Changes in the Murine Nigrostriatal Pathway Following Pyrethroid and Organophosphate Insecticide Exposure: An Immunohistochemical Study
Pittman, Julian Thomas
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Parkinson's disease (PD) is a debilitating motor disorder that primarily afflicts older individuals (> 50yrs). Although its cause is unknown, many factors are thought to contribute to the disease. There is growing epidemiological evidence supporting a link between pesticide exposure and PD. The present immunohistochemical study was undertaken to characterize the role of insecticide exposure in the etiology of idiopathic PD. The insecticides selected for study were the pyrethroid permethrin (PE) and the organophosphate chlorpyrifos (CP), both of which possess properties that could damage or disrupt the nigrostriatal pathway, which is the principal neurodegenerative target in PD. The present study examined possible alteration of the amount of dopamine re-uptake transporter protein (DAT), within the striatum of the C57BL/6 mouse, using DAT antibodies, following low (0.8, 1.5 & 3.0 mg/kg) and high (200 mg/kg) doses of PE, respectively. Possible nigrostriatal terminal degeneration was examined using antibodies to tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, following treatment with 50 mg/kg of CP alone or in combination with the high dose of PE. For both the high dose of PE alone and for the combined PE/CP treatment, glial fibrillary acidic protein (GFAP) antibodies were used to examine the possibility of non-degenerative tissue injury. Groups of matched treated/vehicle-control mice received three IP injections of the insecticide/dose of interest over a 2-week period. Counts of immunoreactive (IR) neuropil in the dorsolateral striatum were made from four pre-selected fields per striatal tissue section. Counts were compared between matched sections, processed on the same slide, from a treated mouse and its vehicle control. A mean difference score, across slides, for each treated/vehicle control pair was determined. All low dose PE groups showed a trend of decreased DAT IR neuropil, but only the 3.0mg/kg group showed a statistically significant reduction (p<.0078). The 200 mg/kg PE group showed a trend toward reduced TH IR neuropil that was not statistically significant, but a significant increase in GFAP IR (p = .048) was observed. No significant change in TH IR neuropil was observed for CP (50mg/kg) alone. A significant increase was observed for GFAP IR neuropil for the PE/CP (200/50 mg/kg) combination dose (p = .033). The combined insecticide treatment failed, however, to produce a significant change in TH IR within the striatum, compared to vehicle controls. These data suggest that the significant increases in GFAP IR neuropil, in the striatum, reflect some form of tissue insult, following exposure to a high dose of PE, or PE/CP in combination, that is insufficient to induce degeneration of dopaminergic terminals within the temporal interval investigated. Although such damage may be sufficient to account for previously reported decreases in maximal dopamine uptake observed with high doses of these compounds, the DAT IR data appear to indicate that this damage is unlikely to be a change in the amount of DAT in these high dose conditions. The decreases in striatal DAT IR neuropil observed for low doses of PE suggest an alteration in the normal integrity of the nigrostriatal pathway and in the route by which environmental toxins may enter dopaminergic neurons.
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