title: Comparative Toxicogenomic Responses to the Flame Retardant mITP in Developing Zebrafish.
abstract: Monosubstituted isopropylated triaryl phosphate (mITP) is a major component of Firemaster 550, an additive flame retardant mixture commonly used in polyurethane foams. Developmental toxicity studies in zebrafish established mITP as the most toxic component of FM 550, which causes pericardial edema and heart looping failure. Mechanistic studies showed that mITP is an aryl hydrocarbon receptor (AhR) ligand; however, the cardiotoxic effects of mITP were independent of the AhR. We performed comparative whole genome transcriptomics in wild-type and ahr2hu3335zebrafish, which lack functional ahr2, to identify transcriptional signatures causally involved in the mechanism of mITP-induced cardiotoxicity. Regardless of ahr2 status, mITP exposure resulted in decreased expression of transcripts related to the synthesis of all-trans-retinoic acid and a host of Hox genes. Clustered gene ontology enrichment analysis showed unique enrichment in biological processes related to xenobiotic metabolism and response to external stimuli in wild-type samples. Transcript enrichments overlapping both genotypes involved the retinoid metabolic process and sensory/visual perception biological processes. Examination of the gene-gene interaction network of the differentially expressed transcripts in both genetic backgrounds demonstrated a strong AhR interaction network specific to wild-type samples, with overlapping genes regulated by retinoic acid receptors (RARs). A transcriptome analysis of control ahr2-null zebrafish identified potential cross-talk among AhR, Nrf2, and Hif1α. Collectively, we confirmed that mITP is an AhR ligand and present evidence in support of our hypothesis that mITP's developmental cardiotoxic effects are mediated by inhibition at the RAR level.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon 97333, United States.
authors.forename: Derik E
authors.initials: DE
authors.lastname: Haggard
authors.affiliation: Pacific Northwest Diabetes Research Institute , Seattle, Washington 98122, United States.
authors.forename: Siba R
authors.initials: SR
authors.lastname: Das
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon 97333, United States.
authors.forename: Robert L
authors.identifier: 0000-0001-6190-3682
authors.initials: RL
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D005411:Flame Retardants / Q000633:toxicity*; D043922:Toxicogenetics; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics
chemical_list: D005411:Flame Retardants