Dolutegravir-Induced Neural Tube Defects in Mice Are Folate Responsive

Authors

Gabriel L Tukeman
Hui Wei
Ying L Lin
Bogdan J Wlodarczyk
Richard H Finnell
Robert M Cabrera

Language

English

Publication Date

3-15-2024

Journal

AIDS

DOI

10.1097/QAD.0000000000003639

PMID

37382903

PMCID

PMC10755062

PubMedCentral® Posted Date

3-15-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Objectives: In 2018, the Botswana Tsepamo Study reported a nine-fold increased risk of neural tube defects in infants whose mothers were treated with dolutegravir (DTG) from the time of conception. As maternal folate supplementation and status is a well known modifier of neural tube defect (NTD) risk, we sought to evaluate birth outcomes in mice fed normal and low folic acid diets treated with DTG during pregnancy.

Design: DTG was evaluated for developmental toxicity using pregnant mice fed normal or low folic acid diet.

Methods: CD-1 mice were provided diet with normal (3 mg/kg) or low (0.3 mg/kg) folic acid. They were treated with water, a human therapeutic-equivalent dose, or supratherapeutic dose of DTG from mouse embryonic day E6.5 to E12.5. Pregnant dams were sacrificed at term (E18.5) and fetuses were inspected for gross, internal, and skeletal defects.

Results: Fetuses with exencephaly, an NTD, were present in both therapeutic human equivalent and supratherapeutic exposures in dams fed low folic acid diet. Cleft palates were also found under both folate conditions.

Conclusions: Recommended dietary folic acid levels during mouse pregnancy ameliorate developmental defects that arise from DTG exposure. Since low folate status in mice exposed to DTG increases the risk for NTDs, it is possible that DTG exposures in people living with HIV with low folate status during pregnancy may explain, at least in part, the elevated NTD risk signal observed in Botswana. Based on these results, future studies should consider folate status as a modifier for DTG-associated NTD risk.

Keywords

Humans, Pregnancy, Female, Animals, Mice, Folic Acid, HIV Infections, Neural Tube Defects, Heterocyclic Compounds, 3-Ring, Oxazines, Piperazines, Pyridones

Published Open-Access

yes

Recommended Citation

Tukeman, Gabriel L; Wei, Hui; Lin, Ying L; et al., "Dolutegravir-Induced Neural Tube Defects in Mice Are Folate Responsive" (2024). Faculty and Staff Publications. 4858.
https://digitalcommons.library.tmc.edu/baylor_docs/4858