Dissecting the Mechanisms of Temperature-induced DNA Damage during Spermatogenesis
Sperm and eggs enable the successful transmission of the genome from one generation to another. All tissues are susceptible to dramatic increases in temperature, however, developing sperm in the testes are unusually sensitive to small temperature fluctuations. In contrast to egg development and other developmental processes, sperm development requires a narrow isotherm of 2-7 °C below core body temperature. Failure to regulate the temperature of the tissue surrounding the developing sperm or prolonged exposure of the testes to elevated temperatures are linked to male infertility. Temperature increases are known to cause DNA damage in developing sperm, but the molecular mechanisms underlying this damage to the genome are unclear. We are establishing and exploiting the nematode Caenorhabiditis elegans as a model system to elucidate the mechanisms of temperature-induced DNA damage during sperm development. The C. elegans model system permits easy access, manipulation, and visualization of both developing sperm and eggs. We have shown that similar to mammals, C. elegans acquires temperature-induced DNA damage specifically in developing sperm. We are developing new genetic and live imaging technologies to monitor and assess DNA damage and DNA repair in the genomes of developing sperm and eggs. These new technologies and existing approaches in C. elegans will enable us to answer fundamental questions about sperm and egg development, such as: How does a temperature increase induce DNA damage in sperm? What is different about spermatocyte chromosomes versus oocyte chromosomes? Why does sperm development require thermoregulation? How does temperature affect development, genome stability, and genetic variation? Overall, these studies will illuminate mechanisms that affect human fertility, cancer, and human development.