Gender effects on the incidence of aneuploidy in mammalian germ cells

Abstract

Aneuploidy occurs in 0.3% of newborns, 4% of stillbirths, and more than 35% of all human spontaneous abortions. Human gametogenesis is uniquely and gender-specific susceptible to errors in chromosome segregation. Overall, between 1% and 4% of sperm and as many as 20% of human oocytes have been estimated by molecular cytogenetic analysis to be aneuploid. Maternal age remains the paramount aetiological factor associated with human aneuploidy. The majority of extra chromosomes in trisomic offspring appears to be of maternal origin resulting from nondisjunction of homologous chromosomes during the first meiotic division. Differences in the recombination patterns between male and female meiosis may partly account for the striking gender- and chromosome-specific differences in the genesis of human aneuploidy, especially in aged oocytes. Nondisjunction of entire chromosomes during meiosis I as well as premature separation of sister chromatids or homologues prior to meiotic anaphase can contribute to aneuploidy. During meiosis, checkpoints at meiotic prophase and the spindle checkpoint at M-phase can induce meiotic arrest and/or cell death in case of disturbances in pairing/recombination or spindle attachment of chromosomes. It has been suggested that gender differences in aneuploidy may result from more permissive checkpoints in females than males. Furthermore, age-related loss of chromosome cohesion in oocytes as a cause of aneuploidy may be female-specific. Comparative data about the susceptibility of human male and female germ cells to aneuploidy-causing chemicals is lacking. Increases of aneuploidy frequency in sperm have been shown after exposure to therapeutic drugs, occupational agents and lifestyle factors. Conversely, data on oocyte aneuploidy caused by exogenous agents is limited because of the small numbers of oocytes available for analysis combined with potential maternal age effects. The vast majority of animal studies on aneuploidy induction in germ cells represent cause and effect data. Specific studies designed to evaluate possible gender differences in induction of germ cell aneuploidy have not been found. However, the comparison of rodent data available from different laboratories suggests that oocytes are more sensitive than male germ cells when exposed to chemicals that effect the meiotic spindle. Only recently, in vitro experiments, analyses of transgenic animals and knockdown of expression of meiotic genes have started to address the molecular mechanisms underlying chromosome missegregation in mammalian germ cells whereby striking differences between genders could be shown. Such information is needed to clarify the extent and the mechanisms of gender effects, including possible differential susceptibility to environmental agents.