Parkinson's disease (PD) is the second most common neurodegenerative
disease. Much data has linked the etiology of PD to a variety of
environmental factors. The majority of cases are thought to arise from a
combination of genetic susceptibility and environmental factors.
Chronic exposures to dietary factors, including meat, have been
identified as potential risk factors. Although heterocyclic amines that
are produced during high-temperature meat cooking are known to be
carcinogenic, their effect on the nervous system has yet to be studied
in depth. In this study, we investigated neurotoxic effects of
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a highly
abundant heterocyclic amine in cooked meat, in vitro. We tested toxicity
of PhIP and the two major Phase I metabolites, N-OH-PhIP and
4'-OH-PhIP, using primary mesencephalic cultures from rat embryos. This
culture system contains both dopaminergic and non-dopaminergic neurons,
which allows specificity of neurotoxicity to be readily examined. We
find that exposure to PhIP or N-OH-PhIP is selectively toxic to
dopaminergic neurons in primary cultures, resulting in a decreased
percentage of dopaminergic neurons. Neurite length is decreased in
surviving dopaminergic neurons. Exposure to 4'-OH-PhIP did not produce
significant neurotoxicity. PhIP treatment also increased formation of
oxidative damage markers, 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine
in dopaminergic neurons. Pre-treatment with N-acetylcysteine was
protective. Finally, treatment with blueberry extract, a dietary factor
with known antioxidant and other protective mechanisms, prevented
PhIP-induced toxicity. Collectively, our study suggests, for the first
time, that PhIP is selectively toxic to dopaminergic neurons likely
through inducing oxidative stress.
disease. Much data has linked the etiology of PD to a variety of
environmental factors. The majority of cases are thought to arise from a
combination of genetic susceptibility and environmental factors.
Chronic exposures to dietary factors, including meat, have been
identified as potential risk factors. Although heterocyclic amines that
are produced during high-temperature meat cooking are known to be
carcinogenic, their effect on the nervous system has yet to be studied
in depth. In this study, we investigated neurotoxic effects of
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a highly
abundant heterocyclic amine in cooked meat, in vitro. We tested toxicity
of PhIP and the two major Phase I metabolites, N-OH-PhIP and
4'-OH-PhIP, using primary mesencephalic cultures from rat embryos. This
culture system contains both dopaminergic and non-dopaminergic neurons,
which allows specificity of neurotoxicity to be readily examined. We
find that exposure to PhIP or N-OH-PhIP is selectively toxic to
dopaminergic neurons in primary cultures, resulting in a decreased
percentage of dopaminergic neurons. Neurite length is decreased in
surviving dopaminergic neurons. Exposure to 4'-OH-PhIP did not produce
significant neurotoxicity. PhIP treatment also increased formation of
oxidative damage markers, 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine
in dopaminergic neurons. Pre-treatment with N-acetylcysteine was
protective. Finally, treatment with blueberry extract, a dietary factor
with known antioxidant and other protective mechanisms, prevented
PhIP-induced toxicity. Collectively, our study suggests, for the first
time, that PhIP is selectively toxic to dopaminergic neurons likely
through inducing oxidative stress.
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