Long Noncoding RNA PCALRx Interacts with Pyruvate Carboxylase to Drive Multi-Organ Developmental Toxicity in...

Area of Science:

• Environmental toxicology
• Molecular biology
• Developmental biology

Background:

• Amoxicillin is prevalent in aquatic environments, posing risks to aquatic life.
• Antibiotic contamination can interfere with sensitive developmental processes.

Purpose of the Study:

• To investigate amoxicillin's developmental toxicity in zebrafish embryos.
• To elucidate the molecular and epigenetic mechanisms underlying amoxicillin's effects.
• To identify potential therapeutic interventions.

Main Methods:

• Zebrafish embryonic amoxicillin exposure (EAE) model.
• Multi-omics analysis to identify molecular pathways.
• Investigation of long noncoding RNA (lncRNA) PCALRx and pyruvate carboxylase (PC) interaction.
• Drug-repurposing screening for mitigation strategies.

Main Results:

• Amoxicillin exposure caused dose- and time-dependent increases in mortality and malformations.
• Impaired organ differentiation (liver, heart, brain) and mitochondrial damage were observed.
• A novel lncRNA, PCALRx, was identified, promoting PC ubiquitination and impairing mitochondrial function.
• Thiamine (vitamin B1) mitigated amoxicillin-induced developmental toxicity in zebrafish and mice.

Conclusions:

• Amoxicillin induces developmental toxicity through lncRNA-mediated disruption of mitochondrial metabolism.
• PCALRx plays a key role in amoxicillin's toxicity by targeting pyruvate carboxylase.
• Thiamine is a potential therapeutic agent against amoxicillin developmental toxicity.