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Environ Mol Mutagen. 2016 Jun;57(5):350-63. doi: 10.1002/em.22020. Epub 2016 May 19.

Transcriptional profiling of the mouse hippocampus supports an NMDAR-mediated neurotoxic mode of action for benzo[a]pyrene.

Author information

1
Environmental Health Science and Research Bureau, Environmental and Radiation Health Sciences Directorate, HECSB, Health Canada, Ottawa, Ontario, Canada, K1A 0K9.
2
Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, London, SE1 9NH, United Kingdom.

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 (32) P-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.

KEYWORDS:

glutamate receptor; human health risk assessment; learning and memory; mode of action; toxicogenomics

PMID:
27195522
PMCID:
PMC4915531
DOI:
10.1002/em.22020
[Indexed for MEDLINE]
Free PMC Article

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