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.
The Mount Sinai Children’s Environmental Health Center, in partnership with Autism Speaks, is holding a one day workshop, Exploring the Environmental Causes of Autism and Learning Disabilities, at the New York Academy of Medicine on Wednesday, December 8, 2010. The goal of the workshop will be to develop new strategies for discovery of environmental risk factors for autism, autism spectrum disorder (ASD) and other neurodevelopmental disorders in children.
The workshop will help identify opportunities to study gene/environment interactions in autism, and help guide research priorities for the newly formed Autism and Learning Disabilities Discovery and Prevention Program at Mount Sinai. Scientists from National Institute of Environmental Health Sciences, Centers for Disease Control and Prevention, National Institute of Child Health and Human Development and leading academic institutions from around the world will present recent research and engage in discussions to identify gaps and opportunities, especially in the area of environmental causation by toxic chemicals.
Staff bloggers Alycia Halladay, Ph.D., Director of Environmental Sciences and Leanne Chukoskie, Ph.D., Assistant Director of Science Communication and Special Projects
A study published on Monday in Pediatrics revealed that newborns who experienced jaundice were at greater risk for a later diagnosis of autism spectrum disorders. Jaundice is a common condition where bilirubin is not properly excreted by the liver, builds up in the blood and leads to a slight yellow pigment of the skin. Bilirubin is a neurotoxin and it is well established that untreated severe jaundice can lead to brain damage and even death. Fortunately, despite the fact that jaundice is very common in newborns, it usually resolves with minimal or no intervention within a few days of birth.
Previous studies have investigated the potential for increased risk of ASD following jaundice with mixed conclusions. The advantage of this study is that the researchers used a large health registry database in Denmark including over 700,000 birth and associated developmental health records. The researchers looked at the development of 35,766 children diagnosed with perinatal jaundice (4.9% of the entire study population). They looked for children diagnosed with ASD as well as a broader definition of disorders of psychological development, which included speech delay. The risk of an ASD was found to be about 52% greater in children who experienced jaundice as newborns versus those who did not.
This may be an overestimate because factors such as season of birth, gestational age, parental age, gender, and the birth order of the child were not considered in this comparison. When these factors were considered, the overall risk increase was no longer statistically reliable. However an interesting pattern emerged from individually considering the factors.
Although preterm children typically experience a greater risk of autism by virtue of the challenges of prematurity, it is the full term babies that have an increased risk for ASD after exposure to jaundice. The authors speculate that there may be some unique window of vulnerability in brain development around 40 weeks gestational age that can explain this finding.
Another interesting relationship emerged from looking at cases from mothers who had previously had children versus those giving birth for the first time. Jaundice increased the risk for developing an ASD in children who were second or later born, but conveyed no increased risk for first born children. This effect is also a bit of a scientific mystery, however we do know that second and later-born children can be exposed to maternal antibodies that accumulate from previous pregnancies.
Lastly, the authors found that birth during the winter months was statistically associated with greater ASD risk than birth in the summer months. Exposure to daylight helps to break down bilirubin, so it is possible that individuals born in summer months, though diagnosed with jaundice had lower levels of bilirubin in their blood simply because they were exposed to more sunlight. The authors also note that sunlight is required for Vitamin D synthesis and low light levels in the winter may alter the body’s ability to as synthesize Vitamin D. Vitamin D deficiency is another autism risk factor under investigation. Autism Speaks is currently supporting a study examining how Vitamin D levels at birth and genes for the Vitamin D receptor are related to a later autism diagnosis.
In summary, it is important to note that although this paper brings many new considerations, it does not establish that jaundice causes autism. Instead, this paper reports on the risk of developing ASD after exposure to jaundice. This risk is significantly modified by several factors. Data from this study suggests that babies with jaundice who were born prior to 37 weeks gestation have little to no increased risk of ASD. However, the data also indicate a substantially elevated risk for full-term babies born to mothers with previous pregnancies and also full-term babies that were born during winter months. Hopefully, this and other information about medical conditions at birth will lead to the further development of screening tools to identify individuals at risk for a later autism diagnosis. Before that is done, scientists need to determine the mechanism by which jaundice may be contributing to the risk of developing ASD. Further research will been needed to determine whether bilirubin is itself an environmental risk factor, or if jaundice is a consequence of both genetic and environmental effects that elevate the risk of developing autism.
On September 8, the National Institute for Environmental Health Sciences and Autism Speaks organized a brain-storming meeting in North Carolina entitled “Autism and the Environment: New Ideas for Advancing the Science”. Researchers, scientists, and parent advocates from within and outside the field of autism were invited to participate. Over the course of the day, the group’s objective was to share novel ideas and unique perspectives in identifying and overcoming the primary obstacles to progress in the field of environmental health research in autism. From these discussions the group was charged with identifying the best opportunities for accelerating research aimed at understanding the role the environment plays in the risk for autism. What made this meeting unique from others is that autism researchers with expertise in the unique challenges of discoveries in this disorder were invited together with experienced, senior researchers in other disorders with known genetic and environmental risk factors. This included schizophrenia, Parkinson’s Disease, and breast cancer. For example, Dr. Caroline Tanner described the sequence of scientific discoveries that led to the conclusion that Parkinson’s Disease has both environmental and genetic causes, and how researchers are using this information to better understand how the two interact. Dr. Tanner commented that, like autism, Parkinson’s Disease is associated with gastrointestinal problems, noting that such problems often occur before the onset of the motor problems that are characteristics of this disorder. Other scientists pointed out how both epidemiological evidence and basic science discoveries have suggested that early immune system challenges, such as maternal influenza, can influence fetal brain development, resulting in an increased risk for schizophrenia. Another feature of the discussion was the broad, inclusive nature of environmental factors under consideration, as well as how basic science and epidemiology can work together in parallel, rather than sequentially, to identify and validate suspected environmental targets.
The meeting was broadcast live via webcast and a summary report will be shared with the public and the NIH Interagency Autism Coordinating Committee for further consideration and comment. Ultimately this report will offer guidance in setting priorities in future environmental research in autism. Some of the suggestions included taking advantage of a variety of existing epidemiological studies the use of newer technologies for data collection of personal environmental exposures – such as sensors that can be worn on the body that are currently under development. Existing epidemiology studies that may not currently include autism as an outcome may be able to be built upon by adding autism as an outcome and gathering additional information on exposures of particular interest In addition, representatives from the National Toxicology Program presented approaches using bioinformatics and high throughput technologies to quickly screen for a variety of environmental exposures of interest. Because autism is complex, the assay may not be simple, and the group stressed the importance of basic research in science to help inform the process. This includes high quality, well designed research in cell biology, neuroanatomy, neurophysiology and genetics. Genetic research will continue to be essential to better understand how individuals with certain genotypes may be vulnerable to specific environmental exposure and to provide clues into the biological systems that are affected in autism. The new findings in genetics with regards to copy number variations are going to be essential to identify biological pathways that may be affected by specific environmental exposures.
As autism is a disorder with multiple symptoms and multiple etiologies, both big and small ideas, short and long term projects were identified for further consideration. Please check the Autism Speaks website for updates on this meeting and plans to follow up on the ideas presented. More information about the agenda and the participants can be found here. We will post a link to the full meeting once it is available.
Last week, the Senate Environment and Public Works Committee convened a panel of experts to investigate the role of environmental factors in autism spectrum disorders (ASD; link to web archive for video). Although genetic factors are known to contribute to the risk of autism, we also need to understand environmental factors and their interactions with genetic susceptibility.
The dramatic increase in autism prevalence over the last two decades—over 600% during this period—underscores the need for more research on environmental factors. Our understanding of typical brain development combined with what we’ve learned from examining the brains of individuals with autism have focused efforts on the prenatal and early postnatal environment. To investigate environmental factors that may be active during this time, researchers are casting a wide net on potential environmental agents that can alter neurodevelopment, including exposure to metals, pesticides, polybrominated diphenylethers and other chemicals.
Isaac Pessah, Ph.D., Director of the University of California, Davis, Children’s Center for Environmental Health and Disease Prevention, participated in the panel and said in his testimony, “We must identify which environmental exposures and combination of exposures are contributing to increased overall risk in the population and identify the most susceptible groups. Only by bringing together the concerted effort of multidisciplinary teams of scientists can we identify which of the >80,000 commercially important chemicals currently in production promote developmental neurotoxicity consistent with the immunological and neurological impairments identified in individuals with idiopathic autism”.
To help speed an understanding of environmental factors, Autism Speaks is supporting research on several fronts. In 2008, Autism Speaks launched the Environmental Factors Initiative to fund investigators researching aspects of environmental causes and autism.
A collaboration with the National Institute for Environmental Health Sciences (NIEHS) has resulted in a network of 35 international scientists who gathered at this year’s International Meeting for Autism Research (IMFAR) to promote collaboration, identify gaps in our understanding and foster opportunities for innovative research which is discussed in more detail in Dr. Dawson’s 2010 IMFAR recap. This fall, Autism Speaks and NIEHS will co-sponsor a workshop to help identify the most promising strategies and scientific directions for understanding the role of the environment in ASD.
A large collaborative study which will pull together data from six international registries is being funded by Autism Speaks to explore early environmental risk factors for ASD.
Autism Speaks is also leveraging longstanding investments to make the best use of research resources that currently exist. For example, the Autism Genetic Resource Exchange (AGRE), a premiere genetic resource for scientists studying autism, is now collecting environmental data from families to pair with the genetic and medical data. Autism Speaks has partnered with the National Institutes of Health to fund the the EARLI and IBIS research networks to study environmental factors in infants at risk for autism. The EARLI network is following 1200 mothers of children with autism from the start of another pregnancy through the baby sibling’s third birthday. The IBIS network is charting the course of brain development in infant siblings of children with autism. Together with Autism Speaks, these groups are exploring both genetic and environmental risk factors for ASD.
Taken together, Autism Speaks’ investment in research on environmental factors promises to shed light on an important area of autism research that has until recently remained in the shadows. We look forwarding to following the new directions illuminated by the discoveries made possible by these various research opportunities.