title: Phenotypically anchored transcriptome profiling of developmental exposure to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic zebrafish.
abstract: Triclosan (TCS) is an antimicrobial agent commonly found in a variety of personal care products and cosmetics. TCS readily enters the environment through wastewater and is detected in human plasma, urine, and breast milk due to its widespread use. Studies have implicated TCS as a disruptor of thyroid and estrogen signaling; therefore, research examining the developmental effects of TCS is warranted. In this study, we used embryonic zebrafish to investigate the developmental toxicity and potential mechanism of action of TCS. Embryos were exposed to graded concentrations of TCS from 6 to 120hours post-fertilization (hpf) and the concentration where 80% of the animals had mortality or morbidity at 120hpf (EC80) was calculated. Transcriptomic profiling was conducted on embryos exposed to the EC80 (7.37μM). We identified a total of 922 significant differentially expressed transcripts (FDR adjusted P-value≤0.05; fold change ≥2). Pathway and gene ontology enrichment analyses identified biological networks and transcriptional hubs involving normal liver functioning, suggesting TCS may be hepatotoxic in zebrafish. Tissue-specific gene enrichment analysis further supported the role of the liver as a target organ for TCS toxicity. We also examined the in vitro bioactivity profile of TCS reported by the ToxCast screening program. TCS had a diverse bioactivity profile and was a hit in 217 of the 385 assay endpoints we identified. We observed similarities in gene expression and hepatic steatosis assays; however, hit data for TCS were more concordant with the hypothesized CAR/PXR activity of TCS from rodent and human in vitro studies.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States.
authors.forename: Derik E
authors.initials: DE
authors.lastname: Haggard
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States; Office of Science Coordination and Policy (OSCP), Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency, Washington, DC, United States.
authors.forename: Pamela D
authors.initials: PD
authors.lastname: Noyes
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, United States.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States. Electronic address: Robert.Tanguay@oregonstate.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology* / Q000633:toxicity; D001921:Brain / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity; D059467:Transcriptome; D014260:Triclosan / Q000494:pharmacology* / Q000633:toxicity; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics
chemical_list: D000891:Anti-Infective Agents, Local; D012333:RNA, Messenger; D013723:Teratogens; D014260:Triclosan
keywords: Hepatotoxicity; Phenotypic anchoring; ToxCast; Transcriptomics; Triclosan; Zebrafish