Transcriptional Response of Male MutaTMMouse Hippocampus to Benzo[a]pyrene (BaP; CAS no. 50-32-8, now also known as benzo[pqr]tetraphene) Exposure

Benzo[a]pyrene (BaP) is a genotoxic carcinogen and a neurotoxicant. The neurotoxicity of BaP is proposed to arise from either genotoxicity leading to neuronal cell death, or perturbed expression of N-methyl-D-aspartate receptor (NMDAR) subunits. To explore these hypotheses, we profiled hippocampal gene expression of adult male MutaTMMouse administered 1, 35, or 70 mg BaP/kg bw per day by oral gavage for three days, by RNA-Sequencing (RNA-Seq), DNA microarrays, and real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) 24 hr post-exposure. RNA-Seq revealed altered expression of zero, 260, and 219 genes (p-value < 0.05, fold-change ≥ ± 1.5) following exposure to the low, medium, and high doses, respectively; 54 genes were confirmed using microarrays. Microarray and RT-PCR analysis showed increased expression of NMDAR subunits Grina and Grin2a. In contrast, no effects on classical BaP targets, including xenobiotic metabolism and DNA-damage response genes, were found, despite comparable BaP-DNA adduct levels in the cerebellum to those detected in the lung and liver in previous studies. Meta-analysis revealed that BaP-induced transcriptional profiles most closely match those from the hippocampus of transgenic mice that share neurotoxicity observed in BaP-exposed mice (i.e., defects in learning). Overall, our results support that BaP-induced neurotoxicity is more likely to be a consequence of NMDAR perturbation than of genotoxicity, and identify other important genes potentially mediating this adverse outcome. Four (N=4) biological replicates were analyzed for control and BaP-treated (70 mg/kg bw per day, for 3 days) 24 h after the last treatment.