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Title: An investigation of the neurotoxicity of trichloroethylene and its metabolite TaClo
Author: Jiang, Zhen.
ISNI:       0000 0001 3590 6169
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2008
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rricrJoroethylene (rCE) is a nonflammable liquid with a high vapour pressure that is primarily used in industry as a metal degreasing agent and is stable for many years. It has moderate solubility in water and can leach from soils into groundwater and therefore water mId food ingestion can be a route of exposure for the general population and illi~alation occupationally. A clinical observation of patients with multiple system atrophy (MSA) suggested an associated with occupational exposure to TCE. Clinical exposure to TCE has recently been proposed to be a possible pathogenic factor in the onset of Parkinson's disease (PD) (Bringmann et aI, 2001) and other neurodegenerative disorders. A mechanism has been indentified in rodents where chloral a metabolite of TCE combined \vith endogenous tryptamine to produce 'TaClo' which, by structural similarities to known neurotoxic compounds, had the potential to be toxic to dopaminergic neurons in the extrapyramidal tracts (Bringmann et aI, 200Gb). Trichloroethylene metabolism to chloral by rat liver subcellular fractions (microsomal and S9) was investigated by GC-ECD. TCE metabolism to chloral showed a biphasic profile. The low capacity high affinity component may be important at occupational and environmental level of TCE exposure. The local TCE metabolism to chloral also was detected using rat brain substania nigra. Although the chloral formation in rat brain (O.05nmol/ g tissue/hour) was much lower than liver (1644nmol/g tissue/hour), local formation may contribute to neurotoxicity. Human CYP2El had a higher capacity to metabolism TCE than other CYP isoforms at high and low TCE concentrations. TaClo was chemically synthesized by reacting tryptamine with chloral (Bringmann, 1990). TaClo was also formed from tryptamine and chloral in buffer and in the presence of cells in vitro, which support its non-enzymatic formation in vitro and in vivo (Bringmann et aI., 2002b). TaClo uptake and efflux from cells was investigated in SH-SY5Y cells. It was found that Na dependent uptake was about three times higher than Na free uptake. Dopamine and OCT2 transporters expressed in oocytes showed little uptake of TaClo and OCTN2 may contribute to uptake of TaClo. TaClo was not transported out of the cell. TaClo selectively inhibited mitochondrial complex I activity and inhibited neuron dendrite outgrowth both indicating apoptosis and neurotoxicity. These results indicated that TaClo can be formed in biological system and be neurotoxic. TaClo and possibly a direct effect of TCE metabolism may induce oxdative stress in neural cells. These observations in vitro support the hypothesis that exposure to TCE may be associated in some individuals with development of neurodegenerative diseases such as MSA and Parkinsonism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available