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

In 2018, data from a surveillance study in Botswana evaluating adverse birthoutcomes raised concerns that women on antiretroviral therapy (ART) containingdolutegravir (DTG) may be at increased risk neural tube defects (NTDs). Themechanism of action for DTG involves chelation of Mg2+ ions in the active siteof the viral integrase. Plasma Mg2+ homeostasis is maintained primarily throughdietary intake and reabsorption in the kidneys. Inadequate dietary Mg2+ intake overseveral months results in slow depletion of plasma Mg2+ and chronic latenthypomagnesemia, a condition prevalent in women of reproductive ageworldwide. Mg2+ is critical for normal embryonic development and neural tubeclosure. We hypothesized that DTG therapy might slowly deplete plasma Mg2+ andreduce the amount available to the embryo, and that mice with pre-existinghypomagnesemia due to genetic variation and/or dietary Mg2+ insufficiency at thetime of conception and initiation of DTG treatment would be at increased risk forNTDs. We used two different approaches to test our hypothesis: 1) we selectedmouse strains that had inherently different basal plasma Mg2+ levels and 2) placedmice on diets with different concentrations of Mg2+. Plasma and urine Mg2+ weredetermined prior to timed mating. Pregnant mice were treated daily with vehicleor DTG beginning on the day of conception and embryos examined for NTDs ongestational day 9.5. Plasma DTG was measured for pharmacokinetic analysis. Ourresults demonstrate that hypomagnesemia prior to conception, due to geneticvariation and/or insufficient dietary Mg2+ intake, increases the risk for NTDs in miceexposed to DTG. We also analyzed whole-exome sequencing data from inbredmouse strains and identified 9 predicted deleterious missense variants in Fam111athat were unique to the LM/Bc strain. Human FAM111A variants are associated withhypomagnesemia and renal Mg2+ wasting. The LM/Bc strain exhibits this samephenotype and was the strain most susceptible to DTG-NTDs. Our results suggestthat monitoring plasma Mg2+ levels in patients on ART regimens that include DTG,identifying other risk factors that impact Mg2+ homeostasis, and correctingdeficiencies in this micronutrient might provide an effective strategy formitigating NTD risk.