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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE75206 | GEO | 2016/11/18

SECONDARY ACCESSION(S): PRJNA302798

REPOSITORIES: GEO

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Project description:BACKGROUND: Benzo[a]pyrene (BaP) is a widespread environmental genotoxic carcinogen that damages DNA by forming adducts. This damage along with activation of the aryl hydrocarbon receptor (AHR) induces complex transcriptional responses in cells. To investigate whether human cells are more susceptible to BaP in a particular phase of the cell cycle, synchronised breast carcinoma MCF-7 cells were exposed to BaP. Cell cycle progression was analysed by flow cytometry, DNA adduct formation was assessed by 32P-postlabeling analysis, microarrays of 44K human genome-wide oligos and RT-PCR were used to detect gene expression (mRNA) changes and Western blotting was performed to determine the expression of some proteins, including cytochrome P450 (CYP) 1A1 and CYP1B1, which are involved in BaP metabolism. RESULTS: Following BaP exposure, cells evaded G1 arrest and accumulated in S-phase. Higher levels of DNA damage occurred in S- and G2/M- compared with G0/G1-enriched cultures. Genes that were found to have altered expression included those involved in xenobiotic metabolism, apoptosis, cell cycle regulation and DNA repair. Gene ontology and pathway analysis showed the involvement of various signalling pathways in response to BaP exposure, such as the Catenin/Wnt pathway in G1, the ERK pathway in G1 and S, the Nrf2 pathway in S and G2/M and the Akt pathway in G2/M. An important finding was that higher levels of DNA damage in S- and G2/M-enriched cultures correlated with higher levels of CYP1A1 and CYP1B1 mRNA and proteins. Moreover, exposure of synchronised MCF-7 cells to BaP-7,8-diol-9,10-epoxide (BPDE), the ultimate carcinogenic metabolite of BaP, did not result in significant changes in DNA adduct levels at different phases of the cell cycle. CONCLUSIONS: This study characterised the complex gene response to BaP in MCF-7 cells and revealed a strong correlation between the varying efficiency of BaP metabolism and DNA damage in different phases of the cell cycle. Our results suggest that growth kinetics within a target-cell population may be important determinants of susceptibility and response to a genotoxic agent.

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

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