Dynamic Zebrafish Interactome Reveals Transcriptional Mechanisms of Dioxin Toxicity

PLoS One

Edward K. Lobenhofer¹  Elwood Linney²  Jerry Yen²  Deena M. Wassenberg²  Joel N. Meyer³  Andrey Alexeyenko⁴  Erik L. L. Sonnhammer⁴ 

[1] Cogenics, Morrisville, North Carolina, United States of America;Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America;Nicholas School of the Environment, Duke University, Durham, North Carolina, United States of America;Stockholm Bioinformatics Centre, Stockholm University, Stockholm, Sweden

关键词: Zebrafish;    Genetic networks;    Gene expression;    Microarrays;    Toxicity;    Gene regulation;    Protein interaction networks;    Embryos;   

DOI  :  10.1371/journal.pone.0010465

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background In order to generate hypotheses regarding the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) causes toxicity, we analyzed global gene expression changes in developing zebrafish embryos exposed to this potent toxicant in the context of a dynamic gene network. For this purpose, we also computationally inferred a zebrafish (Danio rerio) interactome based on orthologs and interaction data from other eukaryotes.Methodology/Principal Findings Using novel computational tools to analyze this interactome, we distinguished between dioxin-dependent and dioxin-independent interactions between proteins, and tracked the temporal propagation of dioxin-dependent transcriptional changes from a few genes that were altered initially, to large groups of biologically coherent genes at later times. The most notable processes altered at later developmental stages were calcium and iron metabolism, embryonic morphogenesis including neuronal and retinal development, a variety of mitochondria-related functions, and generalized stress response (not including induction of antioxidant genes). Within the interactome, many of these responses were connected to cytochrome P4501A (cyp1a) as well as other genes that were dioxin-regulated one day after exposure. This suggests that cyp1a may play a key role initiating the toxic dysregulation of those processes, rather than serving simply as a passive marker of dioxin exposure, as suggested by earlier research.Conclusions/Significance Thus, a powerful microarray experiment coupled with a flexible interactome and multi-pronged interactome tools (which are now made publicly available for microarray analysis and related work) suggest the hypothesis that dioxin, best known in fish as a potent cardioteratogen, has many other targets. Many of these types of toxicity have been observed in mammalian species and are potentially caused by alterations to cyp1a.

【 授权许可】

CC BY