Neuromelanin Modulates Heterocyclic Aromatic Amine-Induced Dopaminergic Neurotoxicity

Abstract

Heterocyclic aromatic amines (HAAs) are mutagens and potential human carcinogens. Our group and others have demonstrated that HAAs may also produce selective dopaminergic neurotoxicity, potentially relevant to Parkinson’s disease (PD). The goal of this study was to elucidate mechanisms of HAA-induced neurotoxicity through examining a translational biochemical weakness of common PD models. Neuromelanin is a pigmented byproduct of dopamine metabolism that has been debated as being both neurotoxic and neuroprotective in PD. Importantly, neuromelanin is known to bind and potentially release dopaminergic neurotoxicants, including HAAs (eg, β-carbolines such as harmane). Binding of other HAA subclasses (ie, aminoimidazoaazarenes) to neuromelanin has not been investigated, nor has a specific role for neuromelanin in mediating HAA-induced neurotoxicity been examined. Thus, we investigated the role of neuromelanin in modulating HAA-induced neurotoxicity. We characterized melanin from Sepia officinalis and synthetic dopamine melanin, proposed neuromelanin analogs with similar biophysical properties. Using a cell-free assay, we demonstrated strong binding of harmane and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to neuromelanin analogs. To increase cellular neuromelanin, we transfected SH-SY5Y neuroblastoma cells with tyrosinase. Relative to controls, tyrosinase-expressing cells exhibited increased neuromelanin levels, cellular HAA uptake, cell toxicity, and oxidative damage. Given that typical cellular and rodent PD models form far lower neuromelanin levels than humans, there is a critical translational weakness in assessing HAA-neurotoxicity. The primary impacts of these results are identification of a potential mechanism by which HAAs accumulate in catecholaminergic neurons and support for the need to conduct neurotoxicity studies in systems forming neuromelanin.

Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target

“…[248,256,257] Studies from our lab have reported that PhIP generates reactive free radicals, leading to an increase in the accumulation of ROS. [43,258,259] Recently, our group showed that PhIP exposure for acute, subacute, and subchronic time points produced oxidative damage and alterations in synaptic proteins. Our study demonstrated that subchronic PhIP exposure promotes Aβ aggregation by increasing the levels of BACE1, APP, and oxidative damage.…”

Heterocyclic aromatic amines (HAAs) target mitochondrial physiology

“…The study of dietary neurotoxicants is important to a) determine the underlying pathogenic mechanisms that may influence neurodegeneration and b) identify modifiable risk factors that can limit the onset or progression of disease pathology. Previous studies have identified significant neurotoxic effects of dietary toxicants such as heterocyclic aromatic amines (HAA) on dopaminergic and cholinergic neurons, linking their potential association with AD and PD (5)(6)(7)(8)(9)(10). HAAs are produced in meat upon high temperature cooking, through Maillard reaction between amino acids, sugar, and creatinine or pyrolysis of aromatic amino acids (11,12).…”

Heterocyclic Aromatic Amines and Risk of Kidney Stones: A Cross-Sectional Study in US Adults

“…Oxidative stress is closely associated with the formation of kidney stones ( 31 ). Lawana et al ( 32 ) found that low doses of Harmane caused a 1.6-fold increase in reactive oxygen species (ROC) production in SH-SY5Y cells, which increased to 3.5-fold at higher doses. Furthermore, there was a dose-dependent increase in ROC synthesis in SH-SY5Y cells in response to Phlp and its metabolites.…”