SUMMARY
Male factor infertility is responsible in as much as 50% of cases of couple infertility; moreover, male infertility has
been observed to represent an early-life predictor of later-life disease risk. Conventional semen parameter
analysis remains the most prevalent diagnostic tool for assessing semen quality, but has well documented limited
ability to explain male factor infertility and poor reproductive success. Limitations are likely due to reliance on
measures that do not identify the underlying biological influences of sperm function, and incomplete use of
information from semen parameters. Development of novel biomarkers of biological determinants of male
reproductive health is a critical step toward developing interventions to improve clinical care and public health.
Our research to date suggests that sperm mitochondrial DNA copy number (mtDNAcn) and deletions
(mtDNAdel) may fill this gap, and directly measure the physiological processes that determine male reproductive
health. Mitochondria play key roles in sperm function and harbor their own genome, which is highly susceptible
to damage. Our published data suggest that mtDNA biomarkers are related to male infertility, fertilization
probability, clinical infertility treatment outcomes, and time-to-pregnancy (TTP). As a next step in this line of
research, it is important to evaluate these potential relations in large study samples. Moreover, while
conventional semen parameters remain controversial in predicting male factor infertility and reproductive
success, little is known on how best to leverage the combination of semen parameter and novel mtDNA
biomarker data to advance clinical care to understand the male contribution to reproductive success. We propose
to evaluate these relationships using data and biospecimens from the NIH funded Folic Acid and Zinc
Supplementation Trial (FAZST) and the Sperm Environmental Epigenetics and Development Study (SEEDS).
Using these resources, we can evaluate hypotheses in large (n=2,570) preconception cohort that includes
couples using a range of fertility treatments and provide opportunity to test mechanistic pathways. The proposed
research represents an efficient approach to evaluate our hypothesis that mtDNA biomarkers are direct
measures of the underlying biology of male reproductive health, and thus represent a biomarker of overall sperm
fitness. For this proposed research, we will analyse associations of sperm mtDNA biomarkers with semen
parameters, determine associations of sperm mtDNA biomarkers with clinical reproductive outcomes, and
develop clinical prediction models integrating sperm mtDNA biomarkers and semen parameters using machine
learning to optimize use of these measures to inform clinical care. The impact of the proposed research is
expected to improve our understanding of the etiology of male reproductive health by evaluating sperm mtDNA
as novel biomarkers of sperm function and overall fitness. This innovative proposal holds promise to positively
impact clinical reproductive care and is a critical step toward developing interventions for male sub- and infertility.