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Duke University Medical Center researchers are advising men to abstain from using cannabis for at least six months before trying to conceive a baby. The advice comes on the back of newly reported research suggesting that the drug causes epigenetic changes to sperm that could feasibly impact on embryonic viability or growth.

Cannabis use is now legal in some form across more than 50% of U.S. states, with National Survey on Drug Use and Health figures showing that in 2015 nearly one-fifth of U.S. males aged 18–25 years reported using the drug within the last month. The new studies in men and rats, reported by the Duke University Medical Center team, found that cannabis use, and in particular its psychoactive component, tetrahydrocannabinol (THC), is associated with extensive epigenetic changes in sperm. The results, reported in Epigenetics, indicated that while THC may impact on hundreds of different genes in human and rat sperm, many of those affected were associated with two molecular pathways involved in growth during development, and final organ size. And both of the pathways can become dysregulated in cancer.

“What we have found is that the effects of cannabis use on males and their reproductive health are not completely null, in that there’s something about cannabis use that affects the genetic profile in sperm,” said Scott Kollins, Ph.D., professor in psychiatry and behavioral sciences at Duke and senior author of the study. “We don’t yet know what that means, but the fact that more and more young males of child-bearing age have legal access to cannabis is something we should be thinking about.” The Duke team reported its findings in a paper titled, “Cannabinoid exposure and altered sperm methylation in rat and human sperm.”

Cannabis is one of the most widely used psychoactive drugs, with estimates suggesting that more than 180 million people around the world use the drug, the authors wrote. Ten U.S. states, in addition to the District of Columbia, have also legalized the drug for recreational use. With between nearly 13% and 20% of U.S. men aged 18–34 years reporting using the drug within the last month, “a substantial number of males of child-bearing age may have recent exposure to cannabis at or around the time they conceive.” And while a large number of studies have looked at potential adverse effects of cannabis on health outcomes—including prenatal exposure during pregnancy due to maternal use—“there is currently a gap in knowledge about cannabis use effects on paternal reproductive factors.”

Epigenetic changes to the genome, including DNA methylation, have been implicated as a potential mechanism that might underpin any heritable effects of preconception cannabis exposure, the authors continued. What isn’t yet well understood is whether cannabis use alters the epigenetic profile of sperm in human men. “Because sperm maturation is a continual process throughout the adult male’s life, exposures like cannabis could have an impact on the integrity of the sperm methylome, with implications for heritability of such alterations by subsequent generations,” the team noted.

The researchers used reduced representation bisulfite sequencing (RRBS) to compare sperm methylation profiles among 24 human cannabis users and non-users. Cannabis users were defined as men who smoked marijuana at least weekly for the previous six months. The results suggested that cannabis use was associated with changes to the methylation status of thousands of CpG sites, and in particular, those associated with genes involved in the Hippo signaling pathway and in pathways in cancer. The higher the THC concentration in participants’ urine, the greater the genetic changes to their sperm. The data also indicated that cannabis users had lower sperm concentrations than non-users.

Subsequent studies in male rats exposed to THC for 12 days replicated the findings on methylation changes in the human male, which the team suggested “indicate that the major epigenetic effect of cannabis exposure may be due to the THC component.” Again the Hippo pathway and pathways in cancer were among those pathways for which epigenetic changes in THC-exposed rat sperm were most evident, and there was some overlap in affected genes between rats and humans. “There were six overlapping genes among those altered by cannabis/THC in the Hippo signaling pathway between humans and rats. For pathways in cancer, there were also six overlapping genes.”

The authors suggested that if the methylation changes in the Hippo signaling and pathways in cancer genes in sperm are carried over into the zygote, they could feasibly result in disruption to the expression of important growth regulatory genes, resulting in nonviable embryos, or alterations to embryonic development and growth. “… if sustained, the changes in DNA methylation could increase risk of later cancer development, which is often characterized by these types of methylation alterations in one or both pathways identified.” And while the team acknowledges that such possibilities remain speculative, and their study was very small and had a number of limitations, they suggest that the findings “point to possible preconception paternal reproductive risks associated with cannabis use.”

“In terms of what it means for the developing child, we just don’t know,” commented lead author Susan K. Murphy, Ph.D., associate professor and chief of the division of reproductive sciences in obstetrics and gynecology at Duke. “We know that there are effects of cannabis use on the regulatory mechanisms in sperm DNA, but we don’t know whether they can be transmitted to the next generation. “In the absence of a larger, definitive study, the best advice would be to assume these changes are going to be there. We don’t know whether they are going to be permanent. I would say, as a precaution, stop using cannabis for at least six months before trying to conceive.”

The team says further research will be “essential to determine the potential for methylation changes to be transmitted inter- and trans-generationally … Future studies should evaluate the functional significance of the present findings, especially in light of evidence supporting intergenerational effects,” they stated. “If there is evidence that the epigenetic changes observed in this study are maintained post-fertilization, such findings should be considered with regard to cannabis use policy decisions in the U.S. and worldwide.”

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