Genetics and Genomics of the Ovarian Reserve and Female Fertility
We study how genotoxic cancer treatments damage ovaries leading to decreased ovarian follicle reserve and accelerated ovarian aging. In woman, depletion of ovarian egg stockpiles with age results in menopause which in turn associates with increased risk of osteoporosis, cardiovascular diseases and cognitive impairments. The risk of premature menopause in cancer survivors depends on many factors, including oocyte susceptibility to DNA damage, the size of the ovarian reserve at the time of treatment, and dynamics of follicle recruitment and atresia during reproductive life. Our preliminary data from pre- and early post-pubertal mice indicates that ovarian reserve size varies significantly between inbred strains at 3 weeks of age. We also observed differences in oocyte susceptibility to DNA-damage induced by ionizing radiation (IR). Some strains showed rapid oocyte loss following radiation while other retained large population of oocytes after exposure with the same dose of IR. Our next goal is to determine the dynamics of oocyte loss during female’s life in various mouse inbred strains. It is known that some strains i.e. CBA show accelerated oocyte loss and early reproductive senescence. However, it has not been described for other strains in particular founders of DO and CC mice. Our long-term goal is to use these reproductive phenotypes quantified in inbred strains to identify genetic factors regulating the size of ovarian reserve, loss of egg stockpiles and oocyte susceptibility to DNA damage. In addition to describing the aging of germ cell compartment we will investigate aging of the ovarian somatic compartment including inflammation and fibrosis phenotypes. Sharing mice with other groups will allow us to potentially correlate ovarian aging phenotype with that of other organs and overall organismal aging.