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Cannabis significantly alters DNA methylation of the human ovarian follicle in a concentration-dependent manner.

ABSTRACT: Cannabis is increasingly consumed by women of childbearing age, and the reproductive and epigenetic effects are unknown. The purpose of this study was to evaluate the potential epigenetic implications of cannabis use on the female ovarian follicle. Whole genome methylation was assessed in granulosa cells from 14 matched case-control patients. Exposure status was determined by liquid-chromatography-mass-spectrometry (LC-MS/MS) measurements of five cannabis-derived phytocannabinoids in follicular fluid. DNA methylation was measured using the Illumina TruSeq Methyl Capture EPIC kit. Differential methylation, pathway analysis and correlation analysis were performed. We identified 3679 differentially methylated sites, with two thirds affecting coding genes. A hotspot region on chromosome 9 was associated with two genomic features, a zinc-finger protein (ZFP37) and a long non-coding RNA (FAM225B). There were 2214 differentially methylated genomic features, 19 of which have been previously implicated in cannabis-related epigenetic modifications in other organ systems. Pathway analysis revealed enrichment in GPCR signaling, cellular transport, immune response and proliferation. Applying strict criteria, we identified 71 differentially methylated regions, none of which were previously annotated in this context. Finally, correlation analysis revealed 16 unique genomic features affected by cannabis use in a concentration-dependent manner. Of these, the histone methyltransferases SMYD3 and ZFP37 were hypomethylated, possibly implicating histone modifications as well. Herein we provide the first DNA methylation profile of human granulosa cells exposed to cannabis. With cannabis increasingly legalized worldwide, further investigation into the heritability and functional consequences of these effects is critical for clinical consultation and for legalization guidelines.

SUBMITTER: Fuchs Weizman N

PROVIDER: S-EPMC9247704 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWe have shown recently that maternal undernutrition (UN) advanced female pubertal onset in a manner that is dependent upon the timing of UN. The long-term consequence of this accelerated puberty on ovarian function is unknown. Recent findings suggest that oxidative stress may be one mechanism whereby early life events impact on later physiological functioning. Therefore, using an established rodent model of maternal UN at critical windows of development, we examined maternal UN-induced changes in offspring ovarian function and determined whether these changes were underpinned by ovarian oxidative stress.Methodology/principal findingsOur study is the first to show that maternal UN significantly reduced primordial and secondary follicle number in offspring in a manner that was dependent upon the timing of maternal UN. Specifically, a reduction in these early stage follicles was observed in offspring born to mothers undernourished throughout both pregnancy and lactation. Additionally, antral follicle number was reduced in offspring born to all mothers that were UN regardless of whether the period of UN was restricted to pregnancy or lactation or both. These reductions were associated with decreased mRNA levels of genes critical for follicle maturation and ovulation. Increased ovarian protein carbonyls were observed in offspring born to mothers UN during pregnancy and/or lactation and this was associated with peroxiredoxin 3 hyperoxidation and reduced mRNA levels; suggesting compromised antioxidant defence. This was not observed in offspring of mothers UN during lactation alone.ConclusionsWe propose that maternal UN, particularly at a time-point that includes pregnancy, results in reduced offspring ovarian follicle numbers and mRNA levels of regulatory genes and may be mediated by increased ovarian oxidative stress coupled with a decreased ability to repair the resultant oxidative damage. Together these data are suggestive of maternal UN potentially contributing to premature ovarian ageing in offspring.

Project description:The supernumerary chromosome 21 in Down syndrome differentially affects the methylation statuses at CpG dinucleotide sites and creates genome-wide transcriptional dysregulation of parental alleles, ultimately causing diverse pathologies. At present, it is unknown whether those effects are dependent or independent of the parental origin of the nondisjoined chromosome 21. Linkage analysis is a standard method for the determination of the parental origin of this aneuploidy, although it is inadequate in cases with deficiency of samples from the progenitors. Here, we assessed the reliability of the epigenetic 5mCpG imprints resulting in the maternally (oocyte)-derived allele methylation at a differentially methylated region (DMR) of the candidate imprinted WRB gene for asserting the parental origin of chromosome 21. We developed a methylation-sensitive restriction enzyme-specific PCR assay, based on the WRB DMR, across single nucleotide polymorphisms (SNPs) to examine the methylation statuses in the parental alleles. In genomic DNA from blood cells of either disomic or trisomic subjects, the maternal alleles were consistently methylated, while the paternal alleles were unmethylated. However, the supernumerary chromosome 21 did alter the methylation patterns at the RUNX1 (chromosome 21) and TMEM131 (chromosome 2) CpG sites in a parent-of-origin-independent manner. To evaluate the 5mCpG imprints, we conducted a computational comparative epigenomic analysis of transcriptome RNA sequencing (RNA-Seq) and histone modification expression patterns. We found allele fractions consistent with the transcriptional biallelic expression of WRB and ten neighboring genes, despite the similarities in the confluence of both a 17-histone modification activation backbone module and a 5-histone modification repressive module between the WRB DMR and the DMRs of six imprinted genes. We concluded that the maternally inherited 5mCpG imprints at the WRB DMR are uncoupled from the parental allele expression of WRB and ten neighboring genes in several tissues and that trisomy 21 alters DNA methylation in parent-of-origin-dependent and -independent manners.

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Cannabis significantly alters DNA methylation of the human ovarian follicle in a concentration-dependent manner.

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