Ligand-specific transcriptional mechanisms underlie aryl hydrocarbon receptor-mediated developmental toxicity of oxygenated PAHs

Goodale, B. C.; La Du, J.; Tilton, S. C.; Sullivan, C. M.; Bisson, W. H.; Waters, K. M.; Tanguay, R. L.

doi:10.1093/toxsci/kfv139

Ligand-specific transcriptional mechanisms underlie aryl hydrocarbon receptor-mediated developmental toxicity of oxygenated PAHs

Journal Article · Fri Jul 03 00:00:00 EDT 2015 · Toxicological Sciences

DOI:https://doi.org/10.1093/toxsci/kfv139· OSTI ID:1235029

Goodale, B. C. ^[1]; La Du, J. ^[2]; Tilton, S. C. ^[3]; Sullivan, C. M. ^[2]; Bisson, W. H. ^[2]; Waters, K. M. ^[4]; Tanguay, R. L. ^[2]

Oregon State Univ., Corvallis, OR (United States); Geisel School of Medicine at Dartmouth, Hanover, NH (United States); Oregon State University Libraries & Press
Oregon State Univ., Corvallis, OR (United States)
Oregon State Univ., Corvallis, OR (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Polycyclic aromatic hydrocarbons (PAHs) are priority environmental contaminants that exhibit mutagenic, carcinogenic, proinflammatory, and teratogenic properties. Oxygen-substituted PAHs (OPAHs) are formed during combustion processes and via phototoxidation and biological degradation of parent (unsubstituted) PAHs. Despite their prevalence both in contaminated industrial sites and in urban air, OPAH mechanisms of action in biological systems are relatively understudied. Like parent PAHs, OPAHs exert structure-dependent mutagenic activities and activation of the aryl hydrocarbon receptor (AHR) and cytochrome p450 metabolic pathway. Four-ring OPAHs 1,9-benz-10-anthrone (BEZO) and benz(a)anthracene-7,12-dione (7,12-B[a]AQ) cause morphological aberrations and induce markers of oxidative stress in developing zebrafish with similar potency, but only 7,12-B[a]AQ induces robust Cyp1a protein expression. We investigated the role of the AHR in mediating the toxicity of BEZO and 7,12-B[a]AQ, and found that knockdown of AHR2 rescued developmental effects caused by both compounds. Using RNA-seq and molecular docking, we identified transcriptional responses that precede developmental toxicity induced via differential interaction with AHR2. Redox-homeostasis genes were affected similarly by these OPAHs, while 7,12-B[a]AQ preferentially activated phase 1 metabolism and BEZO uniquely decreased visual system genes. Analysis of biological functions and upstream regulators suggests that BEZO is a weak AHR agonist, but interacts with other transcriptional regulators to cause developmental toxicity in an AHR-dependent manner. Furthermore, identifying ligand-dependent AHR interactions and signaling pathways is essential for understanding toxicity of this class of environmentally relevant compounds.

View Accepted Manuscript (DOE)

Research Organization:: Oregon State Univ., Corvallis, OR (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1235029

Journal Information:: Toxicological Sciences, Journal Name: Toxicological Sciences Journal Issue: 2 Vol. 147; ISSN 1096-6080

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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