Even very low concentrations of vanillin altered how human embryonic stem cells developed in the lab, while higher concentrations increased cell death. Credit: Stock

Laboratory tests suggest that vanillin used in e-cigarettes can alter early human stem cell development through the TRPV4 channel.

Vanillin, a flavoring chemical commonly used in e-cigarettes, may interfere with early embryonic development, according to laboratory research published August 12, 2026, in Human Reproduction, a leading journal in reproductive medicine.

The findings offer a possible biological explanation for reported links between vaping, difficulty conceiving, and miscarriage.

Directly testing vape chemicals in pregnant women and developing embryos would be both impractical and unethical. Instead, the researchers experimented with human embryonic stem cells, which resemble cells found in human embryos at about three weeks of development. Because the work was conducted entirely in the laboratory, the researchers caution that it cannot establish whether the same effects occur in pregnant women or their embryos.

Phase-contrast images of H9 stem cell colonies: showing that vanillin treatment changes colony shape, making edges rougher and spikier compared to smooth, untreated controls. Credit: Dr Shabnam Etemadi

Low vanillin levels changed cell fate

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 flavor 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.”

Talbot and Dr Shabnam Etemadi, a stem cell biologist and computational scientist at the University of California Riverside, exposed human embryonic stem cells grown in laboratory dishes to different amounts of vanillin. The experiments included nanomolar concentrations, representing lower exposure, and micromolar concentrations, representing higher exposure.

Shabnam Etemadi (left) and Prue Talbot. Credit: European Society of Human Reproduction and Embryology

The researchers also treated cells with a TRPV4 antagonist, which prevents vanillin from binding to TRPV4, as well as an antibody that blocks TRPV4 function. Some cells received vanillin together with either the antagonist or the antibody so the researchers could test whether this channel was responsible for the observed effects.

Embryonic stem cells can potentially develop into any cell type in the body. During normal embryonic development, they give rise to three basic groups of cells: 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.”

Cell death staining (caspase-3 marker, green; nuclei in blue): vanillin-treated colonies show visibly more cell death than untreated controls, suggesting colonies could shrink over time. Credit: Dr Shabnam Etemadi

TRPV4 appears to mediate the changes

When the researchers blocked TRPV4 with the antagonist, vanillin no longer produced the same effects on the stem cells. That result pointed to the TRPV4 channel as the pathway through which vanillin was affecting 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 signaling 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.

OCT4 staining (pluripotency marker): untreated cells show strong green staining (pluripotent); vanillin-treated cells show much weaker staining, indicating loss of pluripotency. Credit: Dr Shabnam Etemadi

“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.”

Other vape chemicals are under study

The researchers have previously studied menthol flavoring in e-cigarettes and found that it contributed to respiratory disease in humans. They are now investigating WS-23, a synthetic cooling chemical commonly used in e-cigarette products, along with the effects of menthol and WS-23 on the differentiation of embryonic cells.

Several important uncertainties remain. The laboratory experiments cannot demonstrate that human embryos exposed during pregnancy would respond in the same way, and the study does not estimate what repeated vanillin exposure over days, weeks, months, or years might do. The researchers note that the effects of long-term exposure could be greater.

Reference: “Nanomolar vanillin, an e-cigarette flavorant, appears to disrupt pluripotency and promote endodermal differentiation in human embryonic stem cells via TRPV4 activation” by Shabnam Etemadi and Prue Talbot, 12 August 2026, Human Reproduction.
DOI: 10.1093/humrep/deag126

The research reported in this publication was supported by grant number T32IR4848 from the Tobacco-Related Disease Research Program (TRDRP), by grant number EDUC4-12752 from the California Institute of Regenerative Medicine (CIRM), and by UCR Yvonne Danielson Endowed Graduate and Dissertation Completion Fellowship Awards.

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