Fathers who use marijuana may be using it for two, suggests a study from Duke Medical Center. Although the study is small, encompassing just 24 men and 15 rats, it highlights a potential transgenerational effect of marijuana exposure—the passing on of sperm in which an autism-associated gene, DLGAP2, has accumulated extra epigenetic marks.

The Duke scientists, led by Susan Murphy, PhD, associate professor of obstetrics and gynecology, identified significant hypomethylation at DLGAP2 in the sperm of men who used marijuana compared to controls. A similar observation was made in the sperm of rats exposed to tetrahydrocannabinol (THC) compared to controls. This hypomethylated state was also detected in the forebrain region of rats born to fathers exposed to THC.

Murphy and colleagues said their 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.

Detailed results from the study appeared August 26 in the journal Epigenetics, in an article titled, “Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm.” DLGAP2 refers to Discs-Large Associated Protein 2, a gene that is involved in synapse organization and neuronal signaling and is strongly implicated in autism.

“We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven using quantitative bisulphite pyrosequencing,” the article’s authors wrote. “Adult male rats exposed to THC showed differential DNA methylation at Dlgap2 in sperm, as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception.”

In earlier work, the researchers noted several gene alterations in the sperm of men who smoke marijuana. The current study homed in on specific genes, notably DLGAP2. Besides being strongly implicated in autism, the gene is also associated with schizophrenia and post-traumatic stress disorder.

Other findings from the current study include a sex-based difference in the relationship between DNA methylation and gene expression in human brain tissues. In both male and female brain tissues, 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 was notable, because the ratio of boys to girls with autism is 4:1, and there are sex differences in the neurobehavioral symptoms.

“It’s possible that the relationship between methylation and expression is modified if the methylation change that we see in sperm is inherited by the offspring,” Murphy noted. “In any event, it’s clear that the region of DNA methylation within DLGAP2 that is altered in association with cannabis use is functionally important in the brain.”

Murphy acknowledged that the study’s sample size was small—including 24 men, half who used marijuana and half who didn’t—and could not account for confounding factors such as diet, sleep, and exercise, but the findings should prompt continued research.

“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,” she emphasized. “Given marijuana’s increasing prevalence of use in the United States 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.

“There’s a perception that marijuana is benign. More studies are needed to determine whether that is true.”

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