Alcohol alters gene function in differentiating cells of the embryo, reveals research

During the tightly regulated gastrulation, embryonic cells differentiate into the three germ layers – endoderm, mesoderm, and ectoderm – which eventually give rise to all tissues and organs. The late, renowned developmental biologist Lewis Wolpert once stated: “It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life.” Gastrulation occurs during the fifth week of pregnancy, a time when many women are not yet aware that they are pregnant.

According to estimates by the Finnish Association on Intellectual and Developmental Disabilities, 600–3,000 children are born in Finland each year with permanent damage caused by alcohol, but due to the challenges of diagnosis, the true number is unknown.

Researchers at the University of Helsinki, in collaboration with the University of Eastern Finland, have now examined the effects of alcohol on this difficult-to-study stage of human development.

In the study, pluripotent embryonic stem cells were differentiated into the three germ layers in culture dishes. The cells were exposed to two different concentrations of alcohol: the lower exposure corresponded to less than one per mille, while the higher exceeded three per mille. The researchers then investigated the effects of alcohol on gene expression, epigenetic markers regulating gene activity, and cellular metabolism.

Stronger alcohol exposure caused more changes than the lower dose, and a dose-response relationship was observed in both gene activity and metabolism. The most significant metabolic changes were detected in the methionine cycle of the cells.

“The methionine cycle produces vital methyl groups in our cells, which attach to DNA strand and influence gene regulation. The observed changes confirm the importance of this epigenetic regulation in the disturbances caused by alcohol exposure,” the doctoral researcher Essi Wallén explains.

The First Neural Cells Are Most Sensitive to Alcohol

The most pronounced changes caused by alcohol exposure were seen in ectodermal cells, which give rise to the nervous system and the brain during development. It is well-known that prenatal alcohol exposure is one of the most significant causes of neurodevelopmental disorders.

“Many of the developmentally important genes altered in this study have previously been linked to prenatal alcohol exposure and its associated features, such as defects in heart and corpus callosum development, as well as holoprosencephaly, a failure of the forebrain to divide properly,” says Adjunct Professor Nina Kaminen-Ahola, who led the study.

According to the study, some of the developmental disorders caused by alcohol may arise during the very first weeks of pregnancy, when even minor changes in gene function may influence the course of development. However, further research is needed to clarify how well the cell model and alcohol concentrations correspond to actual exposure in humans.

This research is part of a broader project investigating the mechanisms by which alcohol affects early development and later health. Prenatal alcohol exposure causes a range of developmental disorders collectively referred to as fetal alcohol spectrum disorders (FASD).

Reference:

E. Wallén, Effects of alcohol on the transcriptome, methylome and metabolome of in vitro gastrulating human embryonic cells, Disease Models & Mechanisms, https://doi.org/10.1242/dmm.052150