PUBLICATION
AHR2-mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of PAHs
- Authors
- Jayasundara, N., Van Tiem Garner, L., Meyer, J.N., Erwin, K., Di Giulio, R.T.
- ID
- ZDB-PUB-141123-8
- Date
- 2015
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 143(2): 469-81 (Journal)
- Registered Authors
- Di Giulio, Richard T.
- Keywords
- Aryl hydrocarbon receptor, cardiac development, polycyclic aromatic hydrocarbons, transcriptomics, zebrafish; cardiotoxicity
- Datasets
- GEO:GSE57946
- MeSH Terms
-
- Animals
- Benzo(a)pyrene/toxicity*
- Calcium/metabolism
- Cardiotoxicity
- Drug Synergism
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Embryonic Development/drug effects*
- Embryonic Development/genetics
- Fluorenes/toxicity*
- Heart/drug effects*
- Heart/embryology
- Heart Defects, Congenital/chemically induced
- Heart Defects, Congenital/metabolism
- Receptors, Aryl Hydrocarbon/genetics
- Receptors, Aryl Hydrocarbon/metabolism*
- Transcriptome/drug effects*
- Transcriptome/genetics
- Zebrafish/embryology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 25412620 Full text @ Toxicol. Sci.
- CTD
- 25412620
Citation
Jayasundara, N., Van Tiem Garner, L., Meyer, J.N., Erwin, K., Di Giulio, R.T. (2015) AHR2-mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of PAHs. Toxicological sciences : an official journal of the Society of Toxicology. 143(2):469-81.
Abstract
Polycyclic aromatic hydrocarbons (PAHs) induce developmental defects including cardiac deformities in fish. The aryl hydrocarbon receptor (AHR) mediates the toxicity of some PAHs. Exposure to a simple PAH mixture during embryo development consisting of an AHR agonist (benzo(a)pyrene-BaP) with fluoranthene (FL), an inhibitor of cytochrome p450 1(CYP1) - a gene induced by AHR activation- results in cardiac deformities. Exposure to BaP or FL alone at similar concentrations alters heart rates, but does not induce morphological deformities. Furthermore, AHR2 knockdown prevents the toxicity of BaP+FL mixture. Here we used a zebrafish microarray analysis to identify heart-specific transcriptomic changes during early development that might underlie cardiotoxicity of BaP+FL. We used AHR2 morphant embryos to determine the role of this receptor in mediating toxicity. Control and knockdown embryos at 36 hours post fertilization were exposed to DMSO, 100 μg/L BaP, 500 μg/L FL, or 100 μg/L BaP + 500 μg/L FL, and heart tissues for RNA were extracted at 2, 6, 12, and 18 hours-post-exposure (hpe), prior to the appearance of cardiac deformities. Data show AHR2-dependent BaP+FL effects on expression of genes involved in protein biosynthesis and neuronal development in addition to signaling molecules and their associated molecular pathways. Ca(2+)-cycling and muscle contraction genes were the most significantly differentially expressed category of transcripts when comparing BaP+FL-treated AHR2 morphant and control embryos. These differences were most prominent at 2 and 6 hpe. Therefore, we postulate that BaP+FL may affect cellular Ca(2+) levels and subsequently cardiac muscle function, potentially underlying BaP+FL cardiotoxicity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping