title: Mono-substituted isopropylated triaryl phosphate, a major component of Firemaster 550, is an AHR agonist that exhibits AHR-independent cardiotoxicity in zebrafish.
abstract: Firemaster 550 (FM550) is an additive flame retardant mixture used within polyurethane foam and is increasingly found in house dust and the environment due to leaching. Despite the widespread use of FM550, very few studies have investigated the potential toxicity of its ingredients during early vertebrate development. In the current study, we sought to specifically investigate mono-substituted isopropylated triaryl phosphate (mITP), a component comprising approximately 32% of FM550, which has been shown to cause cardiotoxicity during zebrafish embryogenesis. Previous research showed that developmental defects are rescued using an aryl hydrocarbon receptor (AHR) antagonist (CH223191), suggesting that mITP-induced toxicity was AHR-dependent. As zebrafish have three known AHR isoforms, we used a functional AHR2 knockout line along with AHR1A- and AHR1B-specific morpholinos to determine which AHR isoform, if any, mediates mITP-induced cardiotoxicity. As in silico structural homology modeling predicted that mITP may bind favorably to both AHR2 and AHR1B isoforms, we evaluated AHR involvement in vivo by measuring CYP1A mRNA and protein expression following exposure to mITP in the presence or absence of CH223191 or AHR-specific morpholinos. Based on these studies, we found that mITP interacts with both AHR2 and AHR1B isoforms to induce CYP1A expression. However, while CH223191 blocked mITP-induced CYP1A induction and cardiotoxicity, knockdown of all three AHR isoforms failed to block mITP-induced cardiotoxicity in the absence of detectable CYP1A induction. Overall, these results suggest that, while mITP is an AHR agonist, mITP causes AHR-independent cardiotoxicity through a pathway that is also antagonized by CH223191.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: Cory V
authors.initials: CV
authors.lastname: Gerlach
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: Siba R
authors.initials: SR
authors.lastname: Das
authors.affiliation: Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Volz
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: Siva K
authors.initials: SK
authors.lastname: Kolluri
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA. Electronic address: Robert.Tanguay@oregonstate.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D054715:Cardiotoxins / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005411:Flame Retardants / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000187:drug effects*; D010755:Organophosphates / Q000633:toxicity*; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D011720:Pyrazoles / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology*
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D001391:Azo Compounds; D054715:Cardiotoxins; C000591741:Firemaster 550; D005411:Flame Retardants; D010755:Organophosphates; D011075:Polybrominated Biphenyls; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D014874:Water Pollutants, Chemical; D019363:Cytochrome P-450 CYP1A1
keywords: Aryl hydrocarbon receptor (AHR); CH223191; Cardiotoxicity; Firemaster 550; Flame retardant; Zebrafish