Language

English

Publication Date

5-1-2026

Journal

Disease Models & Mechanisms

DOI

10.1242/dmm.052632

PMID

42021547

PMCID

PMC13267766

PubMedCentral® Posted Date

5-26-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Integrase strand transfer inhibitors have transformed human immunodeficiency virus (HIV) therapy, yet the widely prescribed drug dolutegravir (DTG) has been linked to developmental toxicity, and its teratogenic mechanism remains unclear. Here, we used zebrafish to dissect DTG toxicity during early vertebrate development. DTG exposure from 2-4 h post-fertilization (hpf) to 24 hpf produced high mortality and abnormal morphology. Co-treatment with folates partially restored normal morphology, whereas calcium had no effect. Strikingly, supplementation with magnesium (Mg) partially rescued DTG-exposed embryos, implicating Mg availability in protection. In competitive binding assays, Mg increased binding of folate to purified folate receptor (FOLR1) by 30% in the presence of DTG. folr1 mutant embryos contained significantly less endogenous folate than wild-type embryos and displayed marked hypersensitivity to DTG that could not be mitigated by folate supplementation. Critically, Mg supplementation partially rescued DTG toxicity in folr1 mutants, indicating a Folr1-independent component and placing the balance between free DTG and Mg-bound DTG upstream of folate transport. These results support a model in which free DTG antagonizes FOLR1 and Mg modifies DTG developmental toxicity through FOLR1-dependent and -independent processes.

Keywords

Animals, Zebrafish, Folic Acid, Piperazines, Magnesium, Heterocyclic Compounds, 3-Ring, Oxazines, Dolutegravir, Embryo, Nonmammalian, Pyridones, Folate Receptor 1, Embryonic Development, Mutation, Zebrafish Proteins, Birth defects, Drug toxicity, Magnesium, Folate

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.