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.
by Sallie Bernard, Autism Speaks’ Board Member, co-founder and Executive Director of Safe Minds
Given the historic inattention of the scientific establishment to the environmental contributions to autism, it was nice to see a day-long conference on the topic held this week by a major research center. “Exploring the Environmental Causes of Autism and Learning Disabilities” was put together by the Children’s Center for Environmental Health at the Mount Sinai School of Medicine in New York City. The center is run by Dr. Phil Landrigan, who has been a prominent researcher on the harmful effects of environmental toxicants for decades. He told the incredible story of the harms of lead exposure on children’s cognition and behavior, and how the successful effort to remove leaded gasoline from the market in the 1970s resulted in rising IQ scores and economic gain to the country. I hope this same massive effort will be applied to autism and the chemicals which underlie the increase in its prevalence.
Also of note was the presence at the meeting of Linda Birnbaum. Dr. Birnbaum is the director of the National Institute of Environmental Health Sciences (NIEHS) which holds the autism/environment portfolio at NIH. The Mt. Sinai meeting follows on a workshop held at NIEHS several months ago which explored the role of the environment in autism. Large scientific initiatives in the field fall to the NIH, so without its support, gains will be painfully slow. Hopefully Dr. Birnbaum’s personal involvement signals a heightened interest at NIEHS to look at autism. Although Dr. Birnbaum stated at the conference that her institute spends $30 million on children’s environmental health, at a Senate hearing earlier this year, it was shown that just $8 million of this is for autism specifically.
A few interesting bits of information came out of the conference. One was the definition of “environment” that the insiders use. It covers synthetic chemicals like pesticides, flame retardants and plasticizers; heavy metals like arsenic, lead and mercury; combustion and industrial by-products; diet and nutrients; medications, medical interventions, and substance abuse; infections; the microbiome; heat and radiation; and lifestyle factors. Some may be harmful; others protective. They may operate before conception, during pregnancy or in early life, and some may alter gene expression through epigenetic modifications to chemicals surrounding our genes. Craig Newshaffer, who runs the EARLI study to look at environmental factors among younger autism siblings, referred to the concept of the “exposome”, that is, everything we are exposed to and its effects on health. Dr. Birnbaum’ made the point that health does not equal medicine, and prevention through reduction in chemical exposures is of equal importance to health. Colleen Boyle from the CDC stated that the next prevalence report will be issued in April 2011. We will see if the 1 in 110 number from last year’s report has changed. New research from Korea was unable to confirm increased risk of autism due to parental age or low birth weight, which have been identified as risk factors in Western studies.
The most informative talk was by Dr. Irva Hertz-Picciotto from UC-Davis. She explained how changes in diagnosis do not account for most of the increase in autism rates, and how recent research by their group on mercury and flame retardant blood levels do not address whether these substances are causative for autism because the blood samples were taken years after the autism diagnosis. A paper out this week from UC-Davis found that proximity to traffic air pollution during pregnancy almost doubles the risk of autism. Another paper just accepted by a journal has found higher antibodies to cerebellar tissue in children with autism relative to controls, highlighting the immune component in autism.
Other than these interesting items, the conference covered minimal new ground as far as the science goes. Rather, the points of the meeting seemed to be to make the case that environmental factors research in autism must now be considered mainstream science and to showcase the work being done or about to be done to investigate the issue. Dr. Landrigan made the case for an environmental role by noting that the rate of autism has increased too much to be solely genetic, and that at most, genetics alone will end up explaining 40% of autism cases with the likely percentage much lower.
Autism Speaks provided funding for the conference so that families could attend for free. Alycia Halladay, who runs our environmental science portfolio, noted that environmental factors and how they interact with genetics became one of Autism Speaks 5 priority areas for science in 2010. Autism Speaks also co-funded the NIEHS workshop on the environment earlier this year. Mt. Sinai plans to make video excerpts of the conference available in a few weeks.