Molecular and genetic basis of normal and toxicant-induced apoptosis in female germ cells

The union of a healthy egg and a healthy sperm is required for propagation of mammalian species, and thus any factor that disrupts the normal production of female or male gametes is a potential threat to reproductive performance. These hazards to gonadal function are derived from both clinical and environmental sources, and can affect either somatic cell or germ cell lineages, or in some cases both, with equal consequences, i.e. the loss of fertility. Females of the species are particularly at risk to gonadal toxicants since, unlike males, females are born with an irreplaceable stockpile of germ cells in their ovaries at the time of birth. Natural selection processes further dwindle this precious reserve such that by the time of puberty, when eggs could actually be used for fertilization and pregnancy, the number of remaining oocytes has been depleted to less than three-quarters of the starting cohort. In the human female, this completely normal loss of oocytes eventually leads to near-exhaustion of the germ cell reserve around the fifth decade of life, and the menopause ensues. Consequently, exposure of women to potentially damaging agents, such as anti-cancer drugs, industrial chemicals or even cigarette smoke, can have a dramatic and irreparable effect on the ovary by accelerating the natural process of germ cell depletion and, as a direct consequence, advance the time to menopause. This mini-review attempts to bring together these concepts from a molecular biological standpoint, and further offers the hypothesis that many gonadal toxicants exert their effects via modulation of discrete signaling pathways linked to apoptotic cell death in the female germline.