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

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?h post-fertilization were exposed to DMSO, 100??g/l BaP, 500??g/l FL, or 100??g/l BaP?+?500??g/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.

SUBMITTER: Jayasundara N

PROVIDER: S-EPMC4306723 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Jayasundara Nishad N Van Tiem Garner Lindsey L Meyer Joel N JN Erwin Kyle N KN Di Giulio Richard T RT

Toxicological sciences : an official journal of the Society of Toxicology 20141119 2

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 do ...[more]

PMID: 25412620

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Project description:Polycyclic aromatic hydrocarbons (PAHs) are pollutants created by the incomplete combustion of carbon, and are increasing in the environment largely due to the burning of fossil fuels. PAHs occur as complex mixtures, and some combinations have been shown to cause synergistic developmental toxicity in fish embryos, characterized by pericardial edema and craniofacial malformations. Previous studies have indicated that in the zebrafish model, this toxicity is mediated by the aryl hydrocarbon receptor 2 (AHR2), and enhanced by inhibition of CYP1A activity. In this study, we further examined this interaction of the model PAH and AHR agonist beta-naphthoflavone (BNF) with and without the AHR partial agonist/antagonist and CYP1A inhibitor alpha-naphthoflavone (ANF) to determine (1) whether ANF was acting as an AHR antagonist, (2) what alterations BNF and ANF both alone and in combination had on mRNA expression of the AHR regulated genes cytochrome P450 (cyp) 1a, 1 b 1, and 1 c 1, and the AHR repressor (ahrr2) prior to versus during deformity onset, and (3) compare CYP1A enzyme activity with mRNA induction. Zebrafish embryos were exposed from 24-48 or 24-96 hpf to BNF, 1-100 microg/L, ANF, 1-150 microg/L, a BNF+ANF co-exposure (1 microg/L+100 microg/L), or a DMSO solvent control. RNA was extracted and examined by quantitative real-time PCR. Both BNF and ANF each individually resulted in a dose dependent increase CYP1A, CYP1B1, CYP1C1, and AHRR2 mRNA, confirming their activities as AHR agonists. In the BNF+ANF co-exposures prior to deformity onset, expression of these genes was synergistic, and expression levels of the AHR regulated genes resembled the higher doses of BNF alone. Gene induction during deformities was also significantly increased in the co-exposure, but to a lesser magnitude than prior to deformity onset. EROD measurements of CYP1A activity showed ANF inhibited activity induction by BNF in the co-exposure group; this finding is not predicted by mRNA expression, which is synergistically induced in this treatment. This suggests that inhibition of CYP1A activity may alter metabolism and/or increase the half-life of the AHR agonist(s), allowing for increased AHR activation. This study furthers a mechanistic understanding of interactions underlying PAH synergistic toxicity.

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

Publications

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

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