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.
Highlights
Bisphenol-A (BPA) used in the manufacture of polycarbonate plastic and epoxy resin is among the highest-production-volume chemicals in the world [1]
The findings corroborated with those reported in rodent studies in terms of BPA exerting endocrine disrupting effects and BPA affected organ-tissues, especially on the nervous, reproductive and blood systems
Our findings revealed that zebrafish toxicogenomics could capture molecular information involving genes and signaling pathways that are useful to infer affected development and function of physiological systems as well as potential health-risks
Summary
Bisphenol-A (BPA) used in the manufacture of polycarbonate plastic and epoxy resin is among the highest-production-volume chemicals in the world [1]. The concern on the ecological impact of BPA has been increasingly raised in the past few years as more studies reveal ontogenetic and endocrine disruptions by BPA on aquatic organisms at environmental relevant concentrations [2,3] In line with this concern are the controversies due to conflicting reports and equivocal findings regarding potential human health effects of early-life exposure to BPA [4,5,6] at the level similar to those used in rodent studies, in which neuro-developmental effects, defect in reproductive tissue development, and predisposition to preneoplastic lesions of the mammary gland and prostate gland in adult life have been reported [7,8,9,10,11]. This may be partly due to the protracted in utero development of rodents which restrict accessibility and experimental manipulation
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