Thursday, April 3, 2025
4/3/2025
Sperm mitochondrial biomarkers and male reproductive health - 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.
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