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Benzo pyrene-induced DNA adducts and gene expression profiles in target and non-target organs for carcinogenesis in mice.

Zuo J, Brewer DS, Arlt VM, Cooper CS, Phillips DH - BMC Genomics (2014)

Bottom Line: BaP-DNA adduct formation occurred in all six organs at levels that did not distinguish between target and non-target. cDNA microarray analysis showed a variety of genes modulated significantly by BaP in the six organs and the overall gene expression patterns were tissue specific.Additionally, several gene expression changes, such as in Trp53 activation and Stat3 activity suggested some similarities in molecular mechanisms in two target organs (lung and spleen), which were not found in the other four organs.Altogether, these findings showed that DNA adduct levels and early gene expression changes did not fully distinguish target from non-target organs.

View Article: PubMed Central - PubMed

Affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK. david.phillips@kcl.ac.uk.

ABSTRACT

Background: Gene expression changes induced by carcinogens may identify differences in molecular function between target and non-target organs. Target organs for benzo[a]pyrene (BaP) carcinogenicity in mice (lung, spleen and forestomach) and three non-target organs (liver, colon and glandular stomach) were investigated for DNA adducts by 32P-postlabelling, for gene expression changes by cDNA microarray and for miRNA expression changes by miRNA microarray after exposure of animals to BaP.

Results: BaP-DNA adduct formation occurred in all six organs at levels that did not distinguish between target and non-target. cDNA microarray analysis showed a variety of genes modulated significantly by BaP in the six organs and the overall gene expression patterns were tissue specific. Gene ontology analysis also revealed that BaP-induced bioactivities were tissue specific; eight genes (Tubb5, Fos, Cdh1, Cyp1a1, Apc, Myc, Ctnnb1 and Cav) showed significant expression difference between three target and three non-target organs. Additionally, several gene expression changes, such as in Trp53 activation and Stat3 activity suggested some similarities in molecular mechanisms in two target organs (lung and spleen), which were not found in the other four organs. Changes in miRNA expression were generally tissue specific, involving, in total, 21/54 miRNAs significantly up- or down-regulated.

Conclusions: Altogether, these findings showed that DNA adduct levels and early gene expression changes did not fully distinguish target from non-target organs. However, mechanisms related to early changes in p53, Stat3 and Wnt/β-catenin pathways may play roles in defining BaP organotropism.

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Related in: MedlinePlus

The 21 miRNAs significantly modulated in 6 female mouse organs. The mice received 5 daily doses of 125 mg/kg b.wt/day of BaP by oral gavage. The numbers represent fold change in expression relative to control organs (red, up-regulated; green, down-regulated). The deregulated miRNAs were filtered by relative expression ratios with fold-change cut-offs of 1.5 (t-test p < 0.05).
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Fig6: The 21 miRNAs significantly modulated in 6 female mouse organs. The mice received 5 daily doses of 125 mg/kg b.wt/day of BaP by oral gavage. The numbers represent fold change in expression relative to control organs (red, up-regulated; green, down-regulated). The deregulated miRNAs were filtered by relative expression ratios with fold-change cut-offs of 1.5 (t-test p < 0.05).

Mentions: The relative miRNA expression values of the BaP-treated compared to control mice revealed the degree of modulation of miRNAs expression by BaP. With a cut-off of 1.5-fold, 41 out of 54 miRNAs displayed up-regulation or down-regulation in one or more organ (Additional file 1: Table S6). For instance, mmu-miR-290 was up-regulated in all organs except forestomach; mmu-miR-465 was down-regulated in lung, spleen and glandular stomach. Twenty one significantly deregulated miRNAs were identified in BaP-treated samples compared with control (p < 0.05, Student’s t-test; Figure 6). The number of miRNAs significantly altered in individual organs was as follows: 7 up, 3 down in lung; 9 up, 1 down in spleen; 7 up, 5 down in forestomach; 8 up, 4 down in liver; 8 up, 0 down in colon; and 9 up, 0 down in glandular stomach (Figure 6). These analyses did not identify any miRNA expression changes that were target organ-specific or non-target organ-specific.Figure 6


Benzo pyrene-induced DNA adducts and gene expression profiles in target and non-target organs for carcinogenesis in mice.

Zuo J, Brewer DS, Arlt VM, Cooper CS, Phillips DH - BMC Genomics (2014)

The 21 miRNAs significantly modulated in 6 female mouse organs. The mice received 5 daily doses of 125 mg/kg b.wt/day of BaP by oral gavage. The numbers represent fold change in expression relative to control organs (red, up-regulated; green, down-regulated). The deregulated miRNAs were filtered by relative expression ratios with fold-change cut-offs of 1.5 (t-test p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4209037&req=5

Fig6: The 21 miRNAs significantly modulated in 6 female mouse organs. The mice received 5 daily doses of 125 mg/kg b.wt/day of BaP by oral gavage. The numbers represent fold change in expression relative to control organs (red, up-regulated; green, down-regulated). The deregulated miRNAs were filtered by relative expression ratios with fold-change cut-offs of 1.5 (t-test p < 0.05).
Mentions: The relative miRNA expression values of the BaP-treated compared to control mice revealed the degree of modulation of miRNAs expression by BaP. With a cut-off of 1.5-fold, 41 out of 54 miRNAs displayed up-regulation or down-regulation in one or more organ (Additional file 1: Table S6). For instance, mmu-miR-290 was up-regulated in all organs except forestomach; mmu-miR-465 was down-regulated in lung, spleen and glandular stomach. Twenty one significantly deregulated miRNAs were identified in BaP-treated samples compared with control (p < 0.05, Student’s t-test; Figure 6). The number of miRNAs significantly altered in individual organs was as follows: 7 up, 3 down in lung; 9 up, 1 down in spleen; 7 up, 5 down in forestomach; 8 up, 4 down in liver; 8 up, 0 down in colon; and 9 up, 0 down in glandular stomach (Figure 6). These analyses did not identify any miRNA expression changes that were target organ-specific or non-target organ-specific.Figure 6

Bottom Line: BaP-DNA adduct formation occurred in all six organs at levels that did not distinguish between target and non-target. cDNA microarray analysis showed a variety of genes modulated significantly by BaP in the six organs and the overall gene expression patterns were tissue specific.Additionally, several gene expression changes, such as in Trp53 activation and Stat3 activity suggested some similarities in molecular mechanisms in two target organs (lung and spleen), which were not found in the other four organs.Altogether, these findings showed that DNA adduct levels and early gene expression changes did not fully distinguish target from non-target organs.

View Article: PubMed Central - PubMed

Affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK. david.phillips@kcl.ac.uk.

ABSTRACT

Background: Gene expression changes induced by carcinogens may identify differences in molecular function between target and non-target organs. Target organs for benzo[a]pyrene (BaP) carcinogenicity in mice (lung, spleen and forestomach) and three non-target organs (liver, colon and glandular stomach) were investigated for DNA adducts by 32P-postlabelling, for gene expression changes by cDNA microarray and for miRNA expression changes by miRNA microarray after exposure of animals to BaP.

Results: BaP-DNA adduct formation occurred in all six organs at levels that did not distinguish between target and non-target. cDNA microarray analysis showed a variety of genes modulated significantly by BaP in the six organs and the overall gene expression patterns were tissue specific. Gene ontology analysis also revealed that BaP-induced bioactivities were tissue specific; eight genes (Tubb5, Fos, Cdh1, Cyp1a1, Apc, Myc, Ctnnb1 and Cav) showed significant expression difference between three target and three non-target organs. Additionally, several gene expression changes, such as in Trp53 activation and Stat3 activity suggested some similarities in molecular mechanisms in two target organs (lung and spleen), which were not found in the other four organs. Changes in miRNA expression were generally tissue specific, involving, in total, 21/54 miRNAs significantly up- or down-regulated.

Conclusions: Altogether, these findings showed that DNA adduct levels and early gene expression changes did not fully distinguish target from non-target organs. However, mechanisms related to early changes in p53, Stat3 and Wnt/β-catenin pathways may play roles in defining BaP organotropism.

Show MeSH
Related in: MedlinePlus