B3899 - Developmentally-induced DNA methylation changes in response to maternal tobacco and cannabis use during pregnancy - 03/11/2021

B number: 
Principal applicant name: 
Amy Osborne | University of Canterbury (New Zealand)
Dr Alexandra Noble, Professor Jack Satsangi, Dr Alex Adams
Title of project: 
Developmentally-induced DNA methylation changes in response to maternal tobacco and cannabis use during pregnancy
Proposal summary: 

Substance use during pregnancy is a large driver of health inequalities in exposed children, and despite the known impacts on infant health that accompany its use, tobacco use during pregnancy is still prevalent. Additionally, cannabis use in pregnant women is increasing. Tobacco use during pregnancy is associated with low birth weight, respiratory distress, and an increased risk of neurodevelopmental disorders and Irritable Bowel Disease (IBD) in exposed offspring. Developmentally-induced health inequalities are often driven by environmentally-induced genetic change, and our recent research has shown a link between DNA methylation and neurodevelopmental disorders. Interestingly, exposure to cannabis during development shows similar phenotypic patterns to tobacco, however, the molecular links between exposure and phenotype have not yet been explored.

Thus, in addition to data derived from our current cohorts (the Christchurch Health and Development Study [CHDS], Southampton Trio Cohort of the UK & Ireland Paediatric IBD Genetics Group) which both have well documented maternal tobacco and cannabis exposure measures, and manifestations of disease in the offspring, we seek to include DNA methylation data from ALSPAC to determine whether maternal tobacco and cannabis use impacts the genome of exposed offspring at genes involved in neurodevelopment and immune regulation, which may help explain the observed link between developmental exposure and offspring outcomes.

This research addresses the knowledge gaps around the association of maternal substance use and health outcomes in children, clarifying the potential risks of substance use, particularly maternal cannabis use, and indicate what this might mean for the health outcomes of exposed children.

Impact of research: 
Our research will be high impact because it will assess the robustness and longevity of developmentally-induced differential methylation, across multiple cohorts, and its association with disease and offspring health. Additionally, there is a paucity of research that seeks to probe the molecular basis of associations between developmental exposures and offspring phenotype, on this level, and across multiple phenotypes. Specifically, currently there is the gap between cannabis and tobacco use during pregnancy and the impacts on offspring phenotype. Prevalence rates suggest that there is an increase in detrimental health outcomes for offspring due to both exposures. Furthermore, maternal cannabis use during pregnancy has been hypothesised to have neurological impacts on offspring. Whereas maternal tobacco use during pregnancy is thought to impact childhood IBD. However, we don't know whether this relationship is causal, partly causal or only correlational. To tackle this question, it is important that we use an adequate number of individuals in our study design. As this is unable to be undertaken in our cohort samples, we propose that the use of the ALSPAC data will add vital numbers to adequately answer our hypotheses, building a robust and high impact research programme. This research pipeline will begin to address this knowledge gap by identifying the precise molecular targets of cannabis and tobacco in developing offspring, which will aid in the understanding of the safety of these two substances for pregnant mothers. Furthermore, we want to assess the differences exhibited by the different exposure groups. Although very little work has thus been undertaken on cannabis only exposure, recent observations from our group using adult cannabis users has revealed distinct methylation differences compared to adult tobacco smoking exposure. Hence, why we are also intrigued to assess these two exposures and the different disease phenotypes. We have previously applied Illumina methylation array technology successfully in other studies (insert a range of citations here), this shows that we are uniquely placed to successfully deliver this important project. We will ensure the impact of our research via a broad dissemination programme. The cannabis in utero findings for this study will be communicated to the New Zealand and UK public via the Canterbury District Health Board maternal drug screening programme (NZ), and through education of other District Health Boards, community organisations, and addiction services both in New Zealand and in the UK. We anticipate at least two high impact manuscripts from this research. Importantly, the IBD findings will be incorporated into relatively new technology (Nanopore adaptive sequencing) to allow us to measure DNA methylation and examine the accuracy of these tests in several cohorts of children. This will allow us to develop our diagnostic test in a platform which would be easy to establish and allow us to test in children the markers for diagnosis, disease aggressiveness and treatment response we have been developing in adults. Furthermore, we hope that the development of these tests will allow us to reduce the need for invasive investigations including colonoscopy in children.
Date proposal received: 
Thursday, 28 October, 2021
Date proposal approved: 
Wednesday, 3 November, 2021
Genetics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Gastrointestinal, DNA methylation, Birth outcomes, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Environment - enviromental exposure, pollution, Epigenetics