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Published on: May 5, 2021
Modulation of PPAR signaling disrupts pancreas development in the zebrafish, Danio rerio
Olivia Venezia1, Sadia Islam1, Christine Cho2
1Department of Environmental Health Sciences, University of Massachusetts-Amherst, Amherst, MA, United States of America.
Abstract:
Peroxisome Proliferator Activated Receptors (PPARs) are transcription factors that regulate processes such as lipid and glucose metabolism. Synthetic PPAR ligands, designed as therapeutics for metabolic disease, provide a tool to assess the relationship between PPAR activity and pancreas development in vivo, an area that remains poorly characterized. Here, we aim to assess the effects of PPAR agonists and antagonists on gene expression, embryonic morphology and pancreas development in transgenic zebrafish embryos. To evaluate developmental perturbations, we assessed gross body and pancreas morphology at 4 days post fertilization (dpf) in response to developmental exposures with PPARα, PPARγ, and PPARβ/δ agonists and antagonists at 0, 0.01, 0.1, 1, and 10 μM concentrations. All ligand exposures, with the exception of the PPARα agonist, resulted in significantly altered fish length and yolk sac area. PPARγ agonist and antagonist had higher incidence of darkened yolk sac and craniofacial deformities, whereas PPARα antagonist had higher incidence of pericardial edema and death. Significantly reduced endocrine pancreas area was observed in both PPARγ ligands and PPARα agonist exposed embryos, some of which also exhibited aberrant endocrine pancreas morphology. Both PPARβ/δ ligands caused reduced exocrine pancreas length and novel aberrant phenotype, and disrupted gene expression of pancreatic targets pdx1, gcga, and try. Lipid staining was performed at 8 dpf and revealed altered lipid accumulation consistent with isoform function. These data indicate chronic exposure to synthetic ligands may induce morphological and pancreatic defects in zebrafish embryos.
Insights
Synthetic Peroxisome Proliferator Activated Receptors (PPARs) ligands disrupt zebrafish embryo development, causing morphological and pancreatic defects. This research highlights potential risks of these metabolic disease therapeutics.
Area of Science:
- Endocrinology and Developmental Biology
- Molecular Toxicology
- Zebrafish as a Model Organism
Background:
- Peroxisome Proliferator Activated Receptors (PPARs) are key regulators of lipid and glucose metabolism.
- Synthetic PPAR ligands are developed as therapeutics for metabolic diseases.
- The impact of PPAR activity on pancreas development is not well understood.
Purpose of the Study:
- To investigate the effects of PPAR agonists and antagonists on gene expression, embryonic morphology, and pancreas development in zebrafish.
- To assess the dose-dependent responses to various PPAR isoform-specific ligands.
Main Methods:
- Transgenic zebrafish embryos were exposed to PPARα, PPARγ, and PPARβ/δ agonists and antagonists at varying concentrations (0-10 μM).
- Embryonic morphology, including body length, yolk sac area, and specific organ development (pancreas), was assessed at 4 days post fertilization.
- Gene expression of pancreatic targets and lipid accumulation were analyzed at 8 days post fertilization.
Main Results:
- Most PPAR ligand exposures altered fish length and yolk sac area, with specific deformities linked to PPARγ and PPARα antagonists.
- Reduced endocrine pancreas area and aberrant morphology were observed with PPARγ ligands and PPARα agonist.
- PPARβ/δ ligands impaired exocrine pancreas development and disrupted key pancreatic gene expression (pdx1, gcga, try).
- Lipid accumulation patterns varied, consistent with PPAR isoform functions.
Conclusions:
- Chronic exposure to synthetic PPAR ligands can induce significant morphological and pancreatic defects in developing zebrafish embryos.
- These findings suggest potential developmental risks associated with therapeutic PPAR modulators.
- Zebrafish embryos serve as a valuable model for evaluating the developmental toxicity of pharmaceutical compounds.
