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Vanillin flavouring in e-cigarettes disrupts human embryonic stem cell development
Vanillin, a common flavouring chemical in e-cigarettes, may disrupt the normal development of embryos in pregnant women who vape, according to a study published today (Thursday) in Human Reproduction, one of the world’s leading reproductive medicine journals. [1]
The finding explains how vaping may be linked to women having difficulty conceiving and to miscarriages.
As it is practically impossible and also unethical to study the effect of chemicals on pregnant women and their developing embryos, researchers instead investigated human embryonic stem cells, which are similar to those in human embryos at three weeks old, in a series of tests in the laboratory. They warn that, as their findings are from a laboratory study, they cannot decisively establish that the same effects would be seen in women and their embryos.
Prue Talbot, Professor of Grad Division in the Molecular Cell & Systems Biology department at the University of California Riverside, USA, who led the study, said: “There is little understanding of how vaping can affect developing embryos in pregnant women who use electronic cigarettes. So we undertook this study to determine if vanillin, a flavour chemical often used in e-cigarettes at high concentrations, could adversely affect the development of young embryos in humans. We wanted to understand how chemicals in vape aerosols can affect young human embryos and identify the type of harm that may occur.”
“We focused on vanillin because it is frequently used in e-cigarette fluids, it is often used at high concentrations, and because we knew that embryonic cells had a channel called TRPV4 on their surfaces that would likely bind with vanillin.”
Prof. Talbot and Dr Shabnam Etemadi, a stem cell biologist and computational scientist also at the University of California Riverside, exposed human embryonic stem cells in dishes in the laboratory to different concentrations of vanillin: nanomolar (low) concentrations, or micromolar (high) concentrations. They also exposed the stem cells to a TRPV4 antagonist (a substance that inhibits vanillin binding to TRPV4), an antibody that blocks the function of TRPV4, or vanillin combined with either the antagonist or the antibody.
Embryonic stem cells have the potential to differentiate into any type of cell. In normal embryonic development, they form three cell types: endoderm, ectoderm and mesoderm.
Prof. Talbot said: “We found that micromolar concentrations tended to kill the cells. Nanomolar concentrations caused cells to lose pluripotency, which is the ability to develop into all cell types. Vanillin also caused the stem cells to differentiate into endoderm, rather than ectoderm or mesoderm. The endoderm is an embryonic tissue that gives rise to the lining of the gut and respiratory tissues. These changes are potentially very serious and could prevent normal development of embryos.”
The effect of vanillin on the stem cells was blocked by the TRPV4 antagonist, which identified the TRPV4 channel as the route by which vanillin adversely affected the cells.
“Our data predict that nanomolar concentrations of vanillin may reach the embryo in pregnant women who vape,” said Prof. Talbot. “At nanomolar concentrations, vanillin binds to a channel called TRPV4 on the surface of embryonic cells allowing a rapid influx of calcium, a signalling molecule. Calcium in turn activates downstream events that result in loss of pluripotency and differentiation of embryonic stem cells into endoderm. In normal development, the embryonic stem cells would form three cell types: endoderm, ectoderm and mesoderm. In embryos lacking ectoderm, the nervous system would fail to develop. In embryos lacking mesoderm, many tissues, such as muscle, would fail to develop.
“Women do not necessarily know the chemicals in vape products. Our findings suggest they should be cautious and advised by physicians not to vape during pregnancy, especially if they are having trouble conceiving or experience miscarriages.
“Regulatory policies are generally based on data derived from adults or adult cells. However, the prenatal stages of development are usually the most sensitive to environmental chemicals. When establishing policies for e-cigarette use and distribution, it would be advisable to consider if and how the products harm the unborn. Regulatory agencies should consider mandatory ingredient disclosure on packaging for e-cigarettes.”
The researchers have already investigated menthol flavouring in e-cigarettes and found that it was a contributor to respiratory disease in humans. They are now studying WS-23, a synthetic coolant often used in e-cigarette products, and examining the effects of menthol and WS-23 on differentiation of embryonic cells.
In addition to the lab study being unable to show definitively that the same effects would happen in human embryos, the researchers point out that their study does not predict the effect of cumulative exposure to vanillin over days, weeks, months or years. The effect of long-term exposure could be higher.
Expert Reaction
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
Associate Professor Alex Polyakov is a Clinical Associate Professor in the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne and is a Medical Director at Genea Fertility Melbourne
"What the study looked at
In this study, researchers investigated vanillin, a sweet vanilla flavouring that is one of the most common ingredients in e-cigarette liquids. Flavourings are often used in vapes at concentrations far higher than would be found in food, and the question was whether vanillin could interfere with the earliest stages of embryo development. They used human embryonic stem cells grown in the laboratory, which behave like the cells of an embryo during the second and third weeks of pregnancy, when the body plan is first being laid down.
What they found
The study found that vanillin acts on a protein channel on the cell's surface called TRPV4, which controls the flow of calcium into cells. At higher concentrations, vanillin was toxic, causing cells to die. More striking was the effect at very low concentrations: vanillin nudged the stem cells to lose their flexible, "undifferentiated" state and begin committing prematurely to becoming a specific tissue type. Using an exposure model, the researchers estimated that these low, biologically active levels could plausibly be reached in the bloodstream of someone vaping during pregnancy and therefore may adversely affect early embryo development. Blocking TRPV4 prevented all these effects, confirming this theory.
What it means for the real world
This is an important early-warning signal. It suggests that the flavourings in vapes may have biological effects on a developing embryo, often during the weeks before a woman even knows she is pregnant. However, I would urge caution in interpretation. This work was carried out on cells in a dish, not in pregnant women, and does not prove that vaping causes harm to real embryos. What it does do is strengthen the case that any amount of vaping should not be considered safe in pregnancy, and it supports calls for clear labelling of vape ingredients. While cigarette smoking in pregnancy has been shown to be harmful, use of vapes for smoking cessation is not a safer alternative, especially when other treatment strategies for nicotine replacement are widely available."
Professor Hui Chen is Associate Head of School (Research) in the School of Life Sciences at University of Technology Sydney (UTS)
"It is interesting that vanilla flavour vanillin affected early foetal development in a culture dish. However, it needs to be noted that this flavouring compound is widely used in food. In some ice creams, the concentration of vanillin is similar to or even higher than in the e-cigarettes shown in this paper.
Should we be panicked? It is too early to say.
On the one hand, this is another paper showing detrimental effects, but from the current study setting, it is hard to predict if foetal responses would be the same as those modelled in the culture system. Two important omissions of the current study are that during e-vaping, vanillin will be heated (in the e-fluid) at a very high temperature, and this may induce chemical reactions among different ingredients; the second is that other toxic components are found in e-cigarettes.
Our own studies suggest that heated e-fluid without nicotine is toxic to foetal development. However, the takeaway message is that: Yes, e-vaping should be avoided during pregnancy or even when preparing for it, no matter what flavour or no flavour."
Oliver Jones is Professor of Chemistry at RMIT University in Melbourne, Australia
"This is an interesting study, and a nice illustration that everything is a chemical and everything is potentially toxic at the right concentration – even things we might usually think of as natural and harmless, such as vanillin. This is not the first time that vanillin in vapes has been implicated in developmental issues, although previous work was done in frogs. The keyword here, though, is 'potentially'. While I can see why the authors conducted the experiment with cells, a group of cells in a petri dish is not the same as a human embryo. Cells in a dish are bathed in chemicals, which is not the case for an embryo. We can’t be sure exposure would be anything like the same.
The TRPV4 channel itself is one of a family of six related types of protein in the body that act like chemical sensors, responding to things like touch, warmth, and water pressure. The V stands for vanilloid. In chemistry, vanilloids are compounds containing a common structural feature called a vanillyl group and include vanillin and capsaicin, the compound responsible for the taste and ‘heat’ of chillies.
The work does not prove a link between vaping and women having difficulty conceiving and/or miscarriages. However, given the potential consequences, I think avoiding vapes and vaping while pregnant or trying to become pregnant is sensible general advice.”
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