ToxSci Advance Access originally published online on October 5, 2005
Toxicological Sciences 2006 89(1):224-234; doi:10.1093/toxsci/kfj005
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Acrylamide Inhibits Dopamine Uptake in Rat Striatal Synaptic Vesicles
* Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 10467; and Center for Environmental and Human Toxicology, University of Florida, Gainesville, Florida 32611-0885
Received July 25, 2005; accepted September 24, 2005
Evidence suggests that acrylamide (ACR) neurotoxicity is mediated by decreased presynaptic neurotransmitter release. Defective release might involve disruption of neurotransmitter storage, and therefore, we determined the effects of in vivo and in vitro ACR exposure on 3H-dopamine (DA) transport into rat striatal synaptic vesicles. Results showed that vesicular DA uptake was decreased significantly in rats intoxicated at either 50 mg/kg/day x 5 days or 21 mg/kg/day x 21 days. ACR intoxication also was accompanied by a reduction in KCl-evoked synaptosomal DA release, although consistent changes in presynaptic membrane transport were not observed. Silver stain and immunoblot analyses suggested that reduced vesicular uptake was not due to active nerve terminal degeneration or to a reduction in the synaptic vesicle content of isolated striatal synaptosomes. Nor did the in vivo presynaptic effects of ACR involve changes in synaptosomal glutathione concentrations. In vitro exposure of striatal vesicles showed that both ACR and two sulfhydryl reagents, N-ethylmaleimide (NEM) and iodoacetic acid (IAA), produced concentration-dependent decreases in 3H-DA uptake. Although ACR was significantly less potent than either NEM or IAA, all three chemicals caused comparable maximal inhibitions of vesicular uptake. Kinetic analysis of DA uptake showed that in vitro exposure to either ACR or NEM decreased Vmax and increased Km. Determination of radiolabel efflux from 3H-DA-loaded vesicles indicated that in vitro ACR did not affect neurotransmitter retention. These data suggest that ACR impaired neurotransmitter uptake into striatal synaptic vesicles, possibly by interacting with sulfhydryl groups on functionally relevant proteins. The resulting disruption of neurotransmitter storage might mediate defective presynaptic release.
Key Words: acrylamide; toxic axonopathy; nerve terminal; synaptic vesicles; neurotransmitter uptake; adduct formation.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. M. LoPachin, B. C. Geohagen, and T. Gavin Synaptosomal Toxicity and Nucleophilic Targets of 4-Hydroxy-2-Nonenal Toxicol. Sci., January 1, 2009; 107(1): 171 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. LoPachin, D. S. Barber, and T. Gavin Molecular Mechanisms of the Conjugated {alpha},{beta}-Unsaturated Carbonyl Derivatives: Relevance to Neurotoxicity and Neurodegenerative Diseases Toxicol. Sci., August 1, 2008; 104(2): 235 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Barber, S. Stevens, and R. M. LoPachin Proteomic Analysis of Rat Striatal Synaptosomes during Acrylamide Intoxication at a Low Dose Rate Toxicol. Sci., November 1, 2007; 100(1): 156 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. LoPachin, T. Gavin, B. C. Geohagen, and S. Das Neurotoxic Mechanisms of Electrophilic Type-2 Alkenes: Soft Soft Interactions Described by Quantum Mechanical Parameters Toxicol. Sci., August 1, 2007; 98(2): 561 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. LoPachin, D. S. Barber, B. C. Geohagen, T. Gavin, D. He, and S. Das Structure-Toxicity Analysis of Type-2 Alkenes: In Vitro Neurotoxicity Toxicol. Sci., January 1, 2007; 95(1): 136 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. LoPachin and D. S. Barber Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants Toxicol. Sci., December 1, 2006; 94(2): 240 - 255. [Abstract] [Full Text] [PDF]
|
|