Assisted yes but where do we draw the line

Do you know what oocyte activation is? According to Wikipedia it is a series of processes that occur in the oocyte during fertilization. Sperm entry causes calcium release into the oocyte. The moment sperm touches the egg surface, sperm protein interacts with an egg surface receptor.

In order to artificially activate oocytes from patients who had poor fertilization rates in previous cycles the use of a calcium ionophore was tried. Calcium ionophore, known as A23187, is a carboxylic antibiotic that binds divalent cations. Under physiological conditions calcium increase in oocytes is caused by intracellular influx and release from specific stores and ion channels.

However, what should not be neglected is that Ca2+ release in an uncontrolled fashion from intracellular stores would not normally be involved in the activation process. Calcium ionophores have a multitude of not examined effects on cell homeostasis, and possibly a long-term effects on gene expression.

One of the suspected reasons for reported successful births is they might be a result of the overriding influence of the injected spermatozoa, rather than the effect of the ionophore.

Taking into account potential epigenetic effects may result in future generations this invasive non-physiological approach, though successful, is worrying. While calcium concentration increase is desirable we should not neglect its effect on later cell development and division.

Although the calcium release is one of the first indications of oocyte activation, its internal mechanism is different in different species, and still not fully understood. Calcium concentration increase is caused by both influx and intracellular release. These activation events don’t occur alone, they are propagative with specific spatial patterns.

During ISCI when sperm is inserted in an egg cell Ca2+ oscillations show a delayed and truncated pattern, and with the Ca2+ waves starting from an arbitrary cortical region, nearby the injected sperm. This clearly shows that oocyte cortex where sperm would naturally interact with oocyte is far more sensitive than the cytoplasm.
Using another ionophore (more specific for Ca ions) in starfish, the ionomycin, shows induced waves lasting for several minutes, unlike the sperm-induced cortical Ca2+ release which is very rapid, lasting only several seconds and is followed by a Ca2+ waves propagating from the sperm–oocyte interaction site to the opposite pole.

Ca2+ ionophore treatment has been widely applied in human oocytes nowadays. Using both A23187 and ionomycin on human oocytes induced Ca2+ elevation in the form of a single transient, not followed by further Ca2+ oscillations. Simultaneous injection of calcium and Ca2+ ionophore can also activate human oocytes injected with sperm cells less capable of penetrating oocytes both in vivo and in vitro.

The dose used was quite low, but now the concern is uncontrolled fashion in which intracellular calcium is released, both spatially and temporally. It is considered that non-physiological activation of oocytes could affect the activity of specific proteins strictly dependent on the spatial and temporal regulation of the Ca2+ increase. Apart from this, ionophores effect cell homeostasis in a ways that are still have not been researched. It is possible that the successful activation is not due to the ionophore, but rather to the fortunate selection of better gametes in the re-trial.

Considering possible epigenetic effects that may appear in future generations, time and efforts should be focused on ways of improving gametogenesis, in vivo and in vitro rather than recovering defective gametes.