Heterocyclic aromatic amines induce Neuro-2a cells cytotoxicity through oxidative stress-mediated mitochondria-dependent apoptotic signals.

Heterocyclic aromatic amines (HAAs) are a class of hazardous compounds produced in food thermal processing. These compounds raise concerns because they have mutagenic and carcinogenic properties. However, the neurotoxicity of these compounds has received limited attention. Here, the toxic effects of three HAAs, i.e. 9H-pyrido[3,4-b]indole (Norharman), 1-methyl-9H-pyrido[3,4-b]indole (Harman), and 2-amino-3-methylimidazole[4,5-f]quinoline (IQ) were investigated in Neuro-2a cells model. The results showed that the survival rate of cells decreased in a dose-dependent manner and apoptosis occurred after exposure to the three HAAs for 24 h and 48 h. Their neurotoxicity was ranked as Harman > Norharman > IQ. Further, treatment of Harman, Norharman, or IQ at 50 and 100 μM for 48 h led to intracellular REDOX imbalance, which was manifested as increased ROS and malondialdehyde (MDA) levels, decreased GSH/GSSG ratio, and reduced SOD and CAT activities. Moreover, Norharman and Harman up-regulated the expression level of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as the mRNA levels of Heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoredutase1 (NQO1), while IQ had no significant effect on the levels of Nrf2, HO-1, and NQO1. Additionally, Harman, Norharman, or IQ exposure significantly reduced mitochondrial membrane potential and intracellular ATP levels and up-regulated the levels of apoptosis-related genes and proteins. Collectively, our finding suggested that HAAs were neurotoxic, with mechanisms related to induction of oxidative stress and mitochondrial dysfunction.