Cannabis use by women during pregnancy does not influence infant DNA methylation of the dopamine receptor DRD4

Abstract

Background: Maternal cannabis use in pregnancy is linked with long-term adverse behavioral outcomes in offspring. Epigenetic processes established in utero that affect dopaminergic (reward) signaling may mediate risks. Associations between cannabis use and offspring DNA methylation have not been investigated; however, maternal tobacco smoking in pregnancy is associated with distinct patterns of DNA methylation at birth and beyond. Objectives: To determine whether maternal cannabis use is associated with methylation of the dopamine receptor gene DRD4 promoter in infants. Methods: Mothers in the Triple B study provided detailed information on drug use in each trimester of pregnancy. Buccal swabs were collected from neonates at 8 weeks (n = 804, 51.7% male, and 48.3% female). DRD4 promoter DNA methylation was measured using SEQUENOM MassARRAY. Results: Fifty-seven of the women in the study reported drug use during pregnancy, of whom 44 used cannabis. Of 19 cytosine-phosphate-guanine dinucleotides (CpG) units tested in DRD4, gestational cannabis use was associated with offspring methylation at 1 CpG unit in multivariate models (β + 1.48, CI: 0.02 to 2.93, and p = 0.047). At another site there was weak evidence that both cannabis and other drug use were independently associated with increased methylation, while the association with tobacco was in the reverse direction (cannabis use β + 0.67, CI: −0.12 to 1.46, and p = 0.09; other drug use β + 1.11, CI: 0.17 to 2.05, and p = 0.02; tobacco use β −0.41, CI: −0.85 to 0.03, and p = 0.07). None of the associations would remain significant after correction for multiple testing. Conclusion: There is no strong evidence that maternal cannabis use in pregnancy is associated with offspring DRD4 methylation.

Cannabis Exposure During Critical Windows of Development: Epigenetic and Molecular Pathways Implicated in Neuropsychiatric Disease

“…Another recent study evaluated whether prenatal cannabis exposure is associated with DNA methylation of dopamine receptor D4 ( DRD4 ) promoter in buccal cells from the neonates of maternal subjects with either cannabis or no cannabis use anytime during pregnancy [ 62 •] (Table 1 ). Buccal epithelial cells have the same developmental origins as neuronal cells, and prior studies provide support for buccal cells as a proxy for neurodevelopmental phenotypes [ 63 ].…”

“…There was no association between DNA methylation at individual CpG sites in DRD4 after correction for multiple testing. It is unclear if the null findings were due to the relatively small sample size ( n = 804 maternal subjects), the tissue specificity, or a lack of biological relevance [ 62 •]. Certain genetic polymorphisms of DRD4 increase risk of drug use and severity of ADHD symptoms in children, both of which have been associated with cannabis exposure [ 64 ].…”

“…• CSNK1E , which encodes the Casein Kinase 1 Epsilon, phosphorylates circadian clock protein PER2 and is implicated in sensitivity to opioids. Fransquet et al 2017 [ 62 •] Nested case-control study n = 804 maternal subjects; 44 cannabis users anytime during pregnancy and 760 non-user controls Prenatal Buccal cells of neonates of maternal subjects F1 generation DNA methylation SEQUENOM MassARRAY • Gestational cannabis use associated with increased methylation at one CpG site tested in DRD4 (CpG.21.22.2) (β + 1.48, 95% CI: 0.02–2.93, p = 0.047). • At CpG.32, weak evidence that gestational cannabis is associated with increased methylation when adjusting for other substance use (β + .67, 95% CI: − 0.12-1.46, p = 0.09).…”

The epigenetic modulation of alcohol/ethanol and cannabis exposure/co-exposure during different stages

“…Another study looked at cannabis effect on infants' DNA methylation in the dopamine receptor promoter at CpG units. There was no significant evidence that cannabis impacted the methylation in these specific areas [41].…”

“…On the other hand, a longitudinal pregnancy cohort of 1634 families studied effects of perinatal maternal gestational cannabis on infants' health through investigating offspring DNA methylation. The study focused on the offspring dopamine receptor gene DRD4 promoter in infants, and found that there is no potential inherited risk in the infants [41]. The study suggested that investigating a larger sample and other genes might have different results [41].…”