AHR2-Mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of PAHs.

Nishad Jayasundara, Lindsey Van Tiem Garner, Joel N Meyer, Kyle N Erwin, Richard T Di Giulio

Toxicological sciences : an official journal of the Society of Toxicology 2015 Feb

filter terms:

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 h 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 h-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. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Citation

Nishad Jayasundara, Lindsey Van Tiem Garner, Joel N Meyer, Kyle N Erwin, Richard T Di Giulio. AHR2-Mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of PAHs. Toxicological sciences : an official journal of the Society of Toxicology. 2015 Feb;143(2):469-81