Thursday, April 3, 2025
4/3/2025
Uncovering the Molecular Signature of PFAS Mixtures on Preconception Male Reproductive Health - Project Summary Infertility affects approximately 16% of couples in the U.S., posing a significant reproductive health challenge. Spermatogenesis, the process of sperm development in adult males, involves intricate epigenetic mechanisms in the testis and maturation through interactions with extracellular vesicles in the epididymis called epididymosomes. These processes enable sperm to adapt to their environment through epigenetic changes. Our previous research linked preconception phthalate exposure to alterations in sperm methylome profiles, RNA cargo of seminal plasma extracellular vesicles, and embryonic development. However, the impact of other endocrine disrupting compounds (EDCs), such as Per- and polyfluoroalkyl substances (PFAS), on male reproductive health remains poorly understood. Emerging evidence suggests that PFAS exposure may affect fertility by influencing testosterone levels and sperm quality. However, the specific mechanisms by which PFAS influence spermatogenesis, sperm epigenetics, and epididymosomes remain largely unexplored. This proposal aims to investigate these mechanisms and explore potential connections between PFAS exposure and adverse effects on male reproductive health. We will conduct single-cell RNA sequencing (scRNA-seq) of the testis and study the small non-coding RNA (ncRNA) cargo of epididymosomes to better understand how PFAS impacts male reproductive health. Leveraging our established mouse PFAS exposure model, we have generated compelling preliminary data, identifying over 2,800 sperm differentially methylated regions (DMRs) associated with behavior, developmental pathways, and lipid metabolism. Thus, the central hypothesis of this proposal is that PFAS exposure negatively affects overall male reproductive health. Our proposed aims will focus on scRNA-seq analysis of testicular somatic and germ cells to decipher the influence of PFAS exposure on spermatogenesis trajectory and transcriptomes. Additionally, we will characterize epididymosomes and evaluate the effect of PFAS exposure on their sRNA cargo. The expected outcomes of this research will enhance our understanding of how PFAS mixtures impact spermatogenesis and the loading of sRNA cargo in epididymosomes. These insights will advance translational research, leading to the development of novel approaches for treating and preventing adverse reproductive health outcomes. Furthermore, this project will provide advanced training in bioinformatics, toxicology, and single-cell techniques, contributing to progress in environmental and reproductive health research.
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