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Gene expression profile and toxic effects in human bronchial epithelial cells exposed to zearalenone.

So MY, Tian Z, Phoon YS, Sha S, Antoniou MN, Zhang J, Wu RS, Tan-Un KC - PLoS ONE (2014)

Bottom Line: The array results showed that after ZEA treatment, 262 genes at 6 h and 1073 genes at 24 h were involved in the differential regulation.Results of further experiments indicated that 40 µM ZEA decreased cell viability, induced apoptosis and promoted reactive oxygen species (ROS) generation in a time-dependent manner.Immuno-suppressive effects of ZEA were further revealed through the suppression of lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6, IL-8 and IL-1β).

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong SAR, China.

ABSTRACT
Zearalenone (ZEA), a mycoestrogen produced by Fusarium fungal species, is mainly found in cereal crops such as maize, wheat and barley. Although ZEA has been reported to be present in air, little is known about the health risk or the molecular basis of action when lung cells are exposed to ZEA. As ZEA has a similar structure to estrogen, its potential risk as an endocrine disrupting chemical (EDC) has thus aroused both environmental and public health concerns. The purpose of this study is to identify the responses and underlying molecular changes that occur when human bronchial epithelial BEAS-2B cells are exposed to ZEA. Differential gene expression profiles were identified in cells that were treated with 40 µM ZEA for 6 h and 24 h by high-throughput microarray analysis using Affymetrix Human Gene 2.0 GeneChip. The array results showed that after ZEA treatment, 262 genes at 6 h and 1073 genes at 24 h were involved in the differential regulation. Pathway analysis revealed that diverse cellular processes were affected when lung cells were exposed to ZEA resulting in impaired response to DNA damage, cell cycle arrest, down-regulation of inflammatory responses and alterations of epigenetic marks. Results of further experiments indicated that 40 µM ZEA decreased cell viability, induced apoptosis and promoted reactive oxygen species (ROS) generation in a time-dependent manner. Immuno-suppressive effects of ZEA were further revealed through the suppression of lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6, IL-8 and IL-1β). Interestingly, the level of global DNA methylation was markedly decreased after 24 h exposure to ZEA. Collectively, these observations suggested that a broad range of toxic effects are elicited by ZEA. Particularly, ROS may play a pivotal role in ZEA-induced cell death. These adverse effects observed in lung cells suggest that exposure to ZEA may increase susceptibility of lung cells to diseases and required further investigations.

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Analysis of the functional gene set enrichment after 24 h ZEA treatment by GSEA.Differential gene expression was ranked by fold change. The most up-regulated genes are shown on the left while the most down-regulated genes are shown on the right. The black vertical lines indicate where the genes in the signature get set appeared. (A) Genes that is down-regulated in the presence of extracellular matrix molecule Tenascin C. (B) Genes that are down-regulated upon knockdown of boh histone deacetylase (HDAC) 1 and 2. (C) Genes that are down-regulated by estradol and down-regulated by estrogen-related receptor alpha. Enrichment score (ES, Y axis) is a running-sum statistic showing if the prior defined set of genes are randomly distributed or found at the extremes (top or bottom) of the list. If the genes are overrepresented at the bottom of our ranked list of genes, the ES will be close to −1 and vice versa. A normalized enrichment score (NES) takes into account the number of genes in the pathway. A negative NES indicates “bottom” enrichment of the list. The interpretation of the plots referred to [61].
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pone-0096404-g003: Analysis of the functional gene set enrichment after 24 h ZEA treatment by GSEA.Differential gene expression was ranked by fold change. The most up-regulated genes are shown on the left while the most down-regulated genes are shown on the right. The black vertical lines indicate where the genes in the signature get set appeared. (A) Genes that is down-regulated in the presence of extracellular matrix molecule Tenascin C. (B) Genes that are down-regulated upon knockdown of boh histone deacetylase (HDAC) 1 and 2. (C) Genes that are down-regulated by estradol and down-regulated by estrogen-related receptor alpha. Enrichment score (ES, Y axis) is a running-sum statistic showing if the prior defined set of genes are randomly distributed or found at the extremes (top or bottom) of the list. If the genes are overrepresented at the bottom of our ranked list of genes, the ES will be close to −1 and vice versa. A normalized enrichment score (NES) takes into account the number of genes in the pathway. A negative NES indicates “bottom” enrichment of the list. The interpretation of the plots referred to [61].

Mentions: To further identify the dysregulated biological processes, differential regulated genes were subjected to Gene Set Enrichment Analysis (GSEA). GSEA enabled us to determine whether a priori defined set of genes is statistically significantly (with nominal p-value <0.05 and FDR<0.25) enriched after treatment with ZEA. The detailed results are shown in Table S6. Interestingly, in addition to the pathways as identified by SEA, gene sets related to the extracellular matrix molecule tenascin C [20], histone deacetylation [21] and estrogenic responses [22] were also recognized to be enriched (Figure 3).


Gene expression profile and toxic effects in human bronchial epithelial cells exposed to zearalenone.

So MY, Tian Z, Phoon YS, Sha S, Antoniou MN, Zhang J, Wu RS, Tan-Un KC - PLoS ONE (2014)

Analysis of the functional gene set enrichment after 24 h ZEA treatment by GSEA.Differential gene expression was ranked by fold change. The most up-regulated genes are shown on the left while the most down-regulated genes are shown on the right. The black vertical lines indicate where the genes in the signature get set appeared. (A) Genes that is down-regulated in the presence of extracellular matrix molecule Tenascin C. (B) Genes that are down-regulated upon knockdown of boh histone deacetylase (HDAC) 1 and 2. (C) Genes that are down-regulated by estradol and down-regulated by estrogen-related receptor alpha. Enrichment score (ES, Y axis) is a running-sum statistic showing if the prior defined set of genes are randomly distributed or found at the extremes (top or bottom) of the list. If the genes are overrepresented at the bottom of our ranked list of genes, the ES will be close to −1 and vice versa. A normalized enrichment score (NES) takes into account the number of genes in the pathway. A negative NES indicates “bottom” enrichment of the list. The interpretation of the plots referred to [61].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008614&req=5

pone-0096404-g003: Analysis of the functional gene set enrichment after 24 h ZEA treatment by GSEA.Differential gene expression was ranked by fold change. The most up-regulated genes are shown on the left while the most down-regulated genes are shown on the right. The black vertical lines indicate where the genes in the signature get set appeared. (A) Genes that is down-regulated in the presence of extracellular matrix molecule Tenascin C. (B) Genes that are down-regulated upon knockdown of boh histone deacetylase (HDAC) 1 and 2. (C) Genes that are down-regulated by estradol and down-regulated by estrogen-related receptor alpha. Enrichment score (ES, Y axis) is a running-sum statistic showing if the prior defined set of genes are randomly distributed or found at the extremes (top or bottom) of the list. If the genes are overrepresented at the bottom of our ranked list of genes, the ES will be close to −1 and vice versa. A normalized enrichment score (NES) takes into account the number of genes in the pathway. A negative NES indicates “bottom” enrichment of the list. The interpretation of the plots referred to [61].
Mentions: To further identify the dysregulated biological processes, differential regulated genes were subjected to Gene Set Enrichment Analysis (GSEA). GSEA enabled us to determine whether a priori defined set of genes is statistically significantly (with nominal p-value <0.05 and FDR<0.25) enriched after treatment with ZEA. The detailed results are shown in Table S6. Interestingly, in addition to the pathways as identified by SEA, gene sets related to the extracellular matrix molecule tenascin C [20], histone deacetylation [21] and estrogenic responses [22] were also recognized to be enriched (Figure 3).

Bottom Line: The array results showed that after ZEA treatment, 262 genes at 6 h and 1073 genes at 24 h were involved in the differential regulation.Results of further experiments indicated that 40 µM ZEA decreased cell viability, induced apoptosis and promoted reactive oxygen species (ROS) generation in a time-dependent manner.Immuno-suppressive effects of ZEA were further revealed through the suppression of lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6, IL-8 and IL-1β).

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong SAR, China.

ABSTRACT
Zearalenone (ZEA), a mycoestrogen produced by Fusarium fungal species, is mainly found in cereal crops such as maize, wheat and barley. Although ZEA has been reported to be present in air, little is known about the health risk or the molecular basis of action when lung cells are exposed to ZEA. As ZEA has a similar structure to estrogen, its potential risk as an endocrine disrupting chemical (EDC) has thus aroused both environmental and public health concerns. The purpose of this study is to identify the responses and underlying molecular changes that occur when human bronchial epithelial BEAS-2B cells are exposed to ZEA. Differential gene expression profiles were identified in cells that were treated with 40 µM ZEA for 6 h and 24 h by high-throughput microarray analysis using Affymetrix Human Gene 2.0 GeneChip. The array results showed that after ZEA treatment, 262 genes at 6 h and 1073 genes at 24 h were involved in the differential regulation. Pathway analysis revealed that diverse cellular processes were affected when lung cells were exposed to ZEA resulting in impaired response to DNA damage, cell cycle arrest, down-regulation of inflammatory responses and alterations of epigenetic marks. Results of further experiments indicated that 40 µM ZEA decreased cell viability, induced apoptosis and promoted reactive oxygen species (ROS) generation in a time-dependent manner. Immuno-suppressive effects of ZEA were further revealed through the suppression of lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6, IL-8 and IL-1β). Interestingly, the level of global DNA methylation was markedly decreased after 24 h exposure to ZEA. Collectively, these observations suggested that a broad range of toxic effects are elicited by ZEA. Particularly, ROS may play a pivotal role in ZEA-induced cell death. These adverse effects observed in lung cells suggest that exposure to ZEA may increase susceptibility of lung cells to diseases and required further investigations.

Show MeSH
Related in: MedlinePlus