Seminal plasma metabolomic signatures, preconception phthalates and reproductive outcomes.

SUMMARY Infertility is one of the most common reproductive health disorders affecting 16% of couples in the U.S. Infertility has been historically treated as a female problem; however, one-half of infertility cases can be attributed partially or completely to male factors. Phthalates, a class of endocrine disrupting compounds used in plastics and

personal care products, are ubiquitous environmental contaminants resulting in widespread human exposure. In humans, male phthalate exposure is associated with low sperm quality, poor embryo development and longer time to pregnancy. Despite major advances in understanding the molecular characteristics of semen,

conventional semen parameter analyses remain the most prevalent diagnostic tool to assess male fertility. Thus, developing novel biomarkers of male reproductive health and determining how these biomarkers are impacted by environmental exposures is vital to improve clinical care and reproductive health. Seminal plasma, which

comprises ~90% of semen, contains a diverse composition of metabolites that protects and nourishes sperm during transit in the male reproductive tract and, subsequently, in the female reproductive tract. These components have been shown to play important roles in sperm development and function, suggesting that the

seminal plasma is not just a medium for sperm transfer and protection but can also be utilized as a biospecimen matrix to study spermatogenesis and male infertility. As such, we propose that seminal plasma metabolomics are key to understanding how male phthalate exposure impacts reproductive health. Our objective is to identify

seminal plasma metabolomic signatures that are associated with paternal phthalate exposure and reproductive health outcomes, such as fertilization, embryo quality, time-to-pregnancy, and probability of live birth. This application capitalizes on extant sample and data collection from the Sperm Environmental Epigenetics and

Development Study (SEEDS), an epidemiologic study investigating the link between paternal phthalate exposure and adverse reproductive health among couples seeking fertility treatment. We also propose a replication aim to analyze seminal plasma metabolomics from samples collected from the Longitudinal Investigation of Fertility and

the Environment (LIFE) study, a prospective preconception cohort of couples from the general population. We will conduct the following aims: 1) determine the associations of preconception urinary phthalate metabolite concentrations with seminal plasma metabolomics in SEEDS; 2) determine the relationships of seminal plasma

metabolites and reproductive outcomes in SEEDS and 3) replicate and further characterize seminal plasma metabolomic findings in an independent set of participants from the LIFE Study. These results will constitute major advances in the fields of environmental and reproductive health by improving clinical assessments of male

fertility, and thus, is a critical step toward developing interventions for male infertility.