OOCYTE SELECTION: THE PRESSURE OF CONSTANT MUTATIONS VERSUS THE NEED FOR HEALTHY OFFSPRING

Problem Statement: Three observations regarding oocyte physiology remain unexplained. Why are oocytes arrested in the diplotene phase of meiosis; what is the reason for rapid oocyte losses during childhood; and why are karyotype abnormalities the major finding in early pregnancy loss? A new theory poses that all DNA is constantly damaged by ionizing radiation (IR, *Front Astron Space Sci 2022;9:1067491). Aim: To investigate whether the new theory can explain the three oocyte observations.

Methods: The effects of IR over time on germline DNA were analyzed using published data about DNA damage due to IR and applied to oocyte survival and DNA structure. Muons were used as source of IR, as they are the prevailing ionizing particles at earth surface level; they hold an average energy of 4 GeV*.

Results: Homologous chromosomes in meiosis attached only at the sites of crossing form a highly fragile state of germline DNA; any ionizing particle hit, particle shower, particle-induced shockwave or particle-induced oxidative stress event likely will result in shearing of the chromosomal structures causing uneven chromosomal separation and/or multiple DNA breaks. The result is karyotype abnormalities as seen in early pregnancy loss tissue.

Each day the human body absorbs enough muon energy to cause one double-strand break (DSB) in each cell*; DNA DSBs are known to accumulate in primordial follicles with age. Oocytes with significant DNA damage are known to undergo apoptosis explaining the exponential decline in viable oocytes over time and loss of most oocytes by the time a woman reaches menarche.

The greatest chance of healthy offspring is fertilization of a mutation-free oocyte; however, by age 15-30 years most oocytes will have many mutations. By exposing germline DNA in meiosis, any ionizing particle event is likely to cause major DNA damage, resulting in either oocyte apoptosis or pregnancy loss. Thus, having the DNA in a highly fragile state results in loss of nearly all oocytes before menarche, yet remaining oocytes are free of mutations and ascertain healthy offspring.

Conclusion: IR explains why oocytes are arrested in meiosis, the extensive loss prior to menarche and the karyotype abnormalities in pregnancy loss tissue.