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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the cat as a test animal for organophosphorous compound-induced delayed neurotoxicity, tri-o-cresyl phosphate (TOCP) was applied directly on the unprotected back of the neck of young adult cats. Single dermal doses, ranging from 250 to 2000 mg/kg TOCP, or subchronic daily administration of 1 to 100 mg/kg produced delayed neurotoxic effects in the cat. Severity of delayed neurotoxicity depended on the dose and duration. Clinical signs were characterized by hindlimb weakness, ataxia, and paresis. Electromyographic abnormalities resulting from acute denervation were observed in most cats that developed a neurologic deficit. No changes were seen in the motor nerve conduction, thus suggesting that the deficits were in the terminal branch rather than being diffuse lesions in the peripheral nerves. These results correlated well with histopathologic results showing lesions in the most distal portion of the longest tracts in both central and peripheral nervous systems. In the spinal cord, histopathologic studies showed that the ascending tracts of the upper cervical levels and descending tracts of the lumbosacral regions were affected most frequently. Although this study shows that the cat, like the chicken, is susceptible to TOCP-induced delayed neurotoxicity, it demonstrates two differences between the cat and the chicken: greater sensitivity of the cat to the acute effect of TOCP, and greater extent of recovery or improvement of the cat from delayed neurotoxicity. This recovery was demonstrated by: improvement of clinical signs, gain in body weight, disappearance of electromyographic abnormalities, and regeneration of peripheral nerves. Dermal administration of a single 100-mg/kg dose or subchronic 0.5-mg/kg doses of TOCP did not produce delayed neurotoxicity.
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PMID:Electromyographic, neuropathologic, and functional correlates in the cat as the result of tri-o-cresyl phosphate delayed neurotoxicity. 395 42

This investigation was designed to study the neurotoxicity produced in hens by the aliphatic hexacarbons n-hexane, methyl n-butyl ketone (MnBK), 2,5-hexanediol (2,5-HDOH), and 2,5-hexanedione (2,5-HD) following daily dermal application of each chemical alone and in combination with O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN). Dermal application was carried out on the unprotected back of the neck. To assess whether the joint neurotoxic action of various chemicals is caused by the enhancement of absorption through the skin or by interaction at the molecular level, two additional experiments were performed. In the first experiment, EPN was dissolved in each of the aliphatic hydrocarbons prior to their topical application. In the second experiment, EPN was dissolved in acetone and applied at a different location from that of the aliphatic hexacarbons. Dermal application was carried out for 90 d followed by a 30-d observation period. The results show that hens treated with EPN developed severe ataxia followed by improvement during the observation period; n-hexane produced leg weakness with subsequent recovery, whereas the same dose of MnBK, 2,5-HDOH, or 2,5-HD produced clinical signs of neurotoxicity characterized by gross ataxia; concurrent dermal application of EPN with n-hexane or 2,5-HDOH at the same site or at different sites produced an additive neurotoxic action; simultaneous dermal application of EPN and MnBK at different sites resulted in an additive effect, whereas it caused potentiation when applied at the same site; and concurrent topical application of EPN and 2,5-HD produced a potentiating neurotoxic effect. While no histopathologic lesion was produced at the end of the observation period when any test chemical was applied alone, binary treatments of EPN and aliphatic hexacarbons resulted in histopathologic changes in some hens, with morphology and distribution characteristic of EPN neurotoxicity. The joint potentiating or additive action of aliphatic hexacarbons on EPN neurotoxicity was: 2,5-HD greater than MnBK greater than 2,5-HDOH greater than n-hexane. The mechanism of this joint action seems to be related both to enhancing skin absorption of EPN and/or its metabolic activation by n-hexane and its related chemicals.
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PMID:Pattern of neurotoxicity of n-hexane, methyl n-butyl ketone, 2,5-hexanediol, and 2,5-hexanedione alone and in combination with O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens. 406 58

This study reports the differential neurotoxic effects of coumaphos [O,O-diethyl O-(3-chloro-4-methyl-7-coumarinyl) phosphorothioate] when applied orally or dermally in the adult hen. Dermal administration of single (50-500 mg/kg) or daily (100 mg/kg) doses resulted in delayed neurotoxicity in hens, similar to that caused by other delayed neurotoxic organophosphorus compounds. Coumaphos caused loss of weight and produced ataxia, which progressed to paralysis and death. Degeneration of axons and myelin in the spinal cord was the most consistent histopathologic alteration and was identical to that reported for other delayed neurotoxic organophosphorus esters. Only one hen showed peripheral nerve degeneration. Oral administration of a single 100 mg/kg dose or daily doses of 10 mg coumaphos caused severe acute toxicity and killed all treated hens 1-8 d. These hens did not develop delayed neurotoxicity. Some hens given a single oral 50-mg/kg dose or daily 5-mg/kg doses of coumaphos recovered from the initial cholinergic effect and developed clinical signs of delayed neurotoxicity. These hens, however, improved with time and did not show unequivocal nervous-tissue damage at termination.
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PMID:Coumaphos: delayed neurotoxic effect following dermal administration in hens. 713 91

Dicyclohexylcarbodiimide (DCC) and Diisopropylcarbodiimide (DIC) are two representative chemicals in the carbodiimide class of chemicals used in industry as stabilizing agents. There is a potential of dermal exposure to these agents in chemical, pharmaceutical and recombinant DNA industries. The National Toxicology Program conducted a number of animal studies to characterize toxicity and carcinogenicity of DIC and DCC. Dermal administration of DCC and DIC in F344/N rats and B6C3F1 mice for 90-days induced skin irritation at the site of application in a dose-dependent manner. Microscopically, dose-dependent increases in epidermal hyperplasia and chronic inflammation were observed. We further evaluated the effects of dermal exposure of DCC and DIC in p53 haploinsufficient and Tg.AC mouse models. Results revealed the skin as the primary target of DCC and DIC exposure as indicated by dose - dependent skin lesions (hyperplasia, inflammation and necrosis). DCC induced squamous cell papillomas in Tg.AC mice but did not induce any neoplastic lesions in p53 haploinsufficient mice. Dermal application of DIC did not induce any neoplastic lesions in Tg.AC mice and p53 haploinsufficient mice. Based on these studies, it was predicted that DIC would be negative and DCC positive for carcinogenic activity in the traditional two-year bioassay. In the subsequent studies, the carcinogenic potential of DIC only in F344 rats and B6C3F1 mice in a traditional 2-year chronic carcinogenicity bioassay was evaluated by the dermal route. Findings revealed the skin as the major target organ of toxicity in both sexes in rats and in male mice. There were no neoplastic lesions observed in rats or mice with the administration of DIC. In rats, there were clinical signs of toxicity in the highest dose-group which included ataxia, excitability, impaired gait, low muscle tone, abnormal breathing, lethargy, and seizures. This was accompanied by non-neoplastic lesions in the brain and lung only at the highest dose level. In conclusion, both DIC and DCC are dermal toxicants. DIC did not have any carcinogenic activity in transgenic mouse models or in the traditional NTP two-year carcinogenicity studies in F344 rats and B6C3F1 mice. DCC was positive in the Tg.AC mouse model and likely to be carcinogenic in the 2-year bioassay as well.
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PMID:Comparative dermal toxicity of dicyclohexylcarbodiimide and diisopropylcarbodiimide in rodents. 2206 Aug 20

Tert-butyl hydroperoxide (TBHP) is a catalyst frequently used in oxidation and sulfonation reactions in the plastics industry. Since the toxicological evaluation of TBHP remains unknown, the National Toxicology Program (NTP) designed studies to characterize and compare TBHP toxicity by the dermal and oral (gavage) routes in male and female Fischer 344 rats and B6C3F1 mice in 14-day exposures. Rats and mice were administered TBHP at 22, 44, 88, 176 or 352 mg/kg in 0.5% aqueous methylcellulose for the gavage studies. In the dermal studies, mice were administered the same doses as above, while rats were administered four doses (22, 44, 88, 176 mg/kg) in 50% aqueous acetone. Results from the gavage studies revealed treatment-related decreases in survival in male rats and body weights in both male and female rats in the 352 mg/kg group. Clinical signs included post-treatment lethargy, thinness, abnormal breathing, ruffled fur, and/or ataxia which occurred sporadically. The male mice showed a statistically significant decrease in body weight in the 44, 88, 176, and 352 mg/kg groups. The major target organs of toxicity were the forestomach in male and female rats and mice, and the esophagus in male and female rats and in male mice. In addition, there was an increase in the absolute and relative liver weight in female mice with hepatocellular hypertrophy in the top-dose group only. Results from spin trapping experiments revealed the presence of electron paramagnetic resonance signals from radical adducts in the blood and organic extracts of the liver and kidneys of rats treated by gavage with 176 mg/kg TBHP, suggesting the involvement of free- radical generation. The no observed adverse effect level (NOAEL) was considered to be 22 mg/kg in rats and male mice, and 44 mg/kg in female mice. In the dermal studies, there was no effect on survival, body weight, or organ weights in either rats or mice. TBHP administration at the site of application resulted in dermal irritation, hyperkeratosis, hyperplasia, and/or inflammation of the epidermis and inflammation of the dermis at 176 mg/kg and above in male and female rats. Dermal irritation at the site of application was noted in all the mice exposed to 352 mg/kg TBHP. Histopathological lesions in the epidermis and dermis were seen in the 88-352 mg/kg males and in the 176-352 mg/kg females. The NOAEL was found to be 88 mg/kg for male rats and female mice, and 44 mg/kg for female rats and male mice. In conclusion, these studies demonstrate that TBHP is metabolized to free radicals and is a contact irritant affecting skin by the dermal route of exposure, and forestomach and esophagus by oral administration. There was no evidence of systemic absorption by the dermal route of exposure based on lack of pathological findings (Supported by National Institute of Environmental Health Sciences Contract No. N01-ES-65406).
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PMID:Subacute oral and dermal toxicity of tert-butyl hydroperoxide in Fischer F344/N rats and B6C3F1 mice. 2236 79

The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) is caused by a CAG-repeat expansion in the ATXN3 gene. In this study, induced pluripotent stem cell (iPSC) lines were established from two SCA3 patients. Dermal fibroblasts were reprogrammed using an integration-free method and the resulting SCA3 iPSCs were differentiated into neurons. These neuronal lines harbored the disease causing mutation, expressed comparable levels of several neuronal markers and responded to the neurotransmitters, glutamate/glycine, GABA and acetylcholine. Additionally, all neuronal cultures formed networks displaying synchronized spontaneous calcium oscillations within 28days of maturation, and expressed the mature neuronal markers NeuN and Synapsin 1 implying a relatively advanced state of maturity, although not comparable to that of the adult human brain. Interestingly, we were not able to recapitulate the glutamate-induced ataxin-3 aggregation shown in a previously published iPSC-derived SCA3 model. In conclusion, we have generated a panel of SCA3 patient iPSCs and a robust protocol to derive neurons of relatively advanced maturity, which could potentially be valuable for the study of SCA3 disease mechanisms.
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PMID:Induced pluripotent stem cell - derived neurons for the study of spinocerebellar ataxia type 3. 2759 58

Dermal fibroblasts were obtained from a 48-year-old female patient with spinocerebellar ataxia type 3 (SCA3). Fibroblasts were reprogrammed by nucleofection with episomal plasmids, carrying L-MYC, LIN28, OCT4, SOX2, KLF4, EBNA-1 and shRNA against p53. The SCA3 patient-specific iPSC line, MUSIi004-A, was characterized by immunofluorescence staining to verify the expression of pluripotent markers. The iPSC line exhibited an ability to differentiate into three germ layers by embryoid body (EB) formation. Karyotypic analysis of the MUSIi004-A line was normal. The mutant allele was still present in the iPSC line. This iPSC line represents a useful tool for studying neurodegeneration in SCA3.
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PMID:Derivation of an induced pluripotent stem cell line (MUSIi004-A) from dermal fibroblasts of a 48-year-old spinocerebellar ataxia type 3 patient. 2985 67