Project 3: Epigenomic Consequences of Early Life Environmental Tobacco Smoke Exposure

Project Leader:  Susan K. Murphy, PhD

  • Co-Investigator: Joseph Lucas, PhD
  • Postdoctoral Researcher: Michelle Taylor, PhD
  • ​Graduate Student: Rashmi Joglekar
  • Graduate Student: Sam Lusk

Early life secondhand smoke (SS) exposure can lead to problems with neurodevelopment, including Attention-Deficit Hyperactivity Disorder (ADHD).  Most of the risk for developing ADHD is because of vairations in DNA sequence. The remaining risk of developing ADHD comes from the environment. Exposure to tobacco smoke during early development is one of the most important environmental ADHD risk factors.  In this project, we will determine how tobacco smoke exposure during pregnancy leads to increased risk of ADHD by examining how regulation of the DNA is changed (epigenetic changes) as a result of this exposure. 

How can tobacco smoke exposure increase the risk of ADHD?  During pregnancy, the baby receives nutrition through the placenta, but is also exposed to the same things the mother is exposed to. Development during pregnancy occurs rapidly and requires that the same DNA sequence be used differently in the different cell types that make up our bodies.  This is controlled in large part by molecular "tags" that are added to the DNA in a defined sequence of events that happens in very early life. Once the molecular tags are added to the DNA in a cell, the same pattern of tags on the DNA is then inherited by the daughter cell whenever the cell divides. The tags provide an additional layer of information – epigenetic information – above the information already provided within the DNA. Exposure to certain environmental contaminants, including tobacco smoke, can interfere with how the epigenetic information is first established or maintained during cell division, including in the developing brain.  The neurons within the brain of children exposed to tobacco smoke in ealry life may have exposure-related shifts in the epigenetic tags that changes how they work.  We believe these changes then contribute to increased risk of developing ADHD.

What are we going to test?  We hypothesize that early life secondhand smoke (SHS) exposure induces persistent and targeted functional changes in DNA methylation that associate with neurodevelopmental phenotypes.

How are we going to do this?

1) Identify tobacco smoke related methylation targets. We will test the hypothesis that early life secondhand smoke exposure in rats will induce measurable shifts in methylation at genes relevant to neurobehavioral outcomes that are detectable in both brain and blood. Whole genome bisulfite sequencing will identify SHS-vulnerable loci with validation by pyrosequencing.

2) Identify SS-altered methylation-expression relationships in frontal cortex. We hypothesize that early life SHS exposure in rats induces changes in frontal cortex gene expression at ADHD-relevant genes. Whole transcriptome profiling will identify these changes. We will also examine methylation-expression relationships from the brain results and also in a model of neuronal differentiation.

3) Determine if DNA methylation varies with SHS dose in humans. Prenatal and perinatal cotinine levels (a marker of tobacco smoke exposure) and DNA methylation in children, from bisulfite pyrosequencing at ADHD-related genes and candidate genes from the above aims, will determine if methylation changes with exposure.

Image of LabHow will the findings help us improve children's health?  This research is expected to reveal SHS-related epigenetically vulnerable genes that help explain the link between ADHD and exposure to SHS. The methylation present at these genes may serve as biomarkers of past exposure. Defining the repertoire of SS-induced functional DNA methylation changes will offer exciting new opportunities to identify chidren at risk of developing ADHD and early interventions to reduce and prevent adverse behavioral and cognitive outcomes of SS exposure.

Many people have stopped smoking.  Why is smoke exposure an issue? Although many people have stopped smoking, 18% (42.1 million) of adults in the United States still smoke. Secondhand smoke exposure in children is associated with ear infections, asthma, a greater risk of sudden infant death syndrome and increased numbers of hosiptalization each year.  The CDC estimates that 88% million nonsmokers in the United States are exposed to SHS, including pregnant women. A recent study showed that approximately 50% of school aged children are exposed to measurable levels of SHS. So even though the rates of smoking have decreased, SHS exposure is still a major issue for nonsmokers.

Is there anything I can do now to reduce the risk of ADHD in my child?  If you are pregnant or thinking about becoming pregnant, please follow your doctor's advice and try and avoid SHS as much as possible.  If you already have a young child, try and reduce the SHS to which your child is exposed.

Will you make the results of the study available?  We will publish findings in peer-reviewed scientific journals. These papers will be listed with links on our Publications page where we will also have a brief description of the findings.

 

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