Toxicogenomic and Phenotypic Analyses of Bisphenol-A Early-Life Exposure Toxicity in Zebrafish
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{"title"=>"Toxicogenomic and phenotypic analyses of bisphenol-a early-life exposure toxicity in zebrafish", "type"=>"journal", "authors"=>[{"first_name"=>"Siew Hong", "last_name"=>"Lam", "scopus_author_id"=>"7402279735"}, {"first_name"=>"Mya Myintzu", "last_name"=>"Hlaing", "scopus_author_id"=>"16679104300"}, {"first_name"=>"Xiaoyan", "last_name"=>"Zhang", "scopus_author_id"=>"54418340200"}, {"first_name"=>"Chuan", "last_name"=>"Yan", "scopus_author_id"=>"54682405600"}, {"first_name"=>"Zhenghua", "last_name"=>"Duan", "scopus_author_id"=>"14218873800"}, {"first_name"=>"Lin", "last_name"=>"Zhu", "scopus_author_id"=>"56409086100"}, {"first_name"=>"Choong Yong", "last_name"=>"Ung", "scopus_author_id"=>"8837403000"}, {"first_name"=>"Sinnakaruppan", "last_name"=>"Mathavan", "scopus_author_id"=>"6701725980"}, {"first_name"=>"Choon Nam", "last_name"=>"Ong", "scopus_author_id"=>"7401968207"}, {"first_name"=>"Zhiyuan", "last_name"=>"Gong", "scopus_author_id"=>"7201947961"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22194820", "issn"=>"19326203", "sgr"=>"83355173062", "pui"=>"363076118", "scopus"=>"2-s2.0-83355173062", "isbn"=>"1932-6203", "doi"=>"10.1371/journal.pone.0028273"}, "id"=>"74912fb5-ad97-31b8-9275-bf72083e4e93", "abstract"=>"Bisphenol-A is an important environmental contaminant due to the increased early-life exposure that may pose significant health-risks to various organisms including humans. This study aimed to use zebrafish as a toxicogenomic model to capture transcriptomic and phenotypic changes for inference of signaling pathways, biological processes, physiological systems and identify potential biomarker genes that are affected by early-life exposure to bisphenol-A. Phenotypic analysis using wild-type zebrafish larvae revealed BPA early-life exposure toxicity caused cardiac edema, cranio-facial abnormality, failure of swimbladder inflation and poor tactile response. Fluorescent imaging analysis using three transgenic lines revealed suppressed neuron branching from the spinal cord, abnormal development of neuromast cells, and suppressed vascularization in the abdominal region. Using knowledge-based data mining algorithms, transcriptome analysis suggests that several signaling pathways involving ephrin receptor, clathrin-mediated endocytosis, synaptic long-term potentiation, axonal guidance, vascular endothelial growth factor, integrin and tight junction were deregulated. Physiological systems with related disorders associated with the nervous, cardiovascular, skeletal-muscular, blood and reproductive systems were implicated, hence corroborated with the phenotypic analysis. Further analysis identified a common set of BPA-targeted genes and revealed a plausible mechanism involving disruption of endocrine-regulated genes and processes in known susceptible tissue-organs. The expression of 28 genes were validated in a separate experiment using quantitative real-time PCR and 6 genes, ncl1, apoeb, mdm1, mycl1b, sp4, U1SNRNPBP homolog, were found to be sensitive and robust biomarkers for BPA early-life exposure toxicity. The susceptibility of sp4 to BPA perturbation suggests its role in altering brain development, function and subsequently behavior observed in laboratory animals exposed to BPA during early life, which is a health-risk concern of early life exposure in humans. The present study further established zebrafish as a model for toxicogenomic inference of early-life chemical exposure toxicity.", "link"=>"http://www.mendeley.com/research/toxicogenomic-phenotypic-analyses-bisphenola-earlylife-exposure-toxicity-zebrafish", "reader_count"=>92, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>4, "Researcher"=>18, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>25, "Student > Postgraduate"=>3, "Student > Master"=>15, "Other"=>3, "Student > Bachelor"=>15, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>4, "Researcher"=>18, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>25, "Student > Postgraduate"=>3, "Student > Master"=>15, "Other"=>3, "Student > Bachelor"=>15, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>11, "Agricultural and Biological Sciences"=>45, "Business, Management and Accounting"=>2, "Chemistry"=>4, "Earth and Planetary Sciences"=>1, "Environmental Science"=>4, "Biochemistry, Genetics and Molecular Biology"=>9, "Nursing and Health Professions"=>1, "Mathematics"=>1, "Medicine and Dentistry"=>6, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Psychology"=>1, "Social Sciences"=>1, "Engineering"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>1}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>11}, "Environmental Science"=>{"Environmental Science"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}, "Engineering"=>{"Engineering"=>1}, "Chemistry"=>{"Chemistry"=>4}, "Neuroscience"=>{"Neuroscience"=>2}, "Earth and Planetary Sciences"=>{"Earth and Planetary Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>45}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>2}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>9}}, "reader_count_by_country"=>{"Republic of Singapore"=>1, "Sweden"=>1, "Pakistan"=>1, "United States"=>2, "Brazil"=>1, "United Kingdom"=>1, "Portugal"=>1, "Germany"=>1, "Spain"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/702229"], "description"=>"<p>(A) <i>Tg(Nkx2.2a-mEGFP)</i> zebrafish larvae exposed to vehicle (control), 500 µg/L BPA and 5000 µg/L BPA. Panel on the right represent the inset region marked by white-outlined box in the corresponding left panel. White arrows indicate axon branching which are normal in control fish but marginally and severely affected in fish exposed to 500 and 5000 µg/L BPA, respectively. (B) <i>ET(krt8-EGFP)<sup>sqet20</sup></i> zebrafish larvae exposed to vehicle (control), 500 µg/L BPA and 5000 µg/L BPA. Panel on the right represent the inset region marked by white-outlined box in the corresponding left panel. White arrows indicate neuromast cells which are rosette circular-like shape in control fish but severely deformed in fish exposed to 500 and 5000 µg/L BPA. (C) <i>Tg(Flia-EGFP)<sup>y1</sup></i> zebrafish larvae exposed to vehicle (control), 500 µg/L and 5000 µg/L BPA. White arrow indicate vascularization in abdominal region which is normal in control fish but suppressed in fish exposed to 500 and (R) 5000 µg/L BPA.</p>", "links"=>[], "tags"=>["bpa", "early-life", "toxicity", "gfp", "transgenic"], "article_id"=>372597, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.g002", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Phenotype_analysis_of_BPA_early_life_exposure_toxicity_in_GFP_transgenic_fish_larvae_/372597", "title"=>"Phenotype analysis of BPA early-life exposure toxicity in GFP transgenic fish larvae.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 00:43:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/702403"], "description"=>"<p>(A) Venn-diagrams showing number (percentage) of genes that were considered significantly deregulated among the three treatment groups (BPA_500 µg/L, BPA_1500 µg/L and BPA_4500 µg/L). B) Expression profiles of gene probes categorized based on their significant deregulation in one, two and three treatment groups. The colored cells reflect the mean expression level of four biological replicates in each concentration group when compared to the control (vehicle) group (<i>n</i> = 4). Shades of red cells reflect up-regulated, green cells reflect down-regulated and black cells reflect unchanged, expression levels when compared to control (vehicle) group.</p>", "links"=>[], "tags"=>["changes", "induced", "bpa", "early-life"], "article_id"=>372771, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.g003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcriptomic_changes_induced_by_BPA_early_life_exposure_toxicity_/372771", "title"=>"Transcriptomic changes induced by BPA early-life exposure toxicity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 00:46:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/703000"], "description"=>"<p>Using samples from a separate validation experiment (n = 5–6 biological replicates; each replicate consist of five pooled larvae), selected down-regulated genes were validated by real-time PCR and compared with corresponding microarray data. Axis titles on the upper left histogram and figure legends are applicable to all histograms.</p>", "links"=>[], "tags"=>["pcr", "validation", "down-regulated", "zebrafish"], "article_id"=>373359, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.g007", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Real_time_PCR_validation_of_selected_down_regulated_zebrafish_genes_/373359", "title"=>"Real-time PCR validation of selected down-regulated zebrafish genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 00:55:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/356794", "https://ndownloader.figshare.com/files/356913", "https://ndownloader.figshare.com/files/356980", "https://ndownloader.figshare.com/files/357030", "https://ndownloader.figshare.com/files/357109", "https://ndownloader.figshare.com/files/357170", "https://ndownloader.figshare.com/files/357253", "https://ndownloader.figshare.com/files/357311", "https://ndownloader.figshare.com/files/357359"], "description"=>"<div><p>Bisphenol-A is an important environmental contaminant due to the increased early-life exposure that may pose significant health-risks to various organisms including humans. This study aimed to use zebrafish as a toxicogenomic model to capture transcriptomic and phenotypic changes for inference of signaling pathways, biological processes, physiological systems and identify potential biomarker genes that are affected by early-life exposure to bisphenol-A. Phenotypic analysis using wild-type zebrafish larvae revealed BPA early-life exposure toxicity caused cardiac edema, cranio-facial abnormality, failure of swimbladder inflation and poor tactile response. Fluorescent imaging analysis using three transgenic lines revealed suppressed neuron branching from the spinal cord, abnormal development of neuromast cells, and suppressed vascularization in the abdominal region. Using knowledge-based data mining algorithms, transcriptome analysis suggests that several signaling pathways involving ephrin receptor, clathrin-mediated endocytosis, synaptic long-term potentiation, axonal guidance, vascular endothelial growth factor, integrin and tight junction were deregulated. Physiological systems with related disorders associated with the nervous, cardiovascular, skeletal-muscular, blood and reproductive systems were implicated, hence corroborated with the phenotypic analysis. Further analysis identified a common set of BPA-targeted genes and revealed a plausible mechanism involving disruption of endocrine-regulated genes and processes in known susceptible tissue-organs. The expression of 28 genes were validated in a separate experiment using quantitative real-time PCR and 6 genes, <em>ncl1, apoeb, mdm1, mycl1b, sp4, U1SNRNPBP</em> homolog, were found to be sensitive and robust biomarkers for BPA early-life exposure toxicity. The susceptibility of <em>sp4</em> to BPA perturbation suggests its role in altering brain development, function and subsequently behavior observed in laboratory animals exposed to BPA during early life, which is a health-risk concern of early life exposure in humans. The present study further established zebrafish as a model for toxicogenomic inference of early-life chemical exposure toxicity.</p> </div>", "links"=>[], "tags"=>["toxicogenomic", "phenotypic", "analyses", "bisphenol-a", "early-life", "toxicity", "zebrafish"], "article_id"=>130512, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0028273.s001", "https://dx.doi.org/10.1371/journal.pone.0028273.s002", "https://dx.doi.org/10.1371/journal.pone.0028273.s003", "https://dx.doi.org/10.1371/journal.pone.0028273.s004", "https://dx.doi.org/10.1371/journal.pone.0028273.s005", "https://dx.doi.org/10.1371/journal.pone.0028273.s006", "https://dx.doi.org/10.1371/journal.pone.0028273.s007", "https://dx.doi.org/10.1371/journal.pone.0028273.s008", "https://dx.doi.org/10.1371/journal.pone.0028273.s009"], "stats"=>{"downloads"=>11, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Toxicogenomic_and_Phenotypic_Analyses_of_Bisphenol_A_Early_Life_Exposure_Toxicity_in_Zebrafish/130512", "title"=>"Toxicogenomic and Phenotypic Analyses of Bisphenol-A Early-Life Exposure Toxicity in Zebrafish", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-12-14 00:08:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/701972"], "description"=>"<p>(A) Percentage of mortality and (B) percentage of larvae with edema when developing zebrafish were exposed to BPA at 50, 100, 500, 1500 and 4500 µg/L BPA or vehicle control for 7 days from 3 hour post-fertilization (hpf) onwards. Error bars represent mean ± SD. Asterisk indicate significant (<i>P</i><0.05) differences when compared to control group (<i>n</i> = 4 replicate batches of embryos; each treatment group consisted of 50 embryos). Inset in (A) represents another set of acute toxicity experiment performed under similar conditions indicating percentage of mortality for developing zebrafish exposed to BPA at 500, 5000,10000, 15000 and 20000 µg/L. Representative samples of zebrafish larvae exposed to: (C) vehicle (control), (D) 50 µg/L, (E) 100, (F) 500, (G) 1500, and (H) 4500 µg/L, of BPA for 7 days from 3 hpf. Adverse toxic effects was observed at higher frequency in 1500 and 4500 µg/L of BPA which include cardiac edema (ce), cranio-facial abnormality (cf) and swimbladder (sb) development/inflation problem. Scale bar = 500 µm.</p>", "links"=>[], "tags"=>["bpa", "early-life", "toxicity", "wild-type", "zebrafish"], "article_id"=>372334, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.g001", "stats"=>{"downloads"=>3, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Phenotype_analysis_of_BPA_early_life_exposure_toxicity_in_wild_type_zebrafish_larvae_/372334", "title"=>"Phenotype analysis of BPA early-life exposure toxicity in wild-type zebrafish larvae.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 00:38:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/702718"], "description"=>"<p>The network shows the connectivity between significantly (Fisher's Exact Test <i>P</i><0.05) enriched functional subcategories with the endocrine-regulated human homologs of zebrafish genes that were commonly deregulated in all the three treatment groups (BPA_500 µg/L, BPA_1500 µg/L and BPA_4500 µg/L). Refer to Additional Files 6 and 7 for more information.</p>", "links"=>[], "tags"=>["common-targeted", "genes", "enriched"], "article_id"=>373084, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.g005", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Connectivity_network_for_common_targeted_genes_with_enriched_functional_subcategories_/373084", "title"=>"Connectivity network for common-targeted genes with enriched functional subcategories.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 00:51:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/702532"], "description"=>"<p>Selected top functional sub-categories within (A) molecular and cellular function, (B) physiological system development and function, (C) disease and disorder, and (D) canonical pathway, which were all significantly enriched (except for those labeled with asterisk ‘*’where Fisher's Exact Test <i>P</i>>0.05) with human homologs of zebrafish genes deregulated in BPA_500 µg/L, BPA_1500 µg/L and BPA_4500 µg/L groups. Refer to Additional Files 2–5 for more information. The figure legend and Y-axis title for the histogram in (A) are applicable to all other histograms.</p>", "links"=>[], "tags"=>["inference", "bpa", "early-life"], "article_id"=>372901, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.g004", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcriptomic_analysis_and_inference_of_BPA_early_life_exposure_toxicity_/372901", "title"=>"Transcriptomic analysis and inference of BPA early-life exposure toxicity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 00:48:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/703142"], "description"=>"<p>*the zebrafish genes were subsequently validated using real-time PCR on a new batch of fish.</p>a<p>average expression fold-change above control (log<sub>2</sub> ratio) for 500 µg/L, 1500 µg/L and 4500 µg/L BPA (microarray data).</p>b<p>refer to <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028273#pone.0028273.s008\" target=\"_blank\">Table S6</a> for references reporting on the endocrine regulation of the genes.</p>c<p>up-regulated at 500 µg/L but down-regulated at 1500 µg/L and 4500 µg/L BPA (microarray data).</p>d<p>down-regulated at 500 µg/L but up-regulated at 1500 µg/L and 4500 µg/L BPA (microarray data).</p>", "links"=>[], "tags"=>["homolog", "zebrafish", "genes", "deregulated", "bpa", "exposed", "groups", "1500", "4500"], "article_id"=>373494, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.t001", "stats"=>{"downloads"=>2, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Human_homolog_of_zebrafish_genes_38_that_were_significantly_deregulated_in_all_three_BPA_exposed_groups_500_181_g_L_1500_181_g_L_and_4500_181_g_L_/373494", "title"=>"Human homolog of zebrafish genes (38) that were significantly deregulated in all three BPA exposed groups (500 µg/L, 1500 µg/L and 4500 µg/L).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-12-14 00:58:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/702887"], "description"=>"<p>Using samples from a separate validation experiment (n = 5–6 biological replicates; each replicate consist of five pooled larvae), selected up-regulated genes were validated by real-time PCR and compared with corresponding microarray data. Axis titles on the upper left histogram and figure legends are applicable to all histograms.</p>", "links"=>[], "tags"=>["pcr", "validation", "up-regulated", "zebrafish"], "article_id"=>373249, "categories"=>["Biochemistry", "Genetics"], "users"=>["Siew Hong Lam", "Mya Myintzu Hlaing", "Xiaoyan Zhang", "Chuan Yan", "Zhenghua Duan", "Lin Zhu", "Choong Yong Ung", "Sinnakaruppan Mathavan", "Choon Nam Ong", "Zhiyuan Gong"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028273.g006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Real_time_PCR_validation_of_selected_up_regulated_zebrafish_genes_/373249", "title"=>"Real-time PCR validation of selected up-regulated zebrafish genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 00:54:09"}

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