Toxicogenomic and phenotypic analyses of bisphenol-A early-life exposure toxicity in zebrafish

• Published in: PloS one 2011-12, Vol.6 (12), p.e28273
• Main Authors: Lam, Siew Hong, Hlaing, Mya Myintzu, Zhang, Xiaoyan, Yan, Chuan, Duan, Zhenghua, Zhu, Lin, Ung, Choong Yong, Mathavan, Sinnakaruppan, Ong, Choon Nam, Gong, Zhiyuan
• Format: Article
• Language: English
• Subjects: Adipocytes; Algorithms; Animals; Animals, Genetically Modified; Axon guidance; Benzhydryl Compounds; Bioindicators; Biological activity; Biology; Biomarkers; Biomarkers - metabolism; Biosynthesis; Bisphenol A; Brain; Chemicals; Clathrin; Contaminants; Danio rerio; Data mining; Data processing; Deregulation; Disruption; Down-Regulation - drug effects; Down-Regulation - genetics; Edema; Endocytosis; Endothelial growth factors; Environmental Exposure; Environmental science; Epoxy resins; Exposure; Failure analysis; Fluorescence; Fluoroscopic imaging; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental - drug effects; Gene Regulatory Networks - drug effects; Gene Regulatory Networks - genetics; Genes; Genetic engineering; Genomes; Green Fluorescent Proteins - metabolism; Health aspects; Health risks; Heart diseases; Homology; Humans; Inference; Inflation (Economics); Integrins; Laboratory animals; Laboratory tests; Larva - drug effects; Larvae; Long-term potentiation; Neuroimaging; Oligonucleotide Array Sequence Analysis; Organs; Pathways; Phenols; Phenols - toxicity; Phenotype; Physiological aspects; Physiological effects; Physiology; Pimephales promelas; Potentiation; Proteins; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Reproductive system; Reproductive systems; Rodents; Signal transduction; Spinal cord; Statistics as Topic; Studies; Toxicity; Toxicogenetics; Transcriptome - drug effects; Transcriptome - genetics; Up-Regulation - genetics; Vascular endothelial growth factor; Vascularization; Zebrafish; Zebrafish - genetics; Zebrafish - growth & development; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028273

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.