Offspring survival is influenced by xanthine oxidase inhibition in combination with maternal vaping during pregnancy in mice

Maternal exposure to electronic cigarettes (Ecigs) is found to reduce litter size at birth andweaning in rodents. We have previously observed that febuxostat (a xanthine oxidase inhibitor) mediates recovery of vascular dysfunction in offspring with a history of in utero exposure to Ecigs from maternal vaping while pregnant. In this study, we tested the hypothesis that treatment of febuxostat concomitant with maternal vaping during pregnancy would prevent or mitigate adverse reproductive and/or offspring outcomes. We exposed time-mated pregnant C57Bl/6J mice to Ecig aerosol and febuxostat [Febx in drinking water 50 mg/L] from gestational day (GD)7 until GD21 (birth) and compared maternal/litter health to controls (both no-drug and air exposed, respectively). Daily aerosol concentration (resulting from 60-puffs/d, 17.5 watts, and e-liquid comprising 50:50 (v:v) VG:PG with no flavor or nicotine additive) was assessed and found to be 914±326 mg/m 3 (mean±SD). We observed no differences in maternal weight gain from GD1 to GD21 in Air (83%, n=7), Air+Febx (86%, n=6), Ecig (84%, n=7) and Ecig+Febx (81%, n=8) treated groups. The number of days on Febx treatment was similar in Air+Febx and Ecig+Febx (15.4 and 15.5 days, respectively). The number of uterine implantation sites (observed after weaning) was not different between any of the groups [range of 7-12 implant sites, with group means ranging from 7.2-9.2 (1.7-1.2 SD)]. However, the number of offspring born and the number alive at weaning was different between Febx-treated Air and Ecig groups (ANOVA interaction effect, p<0.05), where maternal Febx-treatment improved the number ofpups surviving at weaning in Ecig (from Ecig 5.8±1.3 to Ecig+Febx 8.0±1.3, p<0.05) but not in Air-exposed dams (from Air 6.8±1.7 to Air+Febx 4.7±3.8, p=ns). Survival at weaning was not different for male and female offspring. Body mass of pups at weaning was significantly lower in both male (-16.5%) and female (-17.4%) offspring in the Ecig+Febx group compared to all other groups (ANOVA p<0.001). These data suggest that XO inhibition during the second trimester may help to mitigate pup mortality seen at birth/weaning in association with maternal vaping. However, caution must be noted since the body mass of offspring in the Ecig+Febx group was lower compared to controls, and the long-term consequences to offspring health due to in utero exposure to febuxostat are not yet known. NIH R56 ES035719-01A1 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.