The multi-dimensional embryonic zebrafish platform predicts flame retardant bioactivity

Truong, Lisa; Marvel, Skylar W.; Reif, David M.; Thomas, Dennis; Pande, Paritosh; Dasgupta, Subham; Simonich, Michael T.; Waters, Katrina M.; Tanguay, Robyn L

doi:10.1016/j.reprotox.2020.08.007

Cited by 20 publications

(24 citation statements)

References 40 publications

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“…In that study, we built a robust classification model for FRCs based on phenotypes and physicochemical properties and also showed that triphenyl OPFRCs such as triphenyl phosphate (TPP) and isopropylated triphenyl phosphates (IPPs) were the most bioactive. Comparisons with other model systems showed that many of the bioactive FRCs in our study were toxic in mammalian in vivo and in vitro systems (Truong et al, 2020). These data revealed the need for a comparative molecular assessment of different FRC classes to understand their unique and common biological targets and how specific biological processes are associated with phenotypes.…”

Section: Introductionmentioning

confidence: 66%

“…"Conc" represents concentration used for exposures in the study. For FRCs, EC 80 s [exposure concentrations demonstrating 80% morphological effects based on Truong et al (2020)] were used as exposure concentrations, except BDE-47, TCEP and TCPP where limit concentration (85 µM) or TBBPA-DBPE where a TBBPA-matched concentration (4 µM) was used.…”

Section: Chemicalsmentioning

confidence: 99%

“…Our objective was to discover the gene expression changes produced by exposure to FRCs belonging to different physicochemical classes and zebrafish toxicity profiles. We chose the 10 FRCs based on lowest effect level (LEL) values within our 18 morphological and 5 behavioral endpoints from our previous study [Truong et al (2020), also see Supplementary Table 1.1)]. These FRCs belonged to different chemical classes (Figure 1) and phenotypic profiles (Figure 2A), producing both morphological and behavioral phenotypes (TDBPP, TBBPA, TBPH, IPP, TPP), only morphological phenotypes (TiBP), only behavioral phenotypes (BDE-47, TBBPA-DBPE) and no observed phenotypes (TCEP, TCPP) (Figure 2A).…”

Section: Selection Of Frcs and Their Exposure Concentrationsmentioning

confidence: 99%

“…We previously used high-throughput screening in zebrafish with statistical modeling to identify developmental toxicity of FRCs based on their physicochemical classifications and bioactivity profiles (Noyes et al, 2015;Hagstrom et al, 2019;Truong et al, 2020). Recently, we screened a comprehensive library of 61 FRCs for morphological and neurobehavioral endpoints and used a point-of-departure approach to show that FRCs from several classes elicited developmental toxicity (Truong et al, 2020). In that study, we built a robust classification model for FRCs based on phenotypes and physicochemical properties and also showed that triphenyl OPFRCs such as triphenyl phosphate (TPP) and isopropylated triphenyl phosphates (IPPs) were the most bioactive.…”

Section: Introductionmentioning

confidence: 99%

“…Here we investigated the mRNA and miR expression changes following exposure to 10 selected FRCs representing different physicochemical classes and zebrafish toxicity response profiles, ranging from non-responders to high responders (Truong et al, 2020). miRs can act as important post-transcriptional regulators of biological processes in response to an array of metals, dioxins, microcystins, phenols, PM 2 .…”

Section: Introductionmentioning

confidence: 99%

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Phenotypically Anchored mRNA and miRNA Expression Profiling in Zebrafish Reveals Flame Retardant Chemical Toxicity Networks

Dasgupta

Dunham

Truong

et al. 2021

Front. Cell Dev. Biol.

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The ubiquitous use of flame retardant chemicals (FRCs) in the manufacture of many consumer products leads to inevitable environmental releases and human exposures. Studying toxic effects of FRCs as a group is challenging since they widely differ in physicochemical properties. We previously used zebrafish as a model to screen 61 representative FRCs and showed that many induced behavioral and teratogenic effects, with aryl phosphates identified as the most active. In this study, we selected 10 FRCs belonging to diverse physicochemical classes and zebrafish toxicity profiles to identify the gene expression responses following exposures. For each FRC, we executed paired mRNA-micro-RNA (miR) sequencing, which enabled us to study mRNA expression patterns and investigate the role of miRs as posttranscriptional regulators of gene expression. We found widespread disruption of mRNA and miR expression across several FRCs. Neurodevelopment was a key disrupted biological process across multiple FRCs and was corroborated by behavioral deficits. Several mRNAs (e.g., osbpl2a) and miRs (e.g., mir-125b-5p), showed differential expression common to multiple FRCs (10 and 7 respectively). These common miRs were also predicted to regulate a network of differentially expressed genes with diverse functions, including apoptosis, neurodevelopment, lipid regulation and inflammation. Commonly disrupted transcription factors (TFs) such as retinoic acid receptor, retinoid X receptor, and vitamin D regulator were predicted to regulate a wide network of differentially expressed mRNAs across a majority of the FRCs. Many of the differential mRNA-TF and mRNA-miR pairs were predicted to play important roles in development as well as cancer signaling. Specific comparisons between TBBPA and its derivative TBBPA-DBPE showed contrasting gene expression patterns that corroborated with their phenotypic profiles. The newer generation FRCs such as IPP and TCEP produced distinct gene expression changes compared to the legacy FRC BDE-47. Our study is the first to establish a mRNA-miR-TF regulatory network across a large group of structurally diverse FRCs and diverse phenotypic responses. The purpose was to discover common and unique biological targets that will help us understand mechanisms of action for these important chemicals and establish this approach as an important tool for better understanding toxic effects of environmental contaminants.

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Section: Introductionmentioning

confidence: 66%

Section: Chemicalsmentioning

confidence: 99%

Section: Selection Of Frcs and Their Exposure Concentrationsmentioning

confidence: 99%