NIEHS-funded researchers at the University of California at Davis (UCD), reported new findings Dec. 13 in the journal Cell Reports that help explain how genes and environmental factors may jointly contribute to the rise in autism spectrum disorder (ASD).
The researchers found that a certain genetic variation, called Dup15q, combined with exposure to polychlorinated biphenyl (PCB) 95 can substantially alter the activity of genes associated with increased autism risk. PCB 95 is a common environmental pollutant that is known to be neurotoxic.
“This study is an example of how you can have two independent effects that, when combined, affect a larger set of genes important in the developing brain,” said senior author Janine LaSalle, Ph.D., in a UCD press release.
PCB 95 linked with changes that affect gene function
LaSalle and colleagues studied DNA methylation in 41 postmortem brains. Methylation, which is one of several epigenetic mechanisms cells use to turn genes on and off, is the addition of a methyl group to genes. The team observed reduced DNA methylation in people with Dup15q, a duplication of genetic material at chromosome 15, compared with controls.
The scientists then used 23 cell culture samples to confirm the reduced methylation associated with Dup15q and tested what happened to neurons exposed to PCB 95. They observed additional reductions in methylation following PCB 95 exposure, although the environmental effect was not as strong as that from genetic factors. Finally, they showed that many of the genes with reduced methylation were related to ASD, especially regarding the function of synapses, or the gaps between neurons in the brain.
“We found multihit, cumulative impacts that are affecting epigenetic signatures in a common group of genes involved in synapses and autism,” said LaSalle.
Cumulative impact may hold the key
ASD currently affects approximately 1 in 68 children. According to the paper, ASD has a strong genetic component, with more than 800 genes previously identified as possibly having a role. However, there is wide variation in the combination of multiple autism-related genes for each person with ASD. The authors said that Dup15q is one of the most common genetic variations observed in people with ASD.
Likewise, environmental exposures to pollutants like PCBs, air pollution, and pesticides, previously have been associated with modest increases in autism risk, according to the authors. PCBs, which do not easily break down in the environment, are chemicals used to insulate electrical equipment.
"There’s this tendency to put genes and environment in separate boxes — this gene causes autism or this environmental factor causes autism,” said LaSalle. “But by themselves, these direct causal factors are rare. What’s likely more common is the cumulative impact of both.”
“These results have important implications, including adding to our understanding of epigenetic mechanisms that underpin gene-environment interactions in complex disease,” said Cindy Lawler, Ph.D., who leads the NIEHS Genes, Environment, and Health Branch. “The findings also contribute to identifying epigenomic signatures that may serve as biomarkers of cumulative exposures.”
Citation: Dunaway KW, Islam MS, Coulson RL, Lopez SJ, Vogel Ciernia A, Chu RG, Yasui DH, Pessah IN, Lott P, Mordaunt C, Meguro-Horike M, Horike SI, Korf I, LaSalle JM. 2016. Cumulative impact of polychlorinated biphenyl and large chromosomal duplications on DNA methylation, chromatin, and expression of autism candidate genes. Cell Rep 17(11): 3035–3048.
(Virginia Guidry, Ph.D., is a technical writer and public information specialist in the NIEHS Office of Communications and Public Liaison, and a regular contributor to the Environmental Factor.)