Chronic Administration of Benzo(a)pyrene Induces Memory Impairment and Anxiety-Like Behavior and Increases of NR2B DNA Methylation

Abstract

BackgroundRecently, an increasing number of human and animal studies have reported that exposure to benzo(a)pyrene (BaP) induces neurological abnormalities and is also associated with adverse effects, such as tumor formation, immunosuppression, teratogenicity, and hormonal disorders. However, the exact mechanisms underlying BaP-induced impairment of neurological function remain unclear. The aim of this study was to examine the regulating mechanisms underlying the impact of chronic BaP exposure on neurobehavioral performance.MethodsC57BL mice received either BaP in different doses (1.0, 2.5, 6.25 mg/kg) or olive oil twice a week for 90 days. Memory and emotional behaviors were evaluated using Y-maze and open-field tests, respectively. Furthermore, levels of mRNA expression were measured by using qPCR, and DNA methylation of NMDA receptor 2B subunit (NR2B) was examined using bisulfate pyrosequencing in the prefrontal cortex and hippocampus.ResultsCompared to controls, mice that received BaP (2.5, 6.25 mg/kg) showed deficits in short-term memory and an anxiety-like behavior. These behavioral alterations were associated with a down-regulation of the NR2B gene and a concomitant increase in the level of DNA methylation in the NR2B promoter in the two brain regions.ConclusionsChronic BaP exposure induces an increase in DNA methylation in the NR2B gene promoter and down-regulates NR2B expression, which may contribute to its neurotoxic effects on behavioral performance. The results suggest that NR2B vulnerability represents a target for environmental toxicants in the brain.

Neuropeptide Y Expression Confers Benzo[a]pyrene Induced DNA Damage and Microtubule Disruption in Human Neuroblastoma SH-SY5Y Cells

“…In our study, SH-SY5Y cells when exposed to B[a]P induced oxidative stress as demonstrated by the significant increase of S phase cell accumulation and by the activation of the B[a]P metabolites to the antioxidant responses. In the present study, we found exposure to B[a]P in SH-SY5Y human neuroblastoma cell lines causes cell cycle arrest leading to increase proportion of cells at S phase and it finds support from previous reports [42,43,44]. Hence, it seems possible that oxidative stress may represent an important component in the mechanism of action of B[a]P-induced DNA damage in SH-SY5Y cell lines.…”

“…Previous reports suggested that B[a]P exposure leads to cell cycle arrest with significant increase in the number of cells in S-phase of cell cycle [41,42]. Importantly, from late S phase to mitotic onset, the two fully duplicated centrosomes exhibit enhanced recruitment of pericentriolar material components that are essential for microtubule nucleation, a process termed centrosome maturation [41].…”

Integrated Hypoxia Signaling and Oxidative Stress in Developmental Neurotoxicity of Benzo[a]Pyrene in Zebrafish Embryos

“…B[a]P can reach the encephalic central nervous tissues by crossing the blood–brain barrier [ 75 , 76 , 77 ]; this leads to increase nervous oxidative stress in the nervous system which in turn resulting in behavioral changes and alterations to the expression of antioxidant enzymes (e.g., superoxide dismutase, catalase and glutathione peroxidase and cellular lipid peroxidation [ 77 , 78 ]. Epidemiological studies have demonstrated that exposure to B[a]P causes neurological abnormalities such as cognitive impairment, learning difficulties, parasympathetic dysregulation and short-term memory loss [ 79 , 80 , 81 ]. Embryonic B[a]P exposure increases the risk of neural hypoplasia.…”

Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice

“…In order to study effects of environmental pollutant BaP on AD development, we chose a chronic dosing paradigm (daily intraperitoneal injection for 2 months) and a relatively low dose of BaP (1 mg/kg/ bw/day). The dose was chosen based on the environmental/occupational exposure dosage and previous studies [11,13,14]. Vehicle groups were received with equal volume of corn oil (50 μl).…”

“…Epidemiological studies have shown that BaP exposure is associated with learning and memory deficits in healthy adults and coke oven workers, which may be due to neurotransmitter alteration [9,10]. Experimental studies have also shown that BaP exposure in animals induces some AD-like behavior/pathological changes, such as deficits in short-term memory in C57BL/6 J mice [11], accumulation of Aβ42 and neurodegeneration in adult Zebrafish [12], Aβ-related mRNA levels change [13], or tau hyperphosphorylation in SD rats [14].…”