Alcohol-induced cell death in the embryo

Abstract

Exposure to alcohol during gestation can have profound consequences, but not all cells within the embryo are affected equally. Recent advances in molecular embryology have allowed an exploration of this variation. Much of this research has focused on the embryo's vulnerability to the facial malformations characteristic of fetal alcohol syndrome. Studies using mice and chicks show that alcohol exposure at specific stages of early embryo development results in significant death among the cells destined to give rise to facial structures (i.e., cranial neural crest cells). This type of cell death is through activation of the cell's own "self-destruct" machinery (i.e., apoptosis). Researchers have advanced several theories to explain how alcohol triggers apoptosis in the neural crest cells. These theories include deficiency in a type of vitamin A compound, retinoic acid; reduced levels of antioxidant compounds (i.e., free radical scavengers) that protect against damage from toxic oxygen molecules (i.e., free radicals); and interference with the cell's normal internal communication pathways.

Figure 1

Key stages of embryo development. (Note: Structures not drawn to scale.)

Figure 2

Formation of the neural tube (cross view). Early in an embryo’s development, a strip of specialized cells called the notochord (A) induces the cells of the ectoderm directly above it to become the primitive nervous system (i.e., neuroepithelium). The neuroepithelium then wrinkles and folds over (B). As the tips of the folds fuse together, a hollow tube (i.e., the neural tube) forms (C)—the precursor of the brain and spinal cord. Meanwhile, the ectoderm and endoderm continue to curve around and fuse beneath the embryo to create the body cavity, completing the transformation of the embryo from a flattened disk to a three-dimensional body. Cells originating from the fused tips of the neurectoderm (i.e., neural crest cells) migrate to various locations throughout the embryo, where they will initiate the development of diverse body structures (D).

Figure 1

Similarities of facial defects found in (A) humans and (B) mice exposed prenatally to alcohol. Panel C shows a control mouse fetus not exposed to alcohol. (Photograph courtesy of Kathy K. Sulik.)

Figure 2

Neural crest cell death in the chick embryo. Panel A shows a normal embryo after 48 hours of incubation (corresponding to 22 to 25 days of human gestation), when the dark-stained neural crest cells (see arrows) migrate from the primitive brain toward regions of facial development. Panel B shows a 48-hour embryo that was exposed to alcohol at a critical developmental time (i.e., at 18 to 36 hours of incubation). The diffuse, weblike staining (see arrows) in the alcohol-exposed embryo indicates the presence of fewer neural crest cells compared with the many neural crest cells indicated by the denser staining in the control embryo.

Figure 3

Apoptosis in neural crest cells and the primitive brain. Panel A shows a normal 48-hour embryo stained with a bright dye (i.e., acridine orange) that becomes concentrated in apoptotic cells. These dead cells appear as tiny dots (see arrows). Panel B shows a 48-hour embryo that was exposed to alcohol at a critical developmental time (i.e., at 18 to 36 hours of incubation). Many more dead cells, visible as bright dots (see arrows), are seen in the primitive brain and face of the alcohol-exposed embryo compared with the normal embryo. Note that some cell groups are dying in both embryos, but many more cells are dying in the alcohol-exposed embryo. This observation supports the premise that normal and alcohol-induced cell death occur simultaneously in the early brain and neural crest.