A Zebrafish Acromegaly Model Elevates DNA Damage and Impairs DNA Repair Pathways

Area of Science:

• Endocrinology and Molecular Biology
• Zebrafish models for human disease
• Cellular and Molecular Pathology

Background:

• Acromegaly results from excess growth hormone (GH) secretion, leading to severe health complications.
• These complications affect multiple organ systems, suggesting a generalized impact on cellular integrity.
• The specific effects of GH excess on cellular integrity and DNA repair remain incompletely understood.

Purpose of the Study:

• To investigate the impact of excess growth hormone (GH) on cellular integrity.
• To establish and utilize a zebrafish model for studying acromegaly.
• To identify molecular mechanisms underlying GH excess-induced cellular damage.

Main Methods:

• Generation of stable zebrafish lines overexpressing tilapia GH and a red fluorescence protein (RFP) reporter.
• RNA-sequencing (RNA-Seq) analysis of various organs from acromegaly model zebrafish.
• Immunohistochemistry (H2A.X staining) to detect DNA damage.
• Gene Set Enrichment Analysis (GSEA) to assess DNA repair pathway function.

Main Results:

• Zebrafish model of acromegaly exhibited enrichment of DNA damage markers in multiple organs.
• Increased numbers of DNA-damaged cells were observed in larvae, brain, and muscle tissues.
• Impairment of key DNA repair pathways, including double-strand break (DSB) repair, was identified in the liver.
• DNA repair deficiencies were more pronounced in the acromegaly model than in aged zebrafish.

Conclusions:

• Excess growth hormone (GH) significantly affects cellular integrity by inducing DNA damage.
• Acromegaly is characterized by impaired DNA repair mechanisms, particularly in the liver.
• The established zebrafish model provides a valuable tool for studying acromegaly pathogenesis and cellular damage.