title: Toxicogenomic and phenotypic analyses of bisphenol-A early-life exposure toxicity in zebrafish.
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.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, Singapore. dbslsh@nus.edu.sg
authors.forename: Siew Hong
authors.initials: SH
authors.lastname: Lam
authors.forename: Mya Myintzu
authors.initials: MM
authors.lastname: Hlaing
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Chuan
authors.initials: C
authors.lastname: Yan
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Duan
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Choong Yong
authors.initials: CY
authors.lastname: Ung
authors.forename: Sinnakaruppan
authors.initials: S
authors.lastname: Mathavan
authors.forename: Choon Nam
authors.initials: CN
authors.lastname: Ong
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Gong
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001559:Benzhydryl Compounds; D015415:Biomarkers / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004781:Environmental Exposure; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007814:Larva / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010636:Phenols / Q000633:toxicity*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D013223:Statistics as Topic; D043922:Toxicogenetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D015415:Biomarkers; D049452:Green Fluorescent Proteins; D010636:Phenols; D029961:Zebrafish Proteins; C006780:bisphenol A; D000098826:Bisphenol A Compounds