Aryl Phosphate Esters Within a Major PentaBDE Replacement Product Induce Cardiotoxicity in Developing Zebrafish Embryos: Potential Role of the Aryl Hydrocarbon Receptor
- Authors
- McGee, S.P., Konstantinov, A., Stapleton, H.M., and Volz, D.C.
- ID
- ZDB-PUB-130218-6
- Date
- 2013
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 133(1): 144-156 (Journal)
- Registered Authors
- Keywords
- aryl hydrocarbon receptor (AHR), cardiotoxicity, Firemaster 550, flame retardant, TCDD, zebrafish
- MeSH Terms
-
- Animals
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/metabolism
- Embryonic Development/drug effects
- Flame Retardants/toxicity*
- Halogenated Diphenyl Ethers/chemistry
- Halogenated Diphenyl Ethers/toxicity*
- Heart/drug effects
- Heart/embryology
- Heart Defects, Congenital/chemically induced*
- Heart Defects, Congenital/embryology
- Heart Defects, Congenital/metabolism
- Humans
- Molecular Structure
- Organophosphates/chemistry
- Organophosphates/toxicity*
- Real-Time Polymerase Chain Reaction
- Receptors, Aryl Hydrocarbon/antagonists & inhibitors
- Receptors, Aryl Hydrocarbon/genetics
- Receptors, Aryl Hydrocarbon/metabolism*
- Zebrafish/embryology*
- Zebrafish Proteins/genetics
- PubMed
- 23377616 Full text @ Toxicol. Sci.
- CTD
- 23377616
Firemaster® 550 (FM550) is an additive flame retardant formulation of brominated and aryl phosphate ester (APE) components introduced as a major replacement product for the commercial polybrominated diphenyl ether mixture (known as PentaBDE) used primarily in polyurethane foam. However, little is known about the potential effects of FM550-based ingredients during early vertebrate development. Therefore, we first screened the developmental toxicity of each FM550 component using zebrafish as an animal model. Based on these initial screening assays, we found that exposure to the brominated components as high as 10 μM resulted in no significant effects on embryonic survival or development, while exposure to triphenyl phosphate (TPP) or mono-substituted isopropylated triaryl phosphate (Mono-ITP) – two APEs comprising almost 50% of FM550 – resulted in targeted effects on cardiac looping and function during embryogenesis. As these cardiac abnormalities resembled aryl hydrocarbon receptor (AHR) agonist-induced phenotypes, we then exposed developing embryos to TPP or Mono-ITP in the presence or absence of an AHR antagonist (CH223191) or AHR2-specific morpholino. Based on these studies, we found that CH223191 blocked heart malformations following exposure to Mono-ITP but not TPP, while AHR2 knockdown failed to block the cardiotoxic effects of both components. Finally, using a cell-based human AHR reporter assay, we found that Mono-ITP (but not TPP) exposure resulted in a significant increase in human AHR-driven luciferase activity at similar nominal concentrations as a potent reference AHR agonist (β-Naphthoflavone). Overall, our findings suggest that two major APE components of FM550 induce severe cardiac abnormalities during early vertebrate development.