Flavored e-cigarettes modulate embryo development, fetal growth, and potentiate early fetal demise without nicotine

Abstract

Background: Electronic cigarettes (e-cigarettes) function by aerosolizing a base liquid containing nicotine and flavoring, used by an estimated 15% of pregnant women as a supposed safer alternative to traditional cigarettes. Our previous studies demonstrated e-cigarettes can delay gestation. Limited studies have examined in vivo effects on the placenta. Methods: We exposed adult pregnant C57BL/6J female mice to flavored e-cigarettes with and without nicotine (VAPE NIC & VAPE). We measured implantation success (N = 10 SHAM, N = 17 VAPE, N = 13 VAPE NIC), erythrocyte presence (N = 29 SHAM, N = 29 VAPE, N = 26 VAPE NIC) and embryo elongation (N = 25 SHAM, N = 29 VAPE, N = 22 VAPE NIC) per implant site at day 6.5 at 13-21 weeks of age. Fetal and placental weight (N = 11 SHAM, N = 14 VAPE, N = 12 VAPE NIC) was evaluated at day 12.5 in mice aged 15–39 weeks, while placental gene expression was separately analyzed by offspring sex (N = 7 total, N = 3 sex-specific). Results: Here we show that e-cigarettes cause similar embryo elongation and in the absence of nicotine, exhibit elevated implant site blood cell accumulation which may contribute to fetal demise. With nicotine, e-cigarettes elicit a reduction in embryo to placental weight ratios. Genes involved in hypoxia, reactive oxygen species response, and placental growth including hypoxia inducible factor 1, alpha subunit (Hif1a), prostaglandin-endoperoxide synthase 2 (Ptgs2), glutathione peroxidase family members 2 and 3 (Gpx2/Gpx3), thioredoxin reductase 1 (Txnrd1), and mitogen-activated protein kinase 1 (Mapk1) exhibit marked decreases in placental tissue depending on fetal sex and nicotine presence. Conclusions: Our findings conclude flavored e-cigarettes modulate in vivo implantation and placentation mechanisms depending on the presence of nicotine. This work presents a measure of concern for flavored e-cigarette use during pregnancy.