial fibrillary acidic protein (GFAP; non-op/op 300%, op/op 480%) within 24 hr. Macrophage-1 antigen (Mac-1) mRNA levels were lower in all op/op mice and were not induced by TMT exposure. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta mRNA levels were elevated in non-op/op mice while mRNA levels for interferon inducible protein (IP-10) and monocyte chemoattractant protein (MCP-1) were elevated in op/op mice. Tumor necrosis factor alpha (TNFalpha) mRNA levels were significantly elevated in both non-op/op (100%) and op/op (600%) mice. TNFbeta mRNA levels in op/op mice were elevated 200% and interleukin 1alpha (IL-1alpha) 150%. Reverse transcriptase polymerase chain reaction (RT-PCR) showed a TMT-induced elevation in INFalpha and INFbeta mRNA levels and no elevation of INFgamma. mRNA levels of the CSF-1 receptor, c-fms, were unaltered.

Animals↗
PubMed2000

Age-dependent cytokine responses: trimethyltin hippocampal injury in wild-type, APOE knockout, and APOE4 mice.

In this study, the hippocampal neurotoxicant trimethyltin (TMT) was used to examine possible differential susceptibility associated with the apolipoprotein E genotype. Mice-wild type (C57BL6J), APOE knockout, and APOE4 transgenic-received either saline or TMT (2 mg/kg, ip) at either 21 days or 8 months of age. At both ages, similar mRNA levels were seen in the hippocampus across genotypes for ICAM-1, A20, and MAC-1. GFAP mRNA was higher in the APOE knockouts and APOE4 as compared to wild-type mice. Within 24 h, TMT produced cell death of hippocampal dentate granule neurons and mild astrogliosis in all animals. In 21-day-old mice, TMT exposure significantly increased mRNA levels for ICAM-1 and MIP-1alpha in all genotypes. EB-22, GFAP, TNFalpha, and TGF-beta1 levels were significantly elevated in both wild-type and APOE knockout mice following TMT. At 8 months of age, genotype specific differences were observed. mRNA levels for GFAP, TNFbeta, TNFalpha, and MIP-1alpha were increased in both APOE knockout and APOE4 mice compared to wild-type mice. TMT exposure significantly increased mRNA levels for GFAP and MIP-1alpha in all animals. TNFalpha mRNA levels were increased in wild-type and APOE4 mice while EB22 mRNA levels were increased in both the APOE knockout and APOE4 mice but not wild-type mice. These data suggest an age-dependent effect on both microglia early inflammatory responses to injury associated with the APOE genotype.

Aging↗
PubMed2000

Developmental profiles of growth-associated protein (Gap43), Ngfb, Bndf and Ntf4 mRNA levels in the rat forebrain after exposure to 60 Hz magnetic fields.

Fischer 344 rats were exposed to 60 Hz magnetic fields (EMFs) during gestation and lactation. Rats received continuous exposure to 2-, 200- or 1000-microT magnetic fields for 18.5 h per day, 7 days a week, or sham exposure (sham controls). During postnatal development, on postnatal days 1, 3, 6, 9, 15 and 20, forebrain tissue from male pups was examined for alterations in mRNA level for developmentally regulated central nervous system-specific proteins. Alterations in these factors during critical periods of development could result in alterations in the final neural network. Gap43 (growth-associated protein 43) mRNA was measured by Northern hybridization as a developmental indicator of axonal growth during the development of the neuron. Between postnatal days 1 and 9, detectable levels of Gap43 mRNA displayed a similar pattern across all sham control and exposure groups. In addition to Gap43, mRNA levels for the nervous system-specific growth factors ciliary neurotrophic factor (Cntf), brain-derived neurotrophic factor (Bdnf), beta nerve growth factor (Ngfb), neurotrophin-3 (Ntf3), and neurotrophin-4 (Ntf4) were examined by RNase protection assay. While there is public concern for developmental neurotoxicity associated with exposure to EMFs, these data, generated from animals exposed to 2-, 200- or 1000-microT magnetic fields during both gestational and lactational periods of development, suggest that under these conditions no significant alterations in these critical factors for brain development occur.

Animals↗
PubMed1999

Effect of dexamethasone on elevated cytokine mRNA levels in chemical-induced hippocampal injury.

An acute administration of the hippocampal toxicant trimethyltin (TMT) produced a specific pattern of neuronal necrosis in dentate granule cells with accompanying astrogliosis and initiation of a cytokine response within 24 hours. The purpose of this study was to examine the effects of the anti-inflammatory agent, dexamethasone (DEX), on the pattern of cytokine expression and neuronal degeneration occurring after an acute TMT injection. Dexamethasone (0.2 mg/kg or 10 mg/kg) was administered to 21-day-old male mice 1 hour prior to an injection of TMT hydroxide (2.5 mg/kg, i.p.). Mice receiving 0.2 mg/kg DEX received a second injection 6 hours after TMT. Twenty-four hours later, neuronal necrosis and astrogliosis were assessed and found to be similar in animals treated with TMT, either in the presence or absence of dexamethasone. Pretreatment with dexamethasone failed to prevent the neurodegeneration and astrogliosis. The TMT-induced injury response was represented in elevations of mRNA levels for the injury-associated host response genes glial fibrillary acidic protein (GFAP), EB22/5.3, and intercellular adhesion molecule-1 (ICAM-1). The combination of DEX and TMT produced increased elevation in mRNA levels for EB22/5.3 and ICAM, while GFAP levels remained the same as with TMT alone. The injury response from TMT was accompanied by elevations in mRNA levels for the cytokines tumor necrosis factor (TNF) alpha, TNFbeta, and interleukin (IL)-1alpha. Treatment with dexamethasone prior to TMT resulted in significantly elevated levels of TNFalpha, TNFbeta, and IL-1alpha as compared to TMT alone. These data represent the inability of glucocorticoids to downregulate the injury response in rat hippocampus following a systemic injection of TMT and suggest a stimulation and "priming" of hippocampal cells by dexamethasone.

Analysis of Variance↗
PubMed1999

Expression of AP-1 transcription factors in rat hippocampus and cerebellum after trimethyltin neurotoxicity.

Neurotoxic insult causes neurons to degenerate due to necrosis or apoptosis. After this neurodegenerative phase, gene expression in surviving neurons is altered to undergo regeneration and repair to adapt to changes in the cellular environment. In this study, we examined the expression of four AP-1 transcription factors, Jun, JunB, JunD and FRA-2, and AP-1 DNA binding activity in the rat hippocampus to examine changes during the periods of degeneration and then of regeneration and repair after TMT-induced neurotoxicity. The expression of these factors in the cerebellum was examined as a control since this brain region is not grossly affected by TMT. AP-1 DNA binding slowly increased in both the cerebellum and hippocampus from one hour to eight days after TMT exposure. Levels of Jun in the hippocampus significantly increased at 12 hours after TMT while JunB and JunD expression did not change. On the other hand, FRA-2 was induced at 8 days in the hippocampus after TMT treatment and was expressed only in hippocampi containing neurodegeneration as gauged by elevated glial fibrillary acidic protein levels. FRA-2 immunoreactivity was detected in the AP-1 DNA binding complex only in hippocampal extracts from rats after eight days post-trimethyltin administration. Thus, FRA-2 is a component of the AP-1 DNA binding complex suggesting that it is involved in regulating genes during a later stage of TMT neurotoxicity.

Animals↗
PubMed1998

Increase in brain stem cytokine mRNA levels as an early response to chemical-induced myelin edema.

This study examined the early response of pro-inflammatory and regulatory cytokines in the mouse brain following triethyltin (TET)-induced myelin injury characterized by edematous vacuolation. Following an acute intraperitoneal injection of triethyltin (TET) sulfate (3 mg/kg) to 17-day old CD1 mice, significant increases in brain stem TNF-alpha and IL-1alpha mRNA levels occurred at 6 and 24 h, respectively with elevations in TGF-beta1 and MIP-1alpha at 1 h. In the cortex, responses were limited to elevations at 6 h in TNF-alpha, TGF-beta1 and MIP-1alpha. These data suggest that a chemokine/cytokine response can occur with minimal alterations to the integrity of the myelin sheath and may contribute to the initial signaling mechanisms associated with demyelinating disorders.

Animals↗
PubMed1998

Cellular localization and temporal elevation of tumor necrosis factor-alpha, interleukin-1 alpha, and transforming growth factor-beta 1 mRNA in hippocampal injury response induced by trimethyltin.

In certain pathologic states, cytokine production may become spatially and temporally dysregulated, leading to their inappropriate production and potentially detrimental consequences. Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-beta) mediate a range of host responses affecting multiple cell types. To study the role of cytokines in the early stages of brain injury, we examined alterations in the 17-day-old mouse hippocampus during trimethyltin-induced neurodegeneration characterized by neuronal necrosis, microglia activation in the dentate, and astrocyte reactivity throughout the hippocampus. By 24 h after dosing, elevations in mRNA levels for TNF-alpha, IL-1alpha, IL-1beta, and IL-6 mRNA were seen. TGF-beta1 mRNA was elevated at 72 h. In situ hybridization showed that TNF-alpha and IL-1alpha were localized to the microglia, whereas TGF-beta1 was expressed predominantly in hippocampal pyramidal cells. Intercellular adhesion molecule-1, EB-22, Mac-1, and glial fibrillary acidic protein mRNA levels were elevated within the first 3 days of exposure in the absence of increased inducible nitric oxide synthetase and interferon-gamma mRNA. These data suggest that pro-inflammatory cytokines contribute to the progression and pattern of neuronal degeneration in the hippocampus.

Animals↗
PubMed1998

In vitro techniques for the assessment of neurotoxicity.

Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected through specific mechanisms of neurotoxicity. For example, in vitro systems may be useful for certain structurally defined compounds and mechanisms of toxicity, such as organophosphorus compounds and delayed neuropathy, for which target cells and the biochemical processes involved in the neurotoxicity are well known. For other compounds and the different types of neurotoxicity, a mechanism of toxicity needs to be identified first. Once identified, by either in vivo or in vitro methods, a system can be developed to detect and to evaluate predictive ability for the type of in vivo neurotoxicity produced. Therefore, in vitro tests have their greatest potential in providing information on basic mechanistic processes in order to refine specific experimental questions to be addressed in the whole animal.

Animals↗
PubMed1998

Carbon disulfide neurotoxicity in rats: IV. Increased mRNA expression of low-affinity nerve growth factor receptor--a sensitive and early indicator of PNS damage.

Expression of the low-affinity nerve growth factor receptor (NGF-R) in the peripheral nervous system is regulated by Schwann cell-axonal contact. Steady-state mRNA levels for NGF-R are very low in the mature peripheral nervous system, but are markedly upregulated in sciatic nerve during both primary demyelination (tellurium exposure) and secondary demyelination (Wallerian degeneration). Upregulation also occurs in various subdegenerative axonopathy models where there is axonal atrophy, suggesting its usefulness as a marker for subtle perturbations in normal axon-Schwann cell interactions (Roberson et al., Mol Brain Res 1995; 28:231-238). To further test this hypothesis, we examined NGF-R mRNA expression in sciatic nerves of rats exposed to carbon disulfide (CS2), a toxicant known to cause a distal axonopathy. Adult rats were exposed to CS2 gas (50, 500, or 800 ppm, 6 hr/day, 5 days/wk) for 2-13 weeks. RNA was isolated from sciatic nerves and levels of mRNA for NGF-R determined by Northern blot analysis. NGF-R mRNA expression increased in a dose- and time-dependent manner. Message levels were already increased after 2 wks of exposure to 800 ppm CS2, and increased further with continued exposure. Morphological alterations were not apparent in the sciatic nerve, even at the highest dosage levels with the longest exposure times. Upregulation of NGF-R mRNA is thus an indicator of subtle alterations in the normal axon-Schwann cell relationship and provides a sensitive measure of CS2 neurotoxicity. Assay of this marker may also be useful as a rapid and very sensitive general screen for other compounds which are potentially toxic to the peripheral nervous system.

Administration, Inhalation↗
PubMed1998

Carbon disulfide neurotoxicity in rats: V. Morphology of axonal swelling in the muscular branch of the posterior tibial nerve and spinal cord.

The study objectives were to examine the morphological progression and dose response of carbon disulfide (CS2) distal axonopathy in the muscular branch of the posterior tibial nerve (MBPTN) and spinal cord. Male and female F344 rats were exposed to 0, 50, 500 or 800 ppm CS2 by inhalation, 6 hours/day, 5 days per week, for 2, 4, 8 or 13 weeks. At 8 weeks, in the MBPTN, single fascicles contained individual swollen axons. By 13 weeks, multiple fascicles had giant swollen axons with thin myelin sheaths and occasional degenerated and regenerated axons. At 8 weeks, in the spinal cord, white matter changes in cervical segments 1 and 2 consisted of prominent multifocal axonal swelling in the fasciculus gracilis nerve tracts. In lumbar segments 1 and 2, multifocal axonal swelling was first present at 8 weeks in the lateral and ventro-medial funiculus. By 13 weeks, axonal swelling was diffuse in the fasciculus gracilis nerve tracts of the cervical spinal cord and the lateral and ventral funiculus nerve tracts in the lumbar spinal cord. Compared to the spinal cord, where axonal swelling was present in rats exposed to 800 and 500 ppm, in the muscular branch of the posterior tibial nerve, axonal swelling was only present at 800 ppm at both 8 and 13 weeks. Electron microscopic examination demonstrated marked accumulations of neurofilaments in swollen axons in the spinal cord and MBPTN. Axonal swelling was not present in the spinal cord at 50 ppm, or in the MBPT at 50 and 500 ppm. Axonal swelling was not present at earlier time points of 2 and 4 weeks in either the spinal cord or MBPTN.

Administration, Inhalation↗