This important article is the translation of: Les pères fument du cannabis, les enfants trinquent ? published in La Lettre du C N P E R T Janvier 2024 N°88 https://drogaddiction.com/2024/01/16/la-lettre-du-c-n-p-e-r-t-janvier-2024-n88/
Author: Boris Chaumette, MD PhD , University Lecturer – Hospital Practitioner (MCU-PH), Paris Cité University , GHU Paris Psychiatry and Neurosciences .
Cannabis is the most widely consumed illicit drug in developed countries and its harmful effects on health, particularly mental health, are now well known. However, new scientific results suggest that the biological disturbances resulting from its consumption could affect subsequent generations through recently demonstrated epigenetic mechanisms. Results which encourage us to sound the alarm!
Cannabis exerts its biological action through modulation of the endocannabinoid system. This system is present in the human brain, explaining the psychological effects of cannabis consumption. But it also plays a role in reproduction, influencing the production of sperm in men and the maturation of eggs in women. It is involved in fertilization, embryonic development and childbirth.
Its use during pregnancy has been associated with an increased risk of autism spectrum disorder in unborn children. In a study carried out in Canada (Corsi et al. 2020), 2.2% of children exposed in utero to cannabis developed autism compared to 1.4% in the general population. Rates of intellectual disability and attention deficit hyperactivity disorder were also higher in children exposed to cannabis during pregnancy.
Paternal cannabis use may also influence children’s neurodevelopment through epigenetic changes in sperm. The possibility of transgenerational epigenetic transmission remains debated because the epigenome is theoretically reprogrammed after fertilization.
However, epigenetic marks could be preserved and transmitted by the father (Tang et al. 2015), raising the possibility of an impact of the paternal environment on the outcome of future children (Day et al. 2016). It would therefore be theoretically possible that cannabis consumption by the future father modifies the methylation of sperm DNA and has consequences for future children.
A study in animal models showed that exposure of male rats to Δ9-THC before conception leads to changes in cholinergic synapses in various brain regions in the offspring (Slotkin et al. 2020).
The offspring of these exposed rats, although not exposed themselves, show behavioral alterations during adolescence with motor hyperactivity, disruptions in learning and memory (novel object recognition test and radial arm maze). ) (Holloway et al. 2020) and attentional abilities (signal detection test) (Levin et al. 2019).
These results are different depending on the time between cannabis consumption and mating; Recent cannabis consumption would be more likely to induce behavioral changes in offspring. These results suggest the presence of an epigenetic memory of cannabis consumption in sperm that can last several days and be partially transmitted to offspring.
These studies are obviously complicated to carry out in humans. However, DNA methylation analyzes were conducted in small groups of men: more than 6,000 CpG sites were identified as differentially methylated between 12 cannabis users and 12 non-consumers (Murphy et al. 2018). . These sites were notably present at genes involved in the Hippo signaling pathway involved in cell proliferation and apoptosis.
Comparisons between sperm from rats exposed or not exposed to cannabis also showed changes in DNA methylation at the same Hippo biological pathway. Ten genes were found in common in humans and rats ( APC2, GDF6, LLGL1, TCF7L1, BMP7, BMP6, FGF12, PRKACA, GNG7, GNB2 ). APC2 has also been reported to be dysmethylated in the semen of men who smoked tobacco (Jenkins et al. 2017), suggesting that the changes observed for this gene under the influence of cannabis are not specific.
Among the multiple genes identified by their study, the authors then selected DLGAP2 for a more detailed analysis (Schrott et al. 2019). This gene encodes a membrane protein located on postsynaptic neurons, involved in neuronal signaling and the organization of synapses.
It was therefore a good candidate gene for further investigation. The authors carried out a second technique using the same sperm samples and confirmed hypomethylation of 10 CpGs present in an intron of the gene. The study of 28 brain samples from voluntary termination of pregnancy showed a good correlation between the level of methylation of this region and the expression of the gene, suggesting a biological effect of this dysmethylation. Continuing their analyzes using an animal model, the authors found that another region of the DLGAP2 gene was hypomethylated in the sperm of rats exposed to cannabis.
A CpG from this region was also found to be hypomethylated in the nucleus accumbens of the offspring of these rats. On the other hand, in the hippocampus, only one CpG of this region was found as demethylated in the offspring although not appearing in the list of those hypomethylated in the spermatozoa of the progenitor.
Another study looked at differences in DNA methylation in the sperm of fathers who may or may not have had autistic children (Garrido et al. 2021). The comparison of these two groups of 13 fathers each showed differences in methylation in genes known to be associated with autism including this same DLGAP2 gene .
DNA methylation is stable due to the presence of methyltransferases that maintain these epigenetic marks during cell divisions. However, stopping cannabis would gradually reduce certain epigenetic differences observed in sperm, suggesting at least partial reversibility.
Thus, certain methylation modifications were attenuated after 11 weeks of stopping cannabis, i.e. one cycle of spermatogenesis (Schrott et al. 2021). However, certain anomalies persisted or even appeared after the period without cannabis.
In addition, the study of an animal model also showed that epigenetic anomalies could potentially be transmitted over several generations: methylation modifications in the PXYLP1 gene were thus found both in the sperm of male rats exposed to cannabis and in that of their descendants who have never been exposed to this drug (Schrott et al. 2022).
These preliminary studies concern small samples and come from the work of a single team based at Duke University (Durham – USA). It is therefore necessary to independently replicate these results to confirm them and obtain reliable scientific conclusions.
However, these results suggest that cannabis consumption among future fathers can have harmful consequences for their future offspring, in particular for neurodevelopment. Consuming cannabis would therefore no longer be an individual but a family risk, which calls for caution and should lead to informing the population of these potential effects.
The precautionary principle would require that male consumers be encouraged, in the same way as women, to stop using cannabis several months before planning to become pregnant to preserve the epigenome of their spermatozoa. This precaution is all the more necessary as cannabis has a negative effect on male fertility (Hamed, Ekundina, and Akhigbe 2023).
Thank you for reading!