Meeting highlights environmental influences on genetic risk factors for ASD
Everyone knows that some environmental factors can have adverse effects on health, especially early in development. For example, we know that exposure to cigarette smoke is particularly bad for infants and young children, increasing risk for Sudden Infant Death syndrome, respiratory challenges and middle ear infections. While we are still learning what kinds of environmental factors might impact the intricate process of brain development, and exactly how these impacts occur, we all want to know how environmental factors influence risk for autism.
Last week the Society of Toxicology met in Washington D.C. to discuss not only environmental effects, but how they may interact with our genes to confer autism risk. The most popular topic of this 50th anniversary meeting was epigenetics —literally changes made “above the genome”. Different epigenetic changes have the effect of making the genetic code more or less available for reading and the production of proteins. In other words, the environment can actually turn off the functions of genes, resulting in downstream effects on brain and behavioral development.
During a special symposium organized by autism researcher Isaac Pessah, PhD from the University of California at Davis and Cindy Lawler, PhD at the National Institute of Environmental Health Science, , scientists discussed new data and examples of how environmental factors can lead to changes in autism risk. Animal models of autism are essential for carrying out tests such as these, as different amounts of exposure to a particular substance can be carefully delivered and the outcomes observed with all other variables controlled.
Janine LaSalle, PhD at the University of California at Davis studied the effects of a flame retardant on behavioral development and cognitive function. She and her colleagues showed that these cognitive effects, which are similar to those found in autism, are dependent on both the sex of the animal and proper function of epigenetic mechanisms that turn a collection of other genes “on” or “off”.
Researchers in the Tanguay lab at Oregon State University are using the humble zebrafish to study a newly discovered type of gene expression. The research team is studying the effects of alcohol (ethyl alcohol, both the type found in beverages and and as a biofuel additive to gasoline) and a common acne treatment ingredient (retinoic acid, a metabolite of vitamin A ) on gene expression in the zebrafish. They are finding that disruptions in this new type of gene expression (microRNAs) can have surprisingly large effects on the rest of the genome.
We know from many previous studies that duplications or deletions of collections of genes—called copy number variants or CNVs—can be associated with increased autism risk. Scott Selleck, PhD, from Penn State University reported on his study which looked at the genetic background of children in the CHARGE study at UC Davis (http://beincharge.ucdavis.edu/). Individuals with ASD showed increased lengths of CNVs at certain points in the genome. His lab reasons that these CNVs may be areas of what he calls “genomic instability” where environmental chemicals affect gene expression. We need to know more about these CNVs and whether or not they are the reason some individuals are more susceptible to environmental factors in development.
Genes and environment interact, yes, but another important factor is when. Timing of the environmental insult can be crucial. Studies of neural stem cells are showing us that there exist critical periods in the development of these immature brain cells that include times in which cells divide, and also a later time when the immature cells become either neurons or another type of brain cell known as glia. It is at these times when environmental influences might have their biggest effect.
Pat Levitt, Ph.D. from the University of Southern California spoke on how the combination of genetic vulnerabilities and environmental factors can converge to disrupt brain development and function. One example involves the MET gene, which controls the development of a special class of inhibitory neurons. Previous research showed mutations in MET to be associated with autism, especially in individuals with gastrointestinal dysfunction.
Dr. Levitt and his colleagues demonstrated that exposure to chemicals in diesel fuel exhaust also decreases proper expression of the MET protein. This reduction in expression leads to changes in complexity and length of neurons as they reach to connect with other neurons. These changes may contribute to the previously observed effects on brain development. Interestingly, a recent report notes an increased risk for autism in children whose mothers lived within 1000 feet of a major highway during pregnancy.
Autism Speaks is actively supporting a number of research projects investigating the role of epigenetics in autism, including how environmental factors interact with genetic mechanisms to influence behavior. A primary focus of research invited for submission to Autism Speaks in 2011 is the mechanism of gene/environment interactions, including epigenetics.
To read about all the research Autism Speaks is funding in this area, click here http://www.autismspeaks.org/science/research/initiatives/environmental_factors.php.