title: Ligand-Specific Transcriptional Mechanisms Underlie Aryl Hydrocarbon Receptor-Mediated Developmental Toxicity of Oxygenated PAHs.
abstract: 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. Identifying ligand-dependent AHR interactions and signaling pathways is essential for understanding toxicity of this class of environmentally relevant compounds.
authors.affiliation: *Department of Environmental and Molecular Toxicology, The Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97330; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755;
authors.forename: B C
authors.initials: BC
authors.lastname: Goodale
authors.affiliation: *Department of Environmental and Molecular Toxicology, The Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97330;
authors.forename: J
authors.initials: J
authors.lastname: La Du
authors.affiliation: *Department of Environmental and Molecular Toxicology, The Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97330; Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington 99354;
authors.forename: S C
authors.initials: SC
authors.lastname: Tilton
authors.affiliation: *Department of Environmental and Molecular Toxicology, The Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97330; Center for Genome Research and Biocomputing, Oregon State University, Corvallis, Oregon 97330.
authors.forename: C M
authors.initials: CM
authors.lastname: Sullivan
authors.affiliation: *Department of Environmental and Molecular Toxicology, The Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97330;
authors.forename: W H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington 99354;
authors.forename: K M
authors.initials: KM
authors.lastname: Waters
authors.affiliation: *Department of Environmental and Molecular Toxicology, The Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97330; robert.tanguay@oregonstate.edu.
authors.forename: R L
authors.initials: RL
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D008024:Ligands; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D015027:Zebrafish; D000095322:Anthrones
chemical_list: D001551:Benz(a)Anthracenes; D008024:Ligands; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; C000609119:1,9-benz-10-anthrone; D000095322:Anthrones; C077646:7,12-benz(a)anthraquinone
keywords: OPAH; RNA-seq; aryl hydrocarbon receptor; benz(a)anthracene-7,12-dione; benzanthrone; zebrafish