DERT Stories of Success
Janine LaSalle, Ph.D.
Today, a definitive autism diagnosis typically isn’t possible until age 3. However, if children at high risk could be identified sooner, they might be eligible for early behavioral therapies that could improve their quality of life. Research conducted by NIEHS grantee Janine LaSalle, Ph.D., a professor at University of California, Davis, could one day make such early interventions possible.
Epigenetics and gene-environment interactions
LaSalle and her colleagues are sequencing the methylome — the DNA methylation present across the whole genome — to better understand how this epigenetic mark is affected by genetic and environmental factors. Epigenetic marks are chemical modifications to the DNA that modify the way genes are expressed without changing the actual genetic code.
"We want to know where in the genome different gene-environment interactions take place and what is the nature of these interactions," said LaSalle. "Using a whole-genome view of methylation allows us to take an unbiased, big-picture view of the genome and these interactions."
As described in a Cell Reports paper, the researchers sequenced the methylome of normal post-mortem brain samples and those with the Dup15q gene duplication, a genetic mutation that almost always leads to autism. In samples that contained the Dup15q duplication, they found that 975 genes throughout the genome had epigenetic variations.
The researchers also used cultured neurons, or nerve cells, to compare how the neurotoxin polychlorinated biphenyl (PCB) affected the methylome of cells with and without the Dup15q duplication. They found that PCB exposure and the Dup15q genetic duplication could both independently reduce the methylation for a group of genes that are associated with synapses, the junctions between nerve cells. They also noted a compounding effect when neurons with the genetic duplication received the PCB exposure.
"Our study suggests that there is a susceptible group of genes that act on the synapse and could exhibit lower levels of methylation because of an environmental exposure or genetic duplication of a chromosome," LaSalle said. "There are likely multiple genetic and environmental factors that could be impacting methylation of the same genes. It might one day be possible to look at the methylation of those genes and predict the risk of developing autism."
A time capsule of exposure
To use methylation patterns for autism screening requires finding a way to analyze methylation without brain tissue samples. This can be challenging because DNA methylation can vary by tissue and cell type. Two papers published by LaSalle and her colleagues showed that placental tissue, which is normally discarded after birth, can provide critical information about prenatal environment factors that can affect brain development.
"The placenta acts almost like a time capsule of what the fetus was exposed to in the womb," she said. "Analyzing the methylome of placenta could reveal what the fetus was exposed to as well as genetic factors that influence fetal development and a child’s brain."
The research described in both papers involved families who have a child with autism and are participating in the NIEHS-funded Markers of Autism Risk in Babes: Learning Early Signs (MARBLES) study, which is led by Irva Hertz-Picciotto, Ph.D. Younger siblings of children with autism have a higher risk for autism, and by following their mothers before, during, and after pregnancy, MARBLES is gathering real-time information about the pre- and post-natal environment to which the baby is exposed.
For the study published in the Molecular Autism paper, researchers compared placental tissue samples from 24 children with autism and 23 with typical neurodevelopment. In addition to showing that the placenta could be used to study factors that affect fetal neurodevelopment, the researchers identified a gene that is highly methylated in placentas from children with autism.
The other paper, published in Environmental Epigenetics, revealed that the placental methylation is affected by environmental contaminants that affect brain development. For this study, the researchers examined how various environmental exposures affected methylation patterns for placentas from 24 children with autism and 23 with typical neurodevelopment. The exposures included pesticides professionally applied to lawn or garden; pesticides professionally applied to inside of home; and flea/tick pouches, collars, or soaps applied to pets. The most significant changes in placental methylation patterns were associated with pesticides professionally applied outside the home.
Although both studies were based on small numbers of participants, LaSalle said that the findings are promising because they point towards potential biomarkers that might be used in the future to determine the cumulative impacts of genetic and environmental factors. "We're now developing better methods to identify biomarkers in methylation data," she said. "Once we identify statistically significant biomarkers, we will validate those in other samples to see if they might be useful for diagnosis of autism in children."
LaSalle is also collaborating with Hertz-Picciotto on new research funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, which will allow them to gather data from the parents and grandparents of children who participated in the NIEHS-funded Childhood Autism Risks from Genetics and the Environment (CHARGE) study. This work could reveal any autism-related epigenetic patterns that are passed down through generations.