Abstract
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 Muta™Mouse administered 0, 1, 35, or 70 mg BaP/kg bw per day by oral gavage for 3 days. Transcriptional profiles were examined by RNA‐sequencing (RNA‐seq), DNA microarrays, and real‐time quantitative reverse transcription polymerase chain reaction (RT‐PCR). BaP‐DNA adducts in the cerebellum were quantified by 32P‐post‐labeling to measure genotoxicity. RNA‐seq revealed altered expression of 0, 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 by microarrays. Microarray and RT‐PCR analysis showed increased expression of NMDAR subunits Grina and Grin2a. In contrast, no effects on DNA‐damage response genes were observed despite comparable BaP‐DNA adduct levels in the cerebellum and in the lungs and livers of mice at similar BaP doses in previous studies. The results suggest that DNA‐damage response does not play a major role in BaP‐induced adult neurotoxicity. Meta‐analysis revealed that BaP‐induced transcriptional profiles are highly correlated with those from the hippocampus of transgenic mice exhibiting similar neurotoxicity outcomes to BaP‐exposed mice and rats (i.e., defects in learning and memory). Overall, we suggest that BaP‐induced neurotoxicity is more likely to be a consequence of NMDAR perturbation than genotoxicity, and identify other important genes potentially mediating this adverse outcome. Environ. Mol. Mutagen. 57:350–363, 2016. © 2016 Her Majesty the Queen in Right of Canada. Environmental and Molecular Mutagenesis © 2016 Environmental Mutagen Society.
Highlights
Benzo[a]pyrene (BaP)1 is a human carcinogen that operates through a genotoxic mode of action (MOA) [IARC, International Agency for Research on Cancer, 2010]
Since BaP is a well-recognized mutagenic carcinogen, the results showed expected perturbations in the genes involved in the p53-mediated DNA damage response pathway, including cyclindependent kinase inhibitor 1A (Cdkn1a), following acute exposures that are anchored to measured genotoxic effects
The DNA adduct pattern observed by thin-layer chromatography (TLC) 32P-post-labeling in BaP-treated mice consisted of a single adduct spot that was previously identified by mass spectrometry as 10-(deoxyguanosin-N2-yl)27,8,9-trihydroxy-7,8,9,10-tetrahydro-BaP [Arlt et al, 2008] (Fig. 2B)
Summary
Benzo[a]pyrene (BaP) is a human carcinogen that operates through a genotoxic mode of action (MOA) [IARC, International Agency for Research on Cancer, 2010]. In addition to causing tumors at multiple sites in rodent cancer bioassays, rodents exposed to BaP exhibit poor performance in behavioral tests, suggesting that BaP retards learning and memory in laboratory animals (reviewed in [Chepelev et al, 2015]). Oral exposure of neonate pups to BaP for six days leads to a significant decrease in Morris water maze test. Additional Supporting Information may be found in the online version of this article. Grant sponsor: Wellcome Trust; Grant numbers: 101126/Z/13/Z, 101126/B/13/Z.
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