Mono-substituted isopropylated triaryl phosphate, a major component of Firemaster 550, is anAHR agonist that exhibits AHR-independent cardiotoxicity in zebrafish Public

http://ir.library.oregonstate.edu/concern/honors_college_theses/fb494b17q

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  • 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. In this study, we sought to investigate mono-substituted isopropylated triaryl phosphate (mITP), a major component 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). 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 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, 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. Keywords: aryl hydrocarbon receptor (AHR), Firemaster 550, flame retardant, CH223191
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  • description.provenance : Submitted by Cory Gerlach (gerlachc@onid.orst.edu) on 2014-06-03T07:36:43ZNo. of bitstreams: 1CoryVGerlach_HonorsThesis.pdf: 6725504 bytes, checksum: 84405457301adab5821631c48d96b9ed (MD5)
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