TitleStructurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish.
Publication TypeJournal Article
Year of Publication2013
AuthorsGoodale, BC, Tilton, SC, Corvi, MM, Wilson, GR, Janszen, DB, Anderson, KA, Waters, KM, Tanguay, RL
JournalToxicol Appl Pharmacol
Volume272
Issue3
Pagination656-70
Date Published2013 Nov 01
ISSN1096-0333
KeywordsAnimals, Embryo, Nonmammalian, Polycyclic Aromatic Hydrocarbons, Structure-Activity Relationship, Transcription, Genetic, Zebrafish
Abstract

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the aryl hydrocarbon receptor (AHR) in a structurally dependent manner, and induce toxicity via both AHR-dependent and -independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at concentrations that induced developmental malformations by 120 h post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burdens were analyzed at both time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the least number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure, and may provide a path for unraveling the toxicity of complex PAH mixtures.

DOI10.1016/j.taap.2013.04.024
Alternate JournalToxicol. Appl. Pharmacol.
PubMed ID23656968
PubMed Central IDPMC4098828
Grant ListP30 ES000210 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States