Alterations in the nigrostriatal dopamine system after acute systemic PhIP exposure

Abstract

Heterocyclic amines (HCAs) are primarily formed during cooking of meat at high temperature. HCAs have been extensively studied as mutagens and possible carcinogens. Emerging data suggest that HCAs are neurotoxic and may be relevant to Parkinson's disease (PD) etiology. However, the majority of HCAs have not been evaluated for in vivo neurotoxicity. Here, we investigated acute in vivo neurotoxicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). PhIP is the most prevalent genotoxin in many types of meats. Adult, male Sprague-Dawley rats were subjected to acute, systemic PhIP at doses and time-points that have been extensively utilized in cancer studies (100 and 200 mg/kg for 8, 24 h) and evaluated for changes in dopaminergic, serotoninergic, GABAergic, and glutamatergic neurotransmission. PhIP exposure resulted in decreased striatal dopamine metabolite levels and dopamine turnover in the absence of changes to vesicular monoamine transporter 2 levels; other neurotransmitter systems were unaffected. Quantification of intracellular nitrotyrosine revealed higher levels of oxidative damage in dopaminergic neurons in the substantia nigra after PhIP exposure, while other neuronal populations were less sensitive. These changes occurred in the absence of an overt lesion to the nigrostriatal dopamine system. Collectively, our study suggests that acute PhIP treatment in vivo targets the nigrostriatal dopaminergic system and that PhIP should be further examined in chronic, low-dose studies for PD relevance.

Systemic Copper Disorders Influence the Olfactory Function in Adult Rats: Roles of Altered Adult Neurogenesis and Neurochemical Imbalance

“…Neurochemical analysis was performed similarly to described in previous studies [ 59 , 60 ]. Briefly, frozen brain samples were sonicated in 0.5 mL of 0.4 N perchloric acid (HClO 4 ) on ice.…”

Effect of Freeze-Thaw Cycles on the Oxidation of Protein and Fat and Its Relationship with the Formation of Heterocyclic Aromatic Amines and Advanced Glycation End Products in Raw Meat

“…These products can participate in a Maillard reaction to generate heterocyclic aromatic amines (HAAs) [ 9 ] and advanced glycation end products (AGEs). It has been reported that high HAA intake is associated with a variety of acute diseases, such as nonalcoholic fatty liver disease and neuronal damage [ 10 , 11 ]. Excessive intake of AGE will result in their accumulation in the human body.…”

Neuromelanin Modulates Heterocyclic Aromatic Amine-Induced Dopaminergic Neurotoxicity

“…Finally, we quantified 3-nitrotyrosine (3-NT), a byproduct of tyrosine nitration and an established marker of nitrosative stress. Previously, we reported that exposure to HAAs increased intracellular 3-NT levels in primary mesencephalic neurons and in rat brain (Agim and Cannon, 2018;Cruz-Hernandez et al, 2018;Griggs et al, 2014;Lee et al, 2015). Briefly, cells were plated on glass coverslips coated with poly-D-lysine (PDL) in a 24-well cell culture plate.…”

“…In addition, HAAs across 3 subclasses (aminoimidazoaazarenes, a-carbolines, and b-carbolines) are toxic to dopaminergic neurons with varying potency (Cruz-Hernandez et al, 2018). Furthermore, a systemic in vivo study in rats showed that PhIP selectively affects dopaminergic neurotransmission and produces heightened oxidative damage specifically in nigral dopaminergic neurons (Agim and Cannon, 2018). Although the results from this in vivo study further underscore potential PD relevance, the requirement for high doses (100-200 mg/kg) relative to actual exposures and a lack of an overt lesion to the nigrostriatal dopamine system raise questions about translational differences between PD models and human patients Cannon, 2015, 2018).…”