Advance-CTR

Advance-CTR Pilot Projects Program (Cycle 6)

"Prospective Study of Spermatocoal RNA and IVF Embryo Development"

Multi-PI: Virginia Mensah, MD | Contact PI: Daniel Spade, PhD

The goal of this project, titled “Prospective Study of Spermatozoal RNA and IVF Embryo Development,” is to identify the sperm mRNA differences that are most predictive of successful IVF outcomes in human patients. The approach consists of sequencing sperm RNA from three male patient populations: men whose partners have achieved pregnancy through intercourse (pre-vasectomy/known fertile control), and men who have presented for IVF and obtained successful (IVF-high) or unsuccessful (IVF-low) embryo and/or live birth outcomes.

In both humans and rodents, sperm contain over 20,000 RNAs, including mRNAs, miRNAs, piRNAs, tRNA fragments (tRFs). In mice, a requirement for sperm RNA in embryo development has been empirically demonstrated. In humans, the presence or absence of certain sperm RNAs is known to correlate with fertility or success in in vitro fertilization (IVF). In both humans and animals, exposure to reproductive toxicants alters sperm RNA contents. While it is well-known that RNAs contribute to sperm function, probably both before and after fertilization, the biological roles of the RNAs are not fully understood. Moreover, these RNAs represent an enormous and largely untapped opportunity for the development of biomarkers of male fertility or success in assisted reproductive technology (ART) treatments, including IVF. Preliminary data demonstrate that human and animal sperm RNA contents can be altered by lifestyle factors such as stress and alcohol intake, and that abundance of certain rat sperm RNAs are more sensitive measures of pharmaceutical toxicity than testicular histopathology. Based on these preliminary data, it is likely that human sperm RNAs can be leveraged to develop non-invasive biomarkers of male fertility.

This project will test the working hypothesis that mRNA profiles of human sperm predict IVF outcomes. This hypothesis will be tested by fulfilling a single Specific Aim: Discover human sperm mRNAs that correlate with embryo number, embryo quality, and birth outcomes in IVF procedures. The proposed research is innovative because it uses reproductive history, not semen parameters, as the baseline for patient group identification, and because it considers the unique ability of mRNAs to reflect etiologies of human male infertility. The proposed research is significant because it will it will address a critical barrier in the understanding the reasons for fertilization failure following IVF with or without ICSI are unclear, particularly when there are no known female infertility factors. This knowledge will have the potential to enhance the state of the science in male reproductive biology and to contribute to development of new tools for the assessment of male fertility.

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