Nicotine’s effect on the developing embryo studied in new model

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It’s common knowledge that smoking during pregnancy confers a host of risks on a developing embryo and fetus, including miscarriage, low birth weight and premature birth. But for ethical reasons, it’s been difficult to directly study the effects of nicotine exposure before birth, writes Krista Conger for Stanford Medicine.

Now cardiologist and stem cell researcher Joseph C Wu, MD, PhD, and postdoctoral scholars Hongchao Guo, PhD, and Lei Tian, PhD, have found a way to use human embryoid bodies – balls of pluripotent stem cells that mimic aspects of the early human embryo – to examine at the single-cell level how nicotine affects cell development. They published their research in Stem Cell Reports.

As Wu explained: “On average, about 7 percent of women who have given birth smoked cigarettes during pregnancy. In addition to raising the risk of birth defects, maternal smoking is closely associated with adverse neurobehavioral, cardiovascular, respiratory, endocrine, and metabolic outcomes in their children that can persist into adulthood. However, the underlying mechanisms that cause these pathological conditions are not well understood.”

Wu, Guo and Tian hit upon a new way to study how single cells react to nicotine by using human embryonic stem cells, which spontaneously form spheres that begin to become the three main tissue types in a developing embryo.

As Wu explained: “We realized that the spontaneous differentiation of human embryonic stem cells into embryoid bodies, which consist of various lineage-specific progenitors that giving rise to the brain, heart, liver, blood vessel, muscle, and other organs, could allow us to study adverse effects of nicotine on human embryo development using ’embryoid bodies in a dish’ as a surrogate for a developing fetus.”

The researchers used a technique called single-cell RNA sequencing analysis to investigate each cell’s pattern of gene expression in the presence or absence of clinically relevant amounts of nicotine. This allowed them to tease out very specific and subtle effects of the drug.

They found that nicotine exposure interferes with the ability of the cells in the embryoid bodies to communicate with one another. It also increased cell death, elevated the production of DNA-damaging reactive oxygen species, and interfered with other cellular processes.

Although the study didn’t recapitulate the physiology of a pregnant woman and the environmental effects of diet, exercise and hormonal changes, the researchers say that their results should serve as an additional warning call to avoid nicotine exposure from all sources, including tobacco, e-cigarettes, and nicotine gums while pregnant.

They are also hopeful that their new model system will help researchers wishing to investigate the effect of other harmful exposures, such as chemicals in air pollutants, or diseases such as diabetes on the developing fetus.

Major implication

Wu described: “A major implication of our study is that we now have validated a new method for evaluating the effect of drugs and environmental toxicity on human embryonic development. Our study provides robust new scientific evidence showing the harmful effects of nicotine.

“In the future, we plan to further investigate the mechanisms of nicotine-induced fetal birth defects, which we hope will lead to the discovery of novel biomarkers that can help doctors better prevent, diagnose, and treat these diseases.”

Single-Cell RNA Sequencing of Human Embryonic Stem Cell Differentiation Delineates Adverse Effects of Nicotine on Embryonic Development

Authors

Hongchao Guo, Lei Tian, Joe Z Zhang, David T Paik, Won Hee Lee and Joseph C Wu.

Abstract

Nicotine, the main chemical constituent of tobacco, is highly detrimental to the developing fetus by increasing the risk of gestational complications and organ disorders. The effects of nicotine on human embryonic development and related mechanisms, however, remain poorly understood.

Here, we performed single-cell RNA sequencing (scRNA-seq) of human embryonic stem cell (hESC)-derived embryoid body (EB) in the presence or absence of nicotine.

Nicotine-induced lineage-specific responses and dysregulated cell-to-cell communication in EBs, shedding light on the adverse effects of nicotine on human embryonic development. In addition, nicotine reduced cell viability, increased reactive oxygen species (ROS), and altered cell cycling in EBs.

Abnormal Ca2+ signaling was found in muscle cells upon nicotine exposure, as verified in hESC-derived cardiomyocytes. Consequently, our scRNA-seq data suggest direct adverse effects of nicotine on hESC differentiation at the single-cell level and offer a new method for evaluating drug and environmental toxicity on human embryonic development in utero.

Nicotine’s effect on the developing embryo studied in new model Single-Cell RNA Sequencing of Human Embryonic Stem Cell Differentiation Delineates Adverse Effects of Nicotine on Embryonic Development

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