England paying pregnant smokers to switch to e-cigs while evidence of damage to developing fetuses grows

At the same time England is paying pregnant smokers to switch from cigarettes to e-cigarettes new research shows that e-cigarette use inhibits lung and skeletal development in developing fetuses just like cigarette smoking does. 

The British authorities should read Yunus Ozekin and colleagues’ impressive paper “Intrauterine exposure to nicotine through material vaping disrupts embryonic lung development and skeletal development via the Kcnj2 potassium channel.”    They exposed pregnant mice to e-cigarette aerosol for 4 hours a day through most of pregnancy and found that developing pups had less lung development and smaller bones in their skulls, jaws and legs.  Most impressively, they showed that these effects were mediated, at least in part by loss of the Kcnj2 gene that controls the development of a channel that lets potassium into cells.  The demonstrated the importance of this gene and the associated channel by showing that vaping did not have these adverse effects in mice that did not have the gene.

These effects are all consistent with effects that have been observed in smoking mice and people.

My guess is that the British e-cig enthusiasts will dismiss the study on the grounds that people are not mice.  That’s true, but this study is still important and informative for two reasons: First, as the authors explain, many of the changes that they observe in the vaping mice are similar to or consistent with effects of smoking observed in humans.  Second, and more important, because of ethical constraints, it is simply impossible to do such an experiment on people.

The value of these animal experiments is particularly valuable in the context of e-cigarette advocates’ obsession with causality.  As they endlessly point out, it is difficult to draw causal conclusions from human observational studies (most notably epidemiology) because of the possibility that some unknown confounding variable was left out or because the data were collected at a single point in time (in cross-sectional studies).  These issues do not arise in experiments such as this one, where the investigator controls the total environment, so one can be confident that the differences in exposure caused the observed effects. 

This study is particularly strong in this area because not only did they compare e-cigarette exposed mice to mice who breathed air, but that also compared mice who did and did not have the Kcnj2 gene and so the associated ion channel.  (The mice who had the Kcnj2 gene “knocked out” were genetically engineered, another thing that would not be ethically permissible in people.)  Thus, the investigators not only documented the effect of vaping; they also provided strong evidence of how vaping caused the observed damage.

In addition, while there is evidence that e-cigarettes delivered in a clinical context and combined with counseling (what they are planning in England) do increase “switching” from cigarettes to e-cigarettes, this study indicates that switching – as opposed to stopping all tobacco use – would be unlikely to produce any benefits to developing fetuses.  And, of course, as consumer products e-cigarettes do not help smokers quit.  So, the fundamental assumption that continues to dominate thinking about e-cigarettes in England remains wrong.

Here is the abstract:

Smoking cigarettes during pregnancy is associated with adverse effects on infants including low birth weight, defective lung development, and skeletal abnormalities. Pregnant women are increasingly turning to vaping [use of electronic (e)-cigarettes] as a perceived safer alternative to cigarettes. However, nicotine disrupts fetal development, suggesting that like cigarette smoking, nicotine vaping may be detrimental to the fetus. To test the impact of maternal vaping on fetal lung and skeletal development in mice, pregnant dams were exposed to e-cigarette vapor throughout gestation. At embryonic day (E)18.5, vape exposed litter sizes were reduced, and some embryos exhibited growth restriction compared to air exposed controls. Fetal lungs were collected for histology and whole transcriptome sequencing. Maternally nicotine vaped embryos exhibited histological and transcriptional changes consistent with impaired distal lung development. Embryonic lung gene expression changes mimicked transcriptional changes observed in adult mouse lungs exposed to cigarette smoke, suggesting that the developmental defects may be due to direct nicotine exposure. Fetal skeletons were analyzed for craniofacial and long bone lengths. Nicotine directly binds and inhibits the Kcnj2 potassium channel which is important for bone development. The length of the maxilla, palatal shelves, humerus, and femur were reduced in vaped embryos, which was further exacerbated by loss of one copy of the Kcnj2 gene. Nicotine vapor exposed Kcnj2KO/+ embryos also had significantly lower birth weights than unexposed animals of either genotype. Kcnj2 mutants had severely defective lungs with and without vape exposure, suggesting that potassium channels may be broadly involved in mediating the detrimental developmental effects of nicotine vaping. These data indicate that intrauterine nicotine exposure disrupts fetal lung and skeletal development likely through inhibition of Kcnj2.

The full citation is: Ozekin YH, Saal ML, Pineda RH, Moehn K, Ordonez-Erives MA, Delgado Figueroa MF, Frazier C, Korth KM, Königshoff M, Bates EA, Vladar EK. Intrauterine exposure to nicotine through maternal vaping disrupts embryonic lung and skeletal development via the Kcnj2 potassium channel. Dev Biol. 2023 Sep;501:111-123. doi: 10.1016/j.ydbio.2023.06.002. Epub 2023 Jun 22. PMID: 37353105.   It is available here.