Cannabis use may alter gene linked to autism in male sperm

By Dr. Ananya Mandal, MDAug 28 2019

Researchers from Duke University Medical centre, Durham, USA have come up with an important study that shows that use of cannabis among men could alter a specific gene in their sperm that is linked to autism. The study titled, “Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm,” and is published in the latest issue of the journal Epigenetics.

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The authors wrote, “In the U.S., 11 states and Washington D.C. have legalized the recreational use of cannabis and 33 states have legalized the use of medicinal cannabis.” They wrote, “Prenatal cannabis exposure via maternal use during pregnancy is associated with decreased infant birth weight, an increased likelihood to require the neonatal intensive care unit, and the potential for an impaired fetal immune system compared to those infants who are not exposed during gestation,” explaining the effects of maternal cannabis use on the babies. They added regarding the significance of their study, “According to a 2015 Survey on Drug Use and Health, 52.5% of men in the U.S. of reproductive age (≥18) have reported cannabis use at some point in their lives, making cannabis exposure especially relevant for potential future fathers.”

The team explained that use of cannabis by the parents before they got pregnant, has been significantly associated with poor “neurodevelopmental outcomes” among the children. What was unknown till date it the exact change cannabis is capable of causing in the reproductive cells of the parents that could cause such an influence on the offspring.

To understand the mechanism of such damage that parental cannabis could cause to the offspring, the team used a technique called the “reduced representation bisulphite sequencing (RRBS)”. They noted that when cannabis was used extensively by lab rats, they displayed changes in the DNA of their sperms. This was seen in humans as well. There were extensive chemical changes called methylation in the DNA of the sperms of rats and humans.

An earlier study had shown that a particular gene called the Discs-Large Associated Protein 2 (DLGAP2) mutation was responsible for several changes that led to certain features of autism. These included “synapse organization, neuronal signalling” etc. These changes were noted in 17 regions of the DNA of human sperms when exposed to cannabis, explained the researchers.

Ph.D. student Rose Schrott, co author of the study said, “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. 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 researchers exposed the rats to cannabis or its active ingredient called delta-9-tetrahydrocannabinol (THC) and found that there were 9 sites on the sperm DNA that revealed changes for Dlgap2. They also examined the brains of the offspring of these exposed rats. Results revealed that there were significant changes in the brains of these offspring especially in the nucleus accumbens regions.

Senior author Susan Murphy, Ph.D., associate professor in the Department of Obstetrics & Gynecology at Duke University School of Medicine, said in a statement, “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.”

Authors concluded that more studies were necessary to look at, “effects of preconception cannabis use in males and the potential effects on subsequent generations.” Murphy said on the sex difference in effects of cannabis, “It's possible that the relationship between methylation and expression is modified if the methylation change we see in sperm is inherited by the offspring. 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 added that this study included only 24 participants, half og who used cannabis while the other half did not. A larger study would be able to prove their initial findings.

The researchers wrote, “This is the first demonstration of potential heritability of altered methylation resulting from preconceptional paternal THC exposure.” They added in conclusion, “Given the increasing legalization and use of cannabis in the U.S., our results underscore a need for larger studies to determine the potential for heritability of DLGAP2 methylation changes in the human F1 generation and beyond. It will also be important to examine how cannabis-associated methylation changes relate to neurobehavioral phenotypes.”

Murphy signed off saying, “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. There's a perception that marijuana is benign. More studies are needed to determine whether that is true.”

The study received funding partially from the John Templeton Foundation.