Epigenetic Age Acceleration Based on DNA Methylation of Human Sperm Cells Is Predictive of Sperm Quality and Pregnancy Outcomes

Epigenetic age acceleration based on DNA methylation of human sperm cells is predictive of sperm quality and pregnancy outcomes. Hachem Saddiki, Oladele Oluwayiose, Laura Balzer, Richard Pilsner Department of Biostatistics and Epidemiology Department of Environmental Health Sciences

Introduction and Background ‘Epigenetic clocks’ estimate an individual’s chronological age based on epigenetic markers, such as DNA methylation. Differences between predicted age and chronological age can be utilized as an indicator of Epigenetic Age Acceleration’ (EAA), which has been associated with mortality (Marioni et al., 2015) and other age-related diseases (Zheng et al., 2016; Raina et al., 2017). To date, this work has been limited to somatic cells only. We built an epigenetic clock specific to sperm and investigated the relationship between sperm EAA and reproductive health outcomes. Methods We developed an epigenetic clock using DNA methylation measurements of sperm samples from 379 male participants aged 19 to 50 years and enrolled in the Longitudinal Investigation of Fertility and the Environment (LIFE) study. Super Learner, an ensemble machine learning algorithm (van der Laan et al., 2007), was applied to predict chronological age using more than 800,000 genetic locations. Linear and Cox Proportional Hazards regression were used to assess the associations between EEA and sperm concentration and time to pregnancy, respectively. Results Predicted age was highly correlated with chronological age (r=0.9). Our approach also achieved a mean absolute error, the average absolute difference between predicted age and true chronological age, of 1.9 years, outperforming the average errors of 3.6 and 4.9 years reported in (Horvath, 2013) and (Hannum, 2013), respectively. Every 1 year increase in EAA was associated with a decrease in sperm concentration of -2.7 million/mL (95% CI: [-4.9, -0.4], p-value=0.019). After adjusting for male and female chronological ages, increasing EAA was also associated with decreases in couples’ fecundability and thus increases in time to pregnancy: hazard ratio of 0.87 (95% CI: [0.81, 0.95], p-value=0.001).

Figure 1. (a) Plot of sperm concentration versus EAA with the fitted regression line. (b) Plot of the estimated pregnancy probability curves with 95% CI for two values of EAA, the 25th quantile in red and the 75th quantile in blue, holding male and female ages fixedat their mean value. Conclusion We show, for the first time, that epigenetic age acceleration in sperm is associated with decreased sperm concentration and increased time to pregnancy. Our sperm epigenetic clock can serve as a novel biomarker to predict reproductive outcomes. References

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