Dolutegravir Developmental Toxicity is Mitigated by Magnesium and Folate in Zebrafish Embryos

Area of Science:

• Developmental Biology
• Pharmacology
• Toxicology

Background:

• Dolutegravir (DTG) is a key HIV integrase inhibitor.
• DTG is linked to developmental toxicity, but the mechanism is unclear.
• Zebrafish models offer insights into vertebrate development.

Purpose of the Study:

• Investigate the teratogenic mechanism of DTG using zebrafish.
• Identify factors that modify DTG developmental toxicity.
• Explore the role of magnesium and folate in DTG toxicity.

Main Methods:

• DTG exposure in zebrafish embryos from 2-4 hpf to 24 hpf.
• Co-treatment experiments with folic acid, 5-methyltetrahydrofolate, calcium, and magnesium.
• Competitive binding assays for folate receptor 1 (FOLR1).
• Analysis of maternal-zygotic folr1 mutant zebrafish.

Main Results:

• DTG exposure caused high mortality and abnormal morphology.
• Folate and magnesium supplementation partially rescued DTG toxicity.
• Magnesium enhanced folate binding to FOLR1 in the presence of DTG.
• folr1 mutants showed hypersensitivity to DTG, partially rescued by magnesium.

Conclusions:

• Magnesium availability is a critical factor in mitigating DTG developmental toxicity.
• DTG may antagonize FOLR1, with magnesium influencing this interaction.
• Magnesium modifies DTG toxicity via FOLR1-dependent and independent mechanisms.
• Magnesium status is a modifiable determinant of DTG teratogenicity.