Dataset Information

Ciglitazone-a human PPAR? agonist-disrupts dorsoventral patterning in zebrafish.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPAR? in adipogenesis and diabetes has been extensively studied, little is known about PPAR? function during early embryonic development. Within zebrafish, maternally-loaded ppar? transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic ppar? commences at ~48 hpf. Since maternal ppar? transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPAR? regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPAR? agonist and (2) a splice-blocking, ppar?-specific morpholino to knockdown ppar?. We found that initiation of ciglitazone-a potent human PPAR? 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, ppar? knockdown did not block ciglitazone-induced ventralization, suggesting that PPAR? is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPAR?-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development.

SUBMITTER: Cheng V

PROVIDER: S-EPMC6858815 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Ciglitazone-a human PPARγ agonist-disrupts dorsoventral patterning in zebrafish.

Cheng Vanessa V Dasgupta Subham S Reddam Aalekhya A Volz David C DC

PeerJ 20191113

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 ...[more]

PMID: 31741801

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Project description:Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a high-production volume organophosphate flame retardant widely used within the United States. Within zebrafish, initiation of TDCIPP exposure at 0.75 h post-fertilization (hpf) results in genome-wide alterations in methylation during cleavage (2 hpf) as well as epiboly delay or arrest (at higher concentrations) during late-blastula and early-gastrula (4-6 hpf). To determine whether these TDCIPP-induced effects were associated with impacts on the transcriptome, embryos were exposed to vehicle (0.1% DMSO) or 2 µM TDCIPP from 0.75 hpf to 6 hpf, and total RNA was extracted from triplicate embryo pools per treatment and hybridized onto duplicate Affymetrix Zebrafish Gene 1.0 ST Arrays per RNA sample. Based on transcriptome-wide profiling, TDCIPP resulted in a significant impact on biological processes involved in dorsoventral patterning and bone morphogenetic protein (BMP) signaling. Consistent with these responses, TDCIPP exposure also resulted in strongly dorsalized embryos by 24 hpf-a phenotype that mimicked the effects of dorsomorphin, a potent and selective BMP inhibitor. Moreover, the majority of dorsalized embryos were preceded by epiboly arrest at 6 hpf. Our microarray data also revealed that the expression of sizzled (szl)-a gene encoding a secreted Frizzled-related protein that limits BMP signaling-was significantly decreased by nearly 4-fold at 6 hpf. Therefore, we used a splice-blocking morpholino to test the hypothesis that knockdown of szl phenocopies TDCIPP-induced delays in epiboly progression. Interestingly, contrary to our hypothesis, injection of szl MOs did not affect epiboly progression but, similar to chordin (chd) morphants, resulted in mildly ventralized embryos by 24 hpf. Overall, our findings suggest that TDCIPP-induced epiboly delay may not be driven by decreased szl expression, and that TDCIPP-induced dorsalization may-similar to dorsomorphin-be due to interference with BMP signaling during early zebrafish development.

Dataset Information

Ciglitazone-a human PPAR? agonist-disrupts dorsoventral patterning in zebrafish.

Publications

Ciglitazone-a human PPARγ agonist-disrupts dorsoventral patterning in zebrafish.

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