2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is selectively toxic to primary dopaminergic neurons In Vitro

Amy M. Griggs, Zeynep S. Agim, Vartika R. Mishra, Mitali A. Tambe, Alison E. Director-Myska, Ken W Turteltaub, George P. McCabe, Jean Christophe Rochet, Jason R. Cannon

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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. Themajority of cases are thought to arise froma 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 nondopaminergic 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. Pretreatment 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.

Original languageEnglish (US)
Pages (from-to)179-189
Number of pages11
JournalToxicological Sciences
Volume140
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Poisons
Dopaminergic Neurons
Neurons
Meats
Meat
Amines
Toxicity
Parkinson Disease
Neurodegenerative diseases
Blueberry Plants
Oxidative stress
Cooking
Acetylcysteine
Neurology
Metabolites
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
In Vitro Techniques
Neurites
Genetic Predisposition to Disease
Rats

Keywords

  • Heterocyclic amines
  • Neurotoxicity
  • Parkinson's disease
  • PhIP

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is selectively toxic to primary dopaminergic neurons In Vitro. / Griggs, Amy M.; Agim, Zeynep S.; Mishra, Vartika R.; Tambe, Mitali A.; Director-Myska, Alison E.; Turteltaub, Ken W; McCabe, George P.; Rochet, Jean Christophe; Cannon, Jason R.

In: Toxicological Sciences, Vol. 140, No. 1, 2014, p. 179-189.

Research output: Contribution to journalArticle

Griggs, AM, Agim, ZS, Mishra, VR, Tambe, MA, Director-Myska, AE, Turteltaub, KW, McCabe, GP, Rochet, JC & Cannon, JR 2014, '2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is selectively toxic to primary dopaminergic neurons In Vitro', Toxicological Sciences, vol. 140, no. 1, pp. 179-189. https://doi.org/10.1093/toxsci/kfu060
Griggs, Amy M. ; Agim, Zeynep S. ; Mishra, Vartika R. ; Tambe, Mitali A. ; Director-Myska, Alison E. ; Turteltaub, Ken W ; McCabe, George P. ; Rochet, Jean Christophe ; Cannon, Jason R. / 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is selectively toxic to primary dopaminergic neurons In Vitro. In: Toxicological Sciences. 2014 ; Vol. 140, No. 1. pp. 179-189.
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abstract = "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. Themajority of cases are thought to arise froma 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 nondopaminergic 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. Pretreatment 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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AU - Agim, Zeynep S.

AU - Mishra, Vartika R.

AU - Tambe, Mitali A.

AU - Director-Myska, Alison E.

AU - Turteltaub, Ken W

AU - McCabe, George P.

AU - Rochet, Jean Christophe

AU - Cannon, Jason R.

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N2 - 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. Themajority of cases are thought to arise froma 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 nondopaminergic 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. Pretreatment 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.

AB - 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. Themajority of cases are thought to arise froma 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 nondopaminergic 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. Pretreatment 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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