Selecting sperm with distinct metabolic phenotypes to increase ART efficiency

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PROJECT SUMMARY/ABSTRACT More than 80,000 births in the US occur annually as a result of assisted reproductive technology (ART). The success of ART typically requires multiple expensive cycles that together exceed many US families’ yearly household incomes. The necessity of multiple ART cycles stems in part from an insufficient number of healthy preimplantation embryos. Healthy embryos are a direct product of the highest-quality gametes, yet limited methods exist to identify the highest-quality sperm. Within the female reproductive tract, sperm with the highest fertilization competence are naturally selected based on functional parameters – motility patterns, chemotaxis, and the acrosome reaction. The best fertilization-competent sperm also have the lowest levels of oxidative and DNA damage. Unfortunately, current clinical methods for selecting sperm for intracytoplasmic sperm injection (ICSI) do not leverage these parameters. The broad objective of this application is to define the biochemical mechanisms by which sperm undergo motility switching and fertilization competence, and results will both advance the state of basic knowledge and enable optimization of in vitro sperm selection techniques. The optimization of sperm selection for ART will in turn: 1) increase production of healthy embryos; 2) reduce average numbers of costly cycles; and thus 3) lessen the cost burden on lower-income families. In Aim 1, we will utilize complementary comprehensive bioenergetic phenotyping, computer assisted motility analysis (CASA), and a novel dehydrogenase screen to define the underlying mechanisms through which metabolites predictably modulate the essential motility patterns of mouse sperm. In Aim 2, we will test the hypothesis that predictable motility changes in response to metabolites can be used to select the best mouse sperm – those with normal morphology and low levels of DNA damage, the ability to navigate towards a chemotactic signal and initiate hyperactive motility, and complete the acrosome reaction. We will then employ in vitro fertilization (IVF) to determine whether mouse sperm selected based on these metabolism-based motility traits have enhanced ability to generate healthy embryos. In Aim 3, we will exploit our experience working with mouse sperm to define the fundamental differences in the metabolism-based motility responses of human sperm. This project is expected to identify the mechanisms connecting microenvironment to sperm function and thereby provide proof-of-concept for the rapid development of methods to optimize clinical selection of fertilization-competent human sperm for ART.