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Developmental Biology - Autism Gene
Gene Changes in Sperm After Pot Use
More study is needed to determine if this altered gene contributes to autism in children...
A specific gene associated with autism appears to undergo changes in the sperm of men who use marijuana, according to new research from Duke Health at Duke University, North Carolina, USA.
The gene change occurs through a process called DNA methylation, and it could potentially be passed on to his offspring.
Published online Aug. 27 in the journal Epigenetics, the researchers believe the findings do not establish a definitive link between cannabis use and autism, but the possible connection warrants further, urgent study, given efforts throughout the country to legalize marijuana for recreational and/or medicinal uses.
"This study is the first to demonstrate an association between a man's cannabis use and changes of a gene in sperm that has been implicated in autism."
Susan Murphy PhD, Associate Professor, Department of Obstetrics & Gynecology, Duke University School of Medicine and senior author.
Murphy and colleagues, including Rose Schrott PhD student and lead author, conducted studies using human biologics and animal models to analyze differences between sperm of males who smoked or ingested marijuanaas as compared to a control group of men with no such exposures.
In earlier work, published in Epigenetics in December 2018, the researchers noted several gene alterations in sperm of men who smoke marijuana.
The current study concentrated on specific genes, notably one called Discs-Large Associated Protein 2 or DLGAP2. This gene is involved in transmitting neuron signals in the brain and has been strongly implicated in autism, as well as schizophrenia and post-traumatic stress disorder.
"We identified significant hypomethylation at DLGAP2 in the sperm of men who used marijuana compared to controls, as well as in the sperm of rats exposed to THC compared to controls," Schrott explains. "This hypomethylated state was also detected in the forebrain region of rats born to fathers exposed to THC, supporting the potential for intergenerational inheritance of an altered sperm DNA methylation pattern."
The Duke team found a sex-based difference in the relationship between DNA methylation and gene expression in human brain tissues. In both male and female brains, increased DNA methylation was associated with decreased gene activity. This relationship was strongest in females, and seemed to be less well maintained in males, though the reason for this is unknown at this time.
This anomaly is notable, as the ratio of boys to girls with autism is 4:1, and there are also sex differences in neurobehavioral symptoms.
"It's possible that the relationship between methylation and expression [gene function] is modified if the change we see in sperm is inherited by offspring," Murphy said. "In any event, it's clear that the region of DNA methylation within DLGAP2 is altered in association with cannabis use and is functionally important in the brain."
Murphy said the study's sample size was small — 24 men — half who used marijuana and half who didn't, and could not account for confounding factors such as diet, sleep and exercise — however, the findings should prompt continued research.
"Given marijuana's increasing prevalence of use in the U.S. and the increasing numbers of states that have legalized its use, we need more studies to understand how this drug is affecting not only those who smoke it, but their unborn children," Murphy adds. "There's a perception that marijuana is benign. More studies are needed to determine whether that is true."
Abstract
Parental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.
Authors
Rose Schrott, Kelly Acharya, Nilda Itchon-Ramos, Andrew B. Hawkey, Erica Pippen, John T. Mitchell, Scott H. Kollins, Edward D. Levin and Susan K. Murphy.
Acknowledgements
The authors thank the CIPHERS study participants for their generosity and willingness to be involved in this study. We also thank Zhiqing Huang and Carole Grenier for their expert assistance with this project.
No potential conflict of interest was reported by the authors..
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Aug 28 2019 Fetal Timeline Maternal Timeline News
 This is the first study to link male use of cannabis to methylation of a particlular sperm gene linked to autism. CREDIT FreePik.
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