Altered Susceptibility to Dopaminergic Neurotoxicity: Differential Effects of Thiocarbamates and Rotenone. The session began with a presentation by Dr. Diane Miller who prefaced her talk by suggesting an association between Parkinson's disease (PD) and exposure to environmental factors, such as living in a rural area, well water use, or farming, and pesticides. Rotenone, a commonly applied pesticides, and a mitochondrial complexes I and II inhibitor, has been shown to cause selective nigral degeneration with inclusion formation provoked by its systemic administration. Both rotenone and diethyldithio-carbamate (DDC), a prototypic member of a class of compounds called dithiocarbamates (DTCs) widely used in industry and agriculture, have been shown to enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine depletion in mice. The purpose of the study discussed by Dr. Miller was accordingly to determine the effects of these compounds in an MPTP mice model, with specific emphasis on striatal levels of dopamine and its metabolites, tyrosine hydroxylase, the rate limiting enzyme in catecholamine synthesis, and glial fibrillary acidic protein (GFAP), an index of neuronal damage. Dr. Miller detailed the specific effects of rotenone and DDC, respectively, and suggested that in the MPTP model, both rotenone and DDC exerted specific effects that were additive to those induced by MPTP administration alone. In general both rotenone and DDC exacerbates the striatal damage induced by MPTP. However, most interesting was Dr. Miller's observation that rotenone mitigates the MPTP-induced astrocytic response, leading to decreased GFAP expression. The studies portray a complicated picture of injury and raise some intriguing issues. For example, how does rotenone affect GFAP expression? What mechanisms can be invoked to explain this effect? In response to injury of the CNS in the adult, it has been shown that astrocytes become reactive, upregulating the expression of GFAP, and reexpressing vimentin, modifications that contribute to the formation of glial scar that is obstructive to axonal regeneration (Menet et al., 2001). Might it be possible to take advantage of rotenone's effect on GFAP expression, thus increasing the permissivity of astrocytes in regenerative processes? The mechanisms by which the effects of rotenone and DDC occur are largely unknown, but both have been shown to inhibit NF-kappaB, a family of transcription factors participating in the activation of a wide range of genes. A growing body of evidence is accumulating for a specific activation of NF-kappaB proteins in the CNS, and in particular in neuronal cells, during neurodegenerative processes associated to etiologically unrelated conditions. Though it is not fully appreciated whether NF-kappaB activation is part of the neurodegenerative process or of protective mechanisms it is possible that rotenone and DDC act via this pathway to increase the effects of MPTP, though NF-kappaB activation is not involved in a MPTP model of PD (Teismann et al., 2001). It would seem profitable to direct future studies at the effects of DDC and rotenone on NF-kappaB activation. Neurological Effects of Adult Exposure to PCBs: Studies in Human and Non-Human Primates. The next paper was presented by Dr. Rich Seegal of the Wadsworth Center of the New York State Department of Health in Albany, New York. Although the majority of the neurological (e.g. neurochemical, neurobehavioral) research on the consequences and mechanisms of action of PCBs have been carried out in the developing organism (Seegal et al., 1997; Hany et al., 1999), Seegal et al. (1994) have demonstrated significant reductions in dopamine (DA) concentrations in the basal ganglia of non-human primates (NHPs) exposed to PCBs. In the NHP studies, animals were exposed to commercial mixtures of PCBs for 20 weeks. Significant reductions in basal ganglia DA concentrations were seen even though serum PCB concentrations were less than two-fold higher than those reported in former occupationally exposed workers 3 years after exposure ceased. Most importantly basal ganglia DA concentrations were still significantly depressed even after a 24-week washout, when serum levels were significantly reduced. These long-term reductions in basal ganglia DA concentrations may be a consequence of a loss of tyrosine hydroxylase (TH) containing neurons in the substantia nigra (SN)-60 weeks exposure to PCBs significantly reduced the number the number of TH-positive neurons in the SN compared to the number of neurons seen in control animals. Potential mechanisms that may be responsible for these PCB-induced alterations in basal ganglia DA physiology involve inhibition of monoamine transporters, including the dopamine transporter (DAT) (Mariussen and Fonnum, 2001) and the vesicular monoamine transporter (VMAT) (Mariussen et al., 1999). Inhibition of VMAT leads to an increase in free cytosolic DA, which in turn, leads to oxidative stress and alterations in mitochondrial function (Berman and Hastings, 1999). These laboratory studies not only provide a rationale for examining the central consequences of long-term occupational exposure to PCBs in an aging cohort of former capacitor workers, but also raise a number of important questions related to the putative role that this widespread environmental and occupational neurotoxicant might play in the etiology of Parkinsonian-like dysfunctions. Will there be clinically detectable changes in neurological and neuropsychological function in previously occupationally exposed workers that can be associated with job histories and PCB body burdens? Will there be significant reductions in the number of DA-containing terminals in the caudate-putamen of these workers (determined with [123I]-CIT SPECT imaging)? Will these two sets of dependent variables be correlated? If the 'analytical' epidemiological studies demonstrate an association between occupational exposure to PCBs and an increase in the incidence of Parkinsonian-like symptoms, the case for PCBs as an environmental factor in the etiology of idiopathic Parkinsonism will be greatly strengthened.
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