Gene-nutrient interactions that impact magnesium homeostasis increase risk for neural tube defects in mice exposed to dolutegravir.

Abstract

In 2018, data from a surveillance study in Botswana evaluating adverse birth outcomes raised concerns that women on antiretroviral therapy (ART) containing dolutegravir (DTG) may be at increased risk for neural tube defects (NTDs). The mechanism of action for DTG involves chelation of Mg2+ ions in the active site of the viral integrase. Plasma Mg2+ homeostasis is maintained primarily through dietary intake and reabsorption in the kidneys. Inadequate dietary Mg2+ intake over several months results in slow depletion of plasma Mg2+ and chronic latent hypomagnesemia, a condition prevalent in women of reproductive age worldwide. Mg2+ is critical for normal embryonic development and neural tube closure. We hypothesized that DTG therapy might slowly deplete plasma Mg2+ and reduce the amount available to the embryo, and that mice with pre-existing hypomagnesemia due to genetic variation and/or dietary Mg2+ insufficiency at the time of conception and initiation of DTG treatment would be at increased risk for NTDs. We used two different approaches to test our hypothesis: 1) we selected mouse strains that had inherently different basal plasma Mg2+ levels and 2) placed mice on diets with different concentrations of Mg2+. Plasma and urine Mg2+ were determined prior to timed mating. Pregnant mice were treated daily with vehicle or DTG beginning on the day of conception and embryos examined for NTDs on gestational day 9.5. Plasma DTG was measured for pharmacokinetic analysis. Our results demonstrate that hypomagnesemia prior to conception, due to genetic variation and/or insufficient dietary Mg2+ intake, increases the risk for NTDs in mice exposed to DTG. We also analyzed whole-exome sequencing data from inbred mouse strains and identified 9 predicted deleterious missense variants in Fam111a that were unique to the LM/Bc strain. Human FAM111A variants are associated with hypomagnesemia and renal Mg2+ wasting. The LM/Bc strain exhibits this same phenotype and was the strain most susceptible to DTG-NTDs. Our results suggest that monitoring plasma Mg2+ levels in patients on ART regimens that include DTG, identifying other risk factors that impact Mg2+ homeostasis, and correcting deficiencies in this micronutrient might provide an effective strategy for mitigating NTD risk.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.3389/fcell.2023.1175917

Publication Info

Gelineau-van Waes, J, MA van Waes, J Hallgren, J Hulen, M Bredehoeft, AE Ashley-Koch, D Krupp, SG Gregory, et al. (2023). Gene-nutrient interactions that impact magnesium homeostasis increase risk for neural tube defects in mice exposed to dolutegravir. Frontiers in cell and developmental biology, 11. p. 1175917. 10.3389/fcell.2023.1175917 Retrieved from https://hdl.handle.net/10161/30069.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Ashley-Koch

Allison Elizabeth Ashley-Koch

Professor in Medicine

My work focuses on the dissection of human traits using multi-omic technologies (genetics, epigenetics, metabolomics and proteomics).  I am investigating the basis of several neurological and psychiatric conditions such as neural tube defects and post-traumatic stress disorder. I also study modifiers of sickle cell disease.

Gregory

Simon Gray Gregory

Margaret Harris and David Silverman Distinguished Professor

Dr. Gregory is a tenured Professor and Director of the Brain Tumor Omics Program (BTOP) in the Duke Department of Neurosurgery, the Vice Chair of Research in the Department of Neurology, and Director of the Molecular Genomics Core at the Duke Molecular Physiology Institute. 

As a neurogenomicist, Dr. Gregory applies the experience gained from leading the sequencing of chromosome 1 for the Human Genome Project to elucidating the mechanisms underlying multi-factorial diseases using genetic, genomic, and epigenetic approaches. Dr. Gregory’s primary areas of research involve understanding the molecular processes associated with disease development and progression in brain tumors and Alzheimer’s disease, novel drug induced white matter injury repair in multiple sclerosis, and social and behavioral response to oxytocin treatment animal models of autism. 

He is broadly regarded across Duke as a leader in the development of novel single cell and spatial molecular technologies towards understanding the pathogenic mechanisms of disease development. Dr. Gregory is also the Section Chair of Genomics and Epigenetics at the DMPI and Director of the Duke Center of Autoimmunity and MS in the Department of Neurology.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.