Dataset Information

Discontinuation of chronic delta-9-tetrahydrocannabinol diminishes impact on male fertility and the sperm epigenome in rhesus macaques

ABSTRACT: Cannabis is commonly used amongst reproductive age males. Our group and others have shown that chronic delta-9-tetrahydrocannabinol (THC) use adversely impacts male fertility, but less is known about the potential reversibility of these changes. Our study’s objective was to determine if THC discontinuation mitigates THC-associated changes in male reproductive health using a rhesus macaque (RM) model of daily THC edible consumption over a 280-day period (4 spermatogenic cycles). Testicular volume, serum male hormones, semen parameters, sperm DNA fragmentation, seminal fluid proteomics, and whole genome bisulfite sequencing (WGBS) of sperm DNA were assessed at pre-THC, moderate-THC, and heavy-THC dosing, and at 70 and 140 days after THC discontinuation. Chronic THC use resulted in significant testicular atrophy, increased gonadotropins, decreased serum sex steroids, and increased DNA fragmentation. THC discontinuation led to partial recovery of testicular volume, sex steroids and sperm DNA integrity. Seminal fluid proteome analysis revealed differential expression of proteins enriched for processes related to cellular secretion, immune response, and fibrinolysis. WGBS identified significant differential methylation in heavy-THC versus pre-THC sperm, with partial restoration of methylation after discontinuation of THC. Genes associated with differentially methylated regions (DMRs) were enriched for pathways involved in nervous system development and function. This is the first study demonstrating that chronic THC use in RMs adversely impacts male reproductive health, methylation of genes involved in development, and expression of proteins important for male fertility. THC discontinuation improves impacts to male fertility, including partial restoration of THC-associated sperm DMRs in genes important for development.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Macaca Mulatta (rhesus Macaque)

SUBMITTER: Phillip Wilmarth

LAB HEAD: Jamie Lo, MD MCR

PROVIDER: PXD039802 | Pride | 2023-05-18

REPOSITORIES: Pride

ACCESS DATA

Publications

Cessation of chronic delta-9-tetrahydrocannabinol use partially reverses impacts on male fertility and the sperm epigenome in rhesus macaques.

Hedges Jason C JC Hanna Carol B CB Shorey-Kendrick Lyndsey E LE Boniface Emily R ER Bash Jasper C JC Rice-Stitt Travis L TL Burch Fernanda C FC D'Mello Rahul R Morgan Terry K TK Lima Ana Cristina AC Terrobias Juanito Jose D JJD Graham Jason A JA Mishler Emily C EC Jensen Jared V JV Hagen Olivia L OL Urian J Wes JW Spindel Eliot R ER Easley Charles A CA Murphy Susan K SK Lo Jamie O JO

Fertility and sterility 20230327 1

<h4>Objective</h4>To determine whether discontinuation of delta-9-tetrahydrocannabinol (THC) use mitigates THC-associated changes in male reproductive health using a rhesus macaque model of daily THC edible consumption.<h4>Design</h4>Research animal study.<h4>Setting</h4>Research institute environment.<h4>Patient(s)</h4>Adult male rhesus macaques (age, 8-10 years; n = 6).<h4>Intervention(s)</h4>Chronic daily THC edible administration at medically and recreationally relevant contemporary doses fo ...[more]

PMID: 36990913

Similar Datasets

Project description:Infertility is a widespread problem, affecting around 15% of couples worldwide, and is defined as the inability to achieve pregnancy within one year despite unprotected intercourse 1. Infertility can be caused by either male or female reproductive issues. Various medical conditions including malignancies, infections, urogenital conditions, or genetic causes can contribute to male infertility. However, 30-40% of men in their reproductive age are affected by idiopathic infertility, according to the guidelines of European Association of Urology (EAU) 1. Towards a better understanding of male infertility, it is mandatory to achieve a comprehensive understanding of involved genes, their RNA transcripts, and regulatory factors, including miRNAs, which influence the expression level of proteins. Therefore, such proteins need to be identified to investigate their role in spermatogenesis and male infertility. Although there are numerous studies on RNAs, including miRNAs related to male infertility 2-9, there are few studies aiming to cover the whole proteome of human sperm 10. The sperm transcriptome comprises a total of 60,505 transcripts including 11,688 differentially expressed transcripts in infertile and fertile men, as reported by Joshi et al. (2022)11. The entire sperm proteome encompasses 6871 proteins, as summarized by Castillo et al. (2018)10. Nevertheless, there is still a lack of high-throughput studies aiming to identify dysregulated proteins in sperm from subfertile men. Only few studies focused on comparisons of the sperm proteome in men with asthenozoospermia and there is virtually no proteomic studies of oligoasthenozoospermic men 12. Some identified proteins in sperm have functions in maintaining sperm motility and enabling fertilization and are involved in structural composition and/or energy metabolism 12-14 and others are not yet functionally characterized. In this study, we employed Mass spectrometry (MS) technology that is still rarely used in the field of human reproductive research to investigate the proteomic landscape of human sperm and their differential expression patterns in men with subfertility.

Dataset Information

Discontinuation of chronic delta-9-tetrahydrocannabinol diminishes impact on male fertility and the sperm epigenome in rhesus macaques

Publications

Cessation of chronic delta-9-tetrahydrocannabinol use partially reverses impacts on male fertility and the sperm epigenome in rhesus macaques.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure