Disruption of Nuclear Receptor Signaling Alters Triphenyl Phosphate-Induced Cardiotoxicity in Zebrafish Embryos

Mitchell, Constance A.; Dasgupta, Subham; Zhang, Sharon; Stapleton, Heather M.; Volz, David C.

doi:10.1093/toxsci/kfy037

Cited by 54 publications

(40 citation statements)

References 56 publications

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“…Adult wild‐type (5D) zebrafish were maintained and bred on a recirculating system using procedures described by Mitchell et al (2018). Adult breeders were handled in accordance with Institutional Animal Care and Use Committee–approved animal use protocol (No.…”

Section: Methodsmentioning

confidence: 99%

Effects of Phenanthrene Exposure on Cholesterol Homeostasis and Cardiotoxicity in Zebrafish Embryos

McGruer

Tanabe

Vliet

et al. 2021

Enviro Toxic and Chemistry

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Polycyclic aromatic hydrocarbons (PAHs) are pervasive pollutants in aquatic ecosystems, and developing fish embryos are especially sensitive to PAH exposure. Exposure to crude oil or phenanthrene (a reference PAH found in oil) produces an array of gross morphological abnormalities in developing fish embryos, including cardiotoxicity. Recently, studies utilizing transcriptomic analyses in several oil-exposed fish embryos found significant changes in the abundance of transcripts involved in cholesterol biosynthesis. Given the vital role of cholesterol availability in embryonic heart development, we hypothesized that cholesterol dysregulation in early development contributes to phenanthrene-induced cardiotoxicity. We exposed zebrafish embryos to 12 or 15 µM phenanthrene from 6 to 72 h post fertilization (hpf) and demonstrated that, in conjunction with pericardial edema and bradycardia, several genes (fdft1 and hmgcra) in the cholesterol biosynthetic pathway were significantly altered. When embryos were pretreated with a cholesterol solution from 6 to 24 hpf followed by exposure to phenanthrene from 24 to 48 hpf, the effects of phenanthrene on heart rate were partially mitigated. Despite changes in gene expression, whole-mount in situ staining of cholesterol was not significantly affected in embryos exposed to phenanthrene ranging in stage from 24 to 72 hpf. However, the 2-dimensional yolk area was significantly increased with phenanthrene exposure at 72 hpf, suggesting that lipid transport from the yolk to the developing embryo was impaired.

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Section: Methodsmentioning

confidence: 99%

Effects of Phenanthrene Exposure on Cholesterol Homeostasis and Cardiotoxicity in Zebrafish Embryos

McGruer

Tanabe

Vliet

et al. 2021

Enviro Toxic and Chemistry

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show abstract

“…Adult wildtype (strain 5D) zebrafish were maintained and bred on a recirculating system using previously described procedures (Mitchell et al, 2018). All adult breeders were handled and treated in accordance with Institutional Animal Care and Use Committee-approved animal use protocols (#20150035 and #20180063) at the University of California, Riverside.…”

Section: Methodsmentioning

confidence: 99%

Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish

Cheng¹,

Dasgupta²,

Reddam³

et al. 2019

PeerJ

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Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone—a potent human PPARγ agonist—exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development.

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“…Libraries were prepared using a Lexogen Quantseq 3’ mRNA Seq Library Prep Kit FWD, and mRNA-sequencing and bioinformatics were performed as previously described 24 ; libraries derived from all treatments within each time point were sequenced in a single flow cell, resulting in a total of eight flow cells. Raw Illumina (fastq.gz) sequencing files (90 files) are available via NCBI’s BioProject database under BioProject ID PRJNA475635, and a summary of sequencing run metrics are provided in Supplemental File 1 (>90% of reads were ≥Q30 across all runs).…”

Section: Methodsmentioning

confidence: 99%

Tris(1,3-dichloro-2-propyl) Phosphate Exposure During the Early-Blastula Stage Alters the Normal Trajectory of Zebrafish Embryogenesis

Dasgupta

Cheng

Vliet

et al. 2018

Environ. Sci. Technol.

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Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is an organophosphate flame retardant used around the world. Within zebrafish, we previously showed that initiation of TDCIPP exposure during cleavage (0.75 h post-fertilization, hpf) results in epiboly disruption at 6 hpf, leading to dorsalized embryos by 24 hpf, a phenotype that mimics the effects of dorsomorphin (DMP), a bone morphogenetic protein (BMP) antagonist that dorsalizes embryos in the absence of epiboly defects. The objective of this study was to (1) investigate the role of BMP signaling in TDCIPP-induced toxicity during early embryogenesis, (2) identify other pathways and processes targeted by TDCIPP, and (3) characterize the downstream impacts of early developmental defects. Using zebrafish as a model, we first identified a sensitive window for TDCIPP-induced effects following exposure initiation at 0.75 hpf. We then investigated the effects of TDCIPP on the transcriptome during the first 24 h of development using mRNA sequencing and amplicon sequencing. Finally, we relied on whole-mount immunohistochemistry, dye-based labeling, and morphological assessments to study abnormalities later in embryonic development. Overall, our data suggest that the initiation of TDCIPP exposure during early blastula alters the normal trajectory of early embryogenesis by inducing gastrulation defects and aberrant germ-layer formation, leading to abnormal tissue and organ development within the embryo.

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Disruption of Nuclear Receptor Signaling Alters Triphenyl Phosphate-Induced Cardiotoxicity in Zebrafish Embryos

Cited by 54 publications

References 56 publications

Effects of Phenanthrene Exposure on Cholesterol Homeostasis and Cardiotoxicity in Zebrafish Embryos

Effects of Phenanthrene Exposure on Cholesterol Homeostasis and Cardiotoxicity in Zebrafish Embryos

Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish

Tris(1,3-dichloro-2-propyl) Phosphate Exposure During the Early-Blastula Stage Alters the Normal Trajectory of Zebrafish Embryogenesis

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