Epigenetic Changes Associated with Marijuana Use: Unraveling Molecular Mechanisms and Health Implications

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Marijuana, a psychoactive substance derived from the Cannabis plant, has gained widespread popularity and acceptance in the United States.

With an estimated 49% of adults having ever used marijuana, 19% within the past year, and 12% within the past month, its prevalence has risen significantly over the last few decades [1].

This trend is expected to continue with the increasing number of states legalizing marijuana for medical and recreational purposes [2,3,4,5]. Medically, marijuana has been found to have therapeutic benefits, including alleviating chemotherapy-induced nausea and vomiting, managing chronic neuropathic pain, addressing inflammatory conditions, alleviating Parkinson’s disease symptoms, and treating epilepsy [6,7,8,9,10,11].

Despite the therapeutic potential, marijuana use is associated with various adverse effects on health. In the short term, it can lead to impaired short-term memory, altered motor coordination, impaired judgment, and psychotic symptoms [12].

In the long term, marijuana use has been linked to addiction, altered brain development, neurocognitive impairment, and increased risks of cardiovascular and respiratory diseases [13].

Furthermore, marijuana use has been associated with an increased risk of developing psychiatric disorders [14,15,16]. Given the anticipated rise in marijuana use following legalization, it is crucial to understand the molecular and epigenetic mechanisms underlying its short- and long-term impacts on health-related outcomes.

DNA methylation, a well-studied epigenetic modification, plays a significant role in regulating gene expression without altering the underlying genetic sequence.

It involves the addition or removal of methyl groups and can be influenced by environmental and lifestyle factors [17]. As a result, DNA methylation patterns can serve as potential blood-based biomarkers for recent and cumulative exposures. Investigating the relationship between marijuana use and DNA methylation may offer novel insights into the acute and cumulative effects of marijuana on biological processes that influence health outcomes [18,19].

Additionally, the modifiable nature of DNA methylation allows for the exploration of exposure-induced changes to the epigenome, identifying dynamic and/or stable biomarkers [20,21].

Previous studies on marijuana-associated epigenetic modifications have been limited to single time points and have not examined the impact of both recent and cumulative marijuana use on DNA methylation [22,23]. To bridge this knowledge gap, a comprehensive, multiple timepoint epigenome-wide association study was conducted on middle-aged adults.

Epigenetic changes

This study aimed to investigate the association between recent and cumulative marijuana use and repeated genome-wide DNA methylation patterns to gain deeper insights into the epigenetic impact of marijuana on health-related outcomes.

Epigenetic changes are changes to the epigenome, which is the layer of chemical modifications that sit on top of the DNA and can influence how genes are expressed. These modifications can be influenced by environmental factors, such as diet, stress, and exposure to toxins. Marijuana use has been shown to alter the epigenome in a number of ways, including:

  • Increased DNA methylation: DNA methylation is a process by which methyl groups are added to DNA. This can silence genes, making them less likely to be expressed. Marijuana use has been shown to increase DNA methylation in genes that are involved in the regulation of cell growth, differentiation, and development.
  • Decreased histone acetylation: Histone acetylation is a process by which acetyl groups are added to histone proteins, which make DNA more accessible to transcription factors. Marijuana use has been shown to decrease histone acetylation, which can also silence genes.
  • Increased expression of stress-related genes: Marijuana use has been shown to increase the expression of genes involved in the stress response. This can lead to a number of health problems, such as anxiety and depression.

The long-term effects of marijuana use on the epigenome are still being studied. However, there is evidence that marijuana use can increase the risk of developing chronic diseases, such as cancer, heart disease, and Alzheimer’s disease.

Here are some examples of epigenetic changes that have been associated with marijuana use:

  • Increased DNA methylation in the AHRR gene: The AHRR gene is involved in the regulation of the immune system. Marijuana use has been shown to increase DNA methylation in this gene, which may be linked to an increased risk of developing autoimmune diseases.
  • Decreased histone acetylation in the CDH13 gene: The CDH13 gene is involved in the development of the brain and nervous system. Marijuana use has been shown to decrease histone acetylation in this gene, which may be linked to an increased risk of developing neurodevelopmental disorders.
  • Increased expression of the CREB1 gene: The CREB1 gene is involved in the regulation of the stress response. Marijuana use has been shown to increase the expression of this gene, which may be linked to an increased risk of developing anxiety and depression.

Methodology

The study utilized data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, which includes repeated measurements of DNA methylation and self-reported marijuana use. The study analyzed DNA methylation patterns in middle-aged adults over multiple time points to identify methylation markers associated with recent and cumulative marijuana use

Replication of previously reported markers associated with marijuana use was performed, and potential genetic modulation of methylation markers was explored through meQTL analyses. Additionally, longitudinal analyses were conducted to evaluate changes in methylation patterns and marijuana use across examinations.

Results

The multiple timepoint epigenome-wide association study revealed 201 methylation markers associated with recent and cumulative marijuana use across time.

Among these, eight previously reported methylation markers associated with marijuana use were successfully replicated. The study also identified 638 cis-meQTLs associated with marijuana-methylation markers and 198 differentially methylated regions. Pathway and disease analyses indicated that marijuana-associated genes were overrepresented in numerous pathways and diseases related to cellular proliferation, hormone signaling, infection, and psychiatric disorders.

Discussion

The findings of this comprehensive study shed light on the intricate relationship between marijuana use and the epigenome. The association of specific methylation markers, such as cg05575921 in AHRR, with both tobacco and marijuana use suggests common modulating effects on DNA methylation, potentially representing a nondiscriminatory smoke-related biomarker [22]. These epigenetic markers associated with both marijuana and tobacco use may serve as potential biomarkers for identifying individuals with recent and long-term exposure to these substances.

Moreover, the study revealed that marijuana use induces dynamic and stable epigenetic signatures, indicating that both recent and cumulative marijuana use may differentially modulate epigenetic changes during the aging process. The differences observed in CpGs, pathways, and diseases across timepoints may be influenced by age-related pharmacokinetic properties impacting molecular and cellular processes differently [59].

The pathway and disease analyses further highlighted the potential impact of marijuana use on biological processes related to immunological factors, cardiovascular traits, and brain structures. The endocannabinoid system, affected by marijuana use, plays a role in modulating various physiological processes, including reward processing, hormone signaling, and immune function [64,65]. Understanding the common genetic and epigenetic pathways associated with marijuana use may lead to the development of predictive tools for marijuana-associated health outcomes.

Conclusion

Marijuana use is on the rise in the United States, with numerous therapeutic benefits as well as adverse effects on health. Epigenetic modifications, particularly DNA methylation, provide a mechanism to study the impact of marijuana use on biological processes and downstream health outcomes.

This comprehensive multiple timepoint epigenome-wide association study in middle-aged adults revealed novel methylation markers associated with recent and cumulative marijuana use. Replication of previously reported markers and exploration of potential genetic modulation were also conducted, providing further insights into the molecular and epigenetic mechanisms underlying marijuana use.

The study’s findings contribute significantly to our understanding of the associations between marijuana use, DNA methylation, and related biological processes, potentially opening new avenues for preventive and predictive approaches for marijuana-associated health conditions. However, further validation and investigations in diverse populations are warranted to establish the clinical relevance of these epigenetic markers.


reference link : https://www.nature.com/articles/s41380-023-02106-y#Sec22

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