E-Cigarette Exposure Delays Implantation and Causes Reduced Weight Gain in Female Offspring Exposed In Utero

Margeaux Wetendorf; Lewis T. Randall; Mahlet T. Lemma; Sophia H. Hurr; John B. Pawlak; Robert Tarran; Claire M. Doerschuk; Kathleen M. Caron

Disclosures

J Endo Soc. 2019;3(10):1907-1916. 

In This Article

Abstract and Introduction

Abstract

Electronic nicotine delivery system (e-cigarette) use is prevalent among pregnant women as a seemingly safe alternative to traditional tobacco use, known to result in fetal developmental abnormalities and impaired fertility of male offspring. However, little is known about the effects of e-cigarette use on fertility or pregnancy outcomes. A successful pregnancy is initiated by a multitude of dynamic molecular alterations in the uterus resulting in embryo implantation at day 4.5 in the mouse. We examined whether e-cigarette exposure impairs implantation and offspring health. Pregnant C57BL/6J mice were exposed five times a week to e-cigarette vapor or sham. After 4 months, e-cigarette exposed dams exhibited a significant delay in the onset of the first litter. Furthermore, exposure of new dams in early pregnancy significantly impaired embryo implantation, as evidenced by nearly complete absence of implantation sites in e-cigarette–exposed animals at day 5.5, despite exhibiting high levels of progesterone, an indicator of pregnancy. RNA microarray from day 4.5 pseudopregnant mice revealed significant changes in the integrin, chemokine, and JAK signaling pathways. Moreover, female offspring exposed to e-cigarettes in utero exhibited a significant weight reduction at 8.5 months, whereas males exhibited a slight but nonsignificant deficiency in fertility. Thus, e-cigarette exposure in mice impairs pregnancy initiation and fetal health, suggesting that e-cigarette use by reproductive-aged women or during pregnancy should be considered with caution.

Introduction

The use of tobacco products during pregnancy correlates with an increased risk of poor perinatal and obstetrical outcomes.[1] Additionally, babies exposed to cigarette smoke in utero exhibit a higher risk of developmental abnormalities.[1] Increasing in popularity among adolescents and pregnant women,[2,3] electronic nicotine delivery systems (e-cigarettes) are tobacco delivery devices that aerosolize a mixture of propylene glycol and vegetable glycerin with customizable additions of nicotine and flavors into an inhaled vapor.[3] Currently, the England Public Health system has ruled e-cigarettes to be 95% safer than conventional cigarettes,[4] despite the fact that long-term and second-generation clinical studies of e-cigarette exposure do not exist.[5] As a result, the public is encouraged to use e-cigarettes as an effective smoking cessation tool.[6] Contrastingly, the European Respiratory Society reported that the safety of extended use of e-cigarettes compared with conventional tobacco is unknown.[7] Thus, studies of the safety of e-cigarettes are needed, especially among pregnant women and future offspring.

Proper functioning of the receptive uterus and successful embryo implantation is necessary for normal pregnancy. Multiple factors facilitate the preparation of the uterine luminal epithelium for reception of the implanting embryo at day 4.5 in the mouse, a critical period referred to as the window of receptivity.[8,9] Implantation of the blastocyst elicits a dynamic morphological and molecular change of the epithelial and stromal compartments of the uterus.[8,9] Although difficult to quantify, a predicted 60% of pregnancy losses result from improper uterine receptivity and implantation.[10] Thus, identifying factors that influence uterine and blastocyst biology is of great clinical interest.

Recent literature in the mouse reports that e-cigarette exposure in utero causes changes in metabolic, inflammatory, neurologic, and pulmonary factors in exposed offspring.[11,12] However, the reproductive fitness and fetal outcomes of dams exposed to e-cigarettes before and during pregnancy have yet to be determined. Here, we directly examine the effects of e-cigarettes on pregnancy initiation and second-generation fetal reproductive health and find that e-cigarettes delay implantation and impair the health of future offspring.

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