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What is epigenetics, and what does it have to do with autism?

January 20, 2012 11 comments

This week’sGot Questions?” answer comes from Alycia Halladay, PhD, Autism Speaks director of research for environmental sciences

If you’ve been following autism research in recent years, you have probably read—many times—that familial, or inherited, risk is seldom the whole picture. A few inherited genes are sufficient by themselves to cause autism. But most so-called “autism genes” only increase the risk that an infant will go on to develop this developmental disorder. As is the case in many complex diseases, it appears that autism often results from a combination of genetic susceptibility and environmental triggers.

This is where epigenetics comes in. Epigenetics is the study of the factors that control gene expression, and this control is mediated by chemicals that surround a gene’s DNA. Environmental epigenetics looks at how outside influences modify these epigenetic chemicals, or “markers,” and so affect genetic activity.

It is important to remember that scientists use the term “environment” to refer to much more than pollutants and other chemical exposures. Researchers use this term to refer to pretty much any influence beyond genetic mutation. Parental age at time of conception, for example, is an environmental influence associated with increased risk of autism, as are birth complications that involve oxygen deprivation to an infant’s brain.

Because epigenetics gives us a way to look at the interaction between genes and environment, it holds great potential for identifying ways to prevent or reduce the risk of autism. It may also help us develop medicines and other interventions that can target disabling symptoms. We have written about epigenetics previously on this blog (here and here). So in this answer, I’d like to focus on the progress reported at a recent meeting hosted by Autism Speaks.

The Environmental Epigenetics of Autism Spectrum Disorders symposium, held in Washington, D.C. on Dec. 8, was the first of its kind. The meeting brought together more than 30 leaders in autism neurobiology, genetics and epidemiology with investigators in the epigenetics of other complex disorders to promote cross-disciplinary collaborations and identify opportunities for future studies.

Rob Waterland, of Baylor College of Medicine in Texas, described epidemiological studies and animal research that suggested how maternal nutrition during pregnancy can affect epigenetic markers in the brain cells of offspring.

Julie Herbstman, of Columbia University, described research that associated epigenetic changes in umbilical cord blood with a mother’s exposure to air pollutants known as polycyclic aromatic hydrocarbons (PAHs). PAHs are already infamous for their association with cancer and heart disease.

Rosanna Weksberg, of the Hospital for Sick Kids in Toronto, discussed findings that suggest how assisted reproductive technology may lead to changes in epigenetically regulated gene expression. This was of particular interest because assisted reproduction has been associated with ASD. Taking this one step further, Michael Skinner, of Washington State University, discussed “transgenerational epigenetic disease” and described research suggesting that exposures during pregnancy produce epigenetic changes that are then inherited through subsequent generations.

Arthur Beaudet, of Baylor College of Medicine, discussed a gene mutation that controls availability of the amino acid carnitine. This genetic mutation has been found to be more prevalent among children with ASD than among non-affected children, suggesting that it might be related to some subtypes of autism. Further study is needed to follow up on the suggestion that dietary supplementation of carnitine might help individuals with ASD who have this mutation. Caution is needed, however. As Laura Schaevitz, of Tufts University in Massachusetts, pointed out, studies with animal models of autism suggest that dietary supplementation may produce only temporary improvements in symptoms of neurodevelopmental disorders.

So what does this all mean for research that aims to help those currently struggling with autism? The meeting participants agreed that the role of epigenetics in ASD holds great promise but remains understudied and insufficiently understood. For clearer answers, they called for more research examining epigenetic changes in brain tissues. This type of research depends on bequeathed postmortem brain tissue, and Autism Speaks Autism Tissue Program is one of the field’s most important repositories. (Find more information on becoming an ATP family here).

The field also needs large epidemiological studies looking at epigenetic markers in blood samples taken over the course of a lifetime. One such study is the Early Autism Risk Longitudinal Investigation (EARLI). More information on participating in EARLI can be found here.

Autism Speaks remains committed to supporting and guiding environmental epigenetics as a highly important area of research.  We look forward to reporting further results in the coming year and years.

Got more questions? Send them to gotquestions@autismspeaks.org.

Read more autism research news and perspective on the science page.


Commentary on the LA Times Series on Autism

January 3, 2012 18 comments

Posted by Autism Speaks scientific advisory board member Irva Hertz-Picciotto, PhD, MPH. As an epidemiologist at the University of California-Davis MIND Institute, Hertz-Picciotto studies exposures to environmental chemicals, their interactions with nutrition and pregnancy and their effects on prenatal and early child development.

Alan Zarembo’s series on autism in the LA Times  covers a great deal of territory and has brought to light a wide range of personal stories that exemplify the complexity of issues surrounding autism diagnosis, treatment choices and effectiveness, impact on families and population incidence. Zarembo should be commended for the substantial work he has done researching inequities in the delivery of services. Of notable concern, he has put a spotlight on what appear to be serious racial and ethnic disparities in the California Department of Developmental Services (DDS) system and the provision of therapies. If his figures are correct, this result should stimulate an analysis of how to right this situation and ensure that appropriate opportunities are made available to all families with affected children.

Zarembo has also highlighted adults living with an autism spectrum disorder (ASD) but diagnosed late in life. We have too long overlooked the struggles faced by adults with autism as they try to find ways to be productive, live independently and connect with others.

My remaining comments pertain to Zarembo’s conclusions about the rise in autism diagnoses and the role of environmental factors. First, he is right that there is substantial variability in rates of diagnoses in different regions, and that we should not confuse diagnoses with the actual incidence of disease. Not all persons who meet criteria have been correctly diagnosed, and the degree to which this is true has likely changed over time.

Nevertheless, impressions are not the same as a scientific analysis. Zarembo has not demonstrated that the rise is purely social and cultural.  My colleague Lora Delwiche and I published the first quantitative analysis of how much of the increase in diagnosed cases in California could be explained by artifacts (changes in diagnostic criteria, earlier age at diagnosis and inclusion of milder cases).1 We used California state data that provided statistics over many years and found that the numbers simply do not add up. In other words, the actual increase has been far larger than these artifacts could have produced. Combining our results with those of another research team, it appears that about half of the increase in diagnoses in California is due to changes in diagnostic criteria or practices.2 These results left about a three-fold increase unexplained as of 2007. And autism diagnoses in California have continued to rise both in areas with low rates and in areas with high rates. Zarembo is interested in explaining the geographic variation, but the explanations for variation spatially are not necessarily the explanations for variation over time.

These statements were particularly misleading:

“No study points to an environmental reason for the worldwide explosion in cases over the last two decades.

Given the slow pace of genetic change in large populations, genes can’t account for the surge either.

That suggests the explanation for the boom lies mainly in social and cultural forces, notably a broader concept of autism and greater vigilance in looking for it.”

The logic that leads from the first two sentences to the third involves huge assumptions.

How many studies have been done of environmental causes? Very few!  And of these, most were extremely poor studies involving very small samples or lacking individual-level data. Is it surprising we’ve uncovered few leads?  The funding for environmental factors has been paltry – somewhere around $40 to $60 million over the last 10 years, while more than $1 billion has been spent on studying autism genetics.  To imply that environmental factors can be dismissed and that only social/cultural factors should be pursued is nonsensical.

It should be noted, however, that if anyone is looking for “one” environmental factor to explain the increase, they will certainly be disappointed. It doesn’t exist. Autism is far too complex. Moreover, to the extent the increase is due to diagnostic differences over time, we need to find explanations both for the increasing numbers of diagnoses and for the autism that has been around “all along.” In fact, data are emerging about quite a number of environmental factors. In 2011, major papers were published supporting contributions from maternal nutrition around the time of conception (here and here), traffic-related air pollution, and season of conception.3-6 Earlier papers indicated associations with pesticides  (here and here) and air pollution.7-9

One concern raised about the increase in diagnoses is a type of ‘inflation’ from inclusion of a growing number of high-functioning persons whose diagnosis is more likely to be Asperger syndrome than classic autism. This may apply to some studies of changes over time, but in our analysis of CHARGE study data, most of the cases were low functioning.10 This would likely be true for the majority of persons with ASD served by the California Department of Developmental Services (DDS), because in order to qualify for state services, they must have “significant functional limitations” in three areas of major life activities. This requirement would exclude most of those who are higher functioning.

With regard to genetics, Zarembo’s article leaves out the most current information: the largest and most statistically robust study of twin pairs found that 38 percent of concordance is due to shared genetics with 58 percent due to shared environmental factors (most likely prenatal and perinatal).11 This result completely overturns the widespread assumption, based on a number of previous small studies, that the causes of autism are overwhelmingly heritable, or genetic. Unfortunately, most analyses of twins make the incorrect assumption that genes and environment do not interact to influence risk for disordered brain development. This interaction is real, and one study has already shown a whole class of genes that primarily affect development in children whose mothers had not taken prenatal vitamin supplements during the months preceding and immediately following conception. 3

In summary, Zarembo’s investigative journalism provides unusual depth into difficult aspects of autism occurrence and the social policies that bear on the lives of affected families. He has raised several critical challenges facing the autism community. What was lacking from his series is a more balanced view of the role environment likely plays and the need to advance the agenda of discovering modifiable causative factors.

Autism Speaks is one of a few organizations that have begun to turn in this direction. I look forward to a continued strong commitment by Autism Speaks and others willing to support and significantly expand the scientific research aimed at identifying and understanding environmental contributions to autism, factors driving increased prevalence and ways to intervene so as to eliminate or lower human exposure levels. This will be the fastest road to reducing the occurrence of ASD in the next generation.

References
1             Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology 2009;20: 84-90.
2             King M, Bearman P. Diagnostic change and the increased prevalence of autism. Int J Epidemiol. 2009; 38:1224-34.
3             Schmidt, R J, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology 2011;22:476-85.
4             Cheslack-Postava K, Liu K, Bearman PS. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics 2011;127:246-53.
5             Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect 2011;119: 873-7.
6             Zerbo O, Iosif AM, Delwiche L, Walker C, Hertz-Picciotto I. Month of conception and risk of autism. Epidemiology 2011;22:469-75.
7             Roberts EM, et al. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. 2007;115:1482-9.
8             Eskenazi B, et al. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect 2007;115:792-8.
9             Windham G, Zhang L, Gunier R, Croen L, Grether J. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay Area. Environ Health Perspect. 2006; 114(9):1438-44.
10           Hertz-Picciotto, I. et al. The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ Health Perspect. 2006;114: 1119-25.
11           Hallmayer, J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011(68):1095-102.

Autism and Environmental Health in China

November 9, 2011 1 comment

From left: Drs. Jinsong Zhang, Alycia Halladay, Jim Zhang, Alice Kau, Fenxi Ouyang and Xiaoddan Yu


Posted by Autism Speaks Director of Research for Environmental Science, Alycia Halladay, Ph.D.

To date, relatively few scientists are studying autism in China. Clearly the need there is great, for with its population of over a billion, we may be looking at millions of persons affected by autism. With this in mind, Autism Speaks partnered with China’s Fudan University to convene a meeting of leading international experts in autism and children’s health in Shanghai last week.

As part of this visit, I and development psychologist Alice Kau, Ph.D., of the National Institute for Child Health & Human Development, visited Xin Hua Hospital and its recently completed Shanghai Key Lab of Children’s Environmental Health. Both are affiliated Shanghai’s Jiao Tong University School of Medicine.

There we met the lab’s executive director, Jun Jim Zhang, MD, Ph.D., and his colleagues. In recent years, they have been studying how exposure to heavy metals such as mercury and lead affects child development. Environmental lead contamination, a problem largely minimized in the United States, remains a widespread problem in China, owing to unsafe disposal of lead products including waste from lead battery plants.

The Shanghai Key Lab’s affiliation with Xin Hua Hospital allows its scientists to collect blood samples at birth and throughout a child’s development. Their lab is also collecting information on intellectual function and other developmental behaviors. Among their projects is the Shanghai Birth Cohort, which will recruit 100,000 pregnant women from hospitals throughout Shanghai and follow their children throughout adolescence.

To date, the researchers at Shanghai’s Key Lab have been focusing their research on potential environmental causes of childhood asthma, sleep disorders and leukemia. Looking forward, they are keenly interested in expanding their research to include neurodevelopmental issues such as autism.

Thanks to our new collaboration, they will be participating in Autism Speaks Environmental Epidemiology of Autism Research Network. In doing so, they will be sharing their information with autism researchers in North America and elsewhere, even as they receive guidance on screening for autism spectrum disorder (ASD).

Given the unique physical, chemical and psychosocial environment in China, we believe that this collaboration can greatly advance our understanding of the environmental and genetic risk factors that contribute to the development of ASD. We look forward to working with this wonderful research team to help solve the autism puzzle in China, North America, and around the world.

If environmental factors can lead to autism, why does only one of my twin boys have autism?

October 21, 2011 41 comments


This week’s “Got Questions?” response comes from Alycia Halladay, PhD, Autism Speaks’ director of research for environmental science
.

Today’s question came in response to my last blog post. In it, I explained that when scientists talk about the “environmental factors” that increase the risk of a disorder, they’re referring to pretty much any influence beyond genetics.

In the case of autism, the clearest evidence of environmental influence seems to surround very early events such as conception, pregnancy and birth. Those with the strongest link include parental age at time of conception (both mom and dad), maternal nutrition or illness during pregnancy, and certain birth complications.

The commenter’s question is a great one that scientists are actively exploring. The short answer is that inherited genes (DNA) and environmental factors seem to interact to influence whether an infant goes on to develop autism. So if the commenter’s twins are fraternal (meaning they share about half their DNA), the difference in their genetic makeup might explain why only one developed autism.

But what if the boys are identical twins–meaning they share exactly the same DNA? In this case, something beyond genes likely accounts for the different outcomes. Comparing the rates of autism among identical and fraternal twins provides clues.

In July, researchers used our Autism Genetic Resource Exchange (AGRE) to complete the largest autism twin study to date. They found a 70 percent overlap in autism among identical twins and a 35 percent overlap among fraternal twins. That overlap between fraternal twins is much higher than the estimated 19 percent overlap between different-age siblings.

These numbers tell us that it’s not always genes alone that determine whether a child develops autism. If it were, two identical twins would always share the same outcome, and the rate of a shared autism among fraternal twins would look more like that for different-age siblings. So we conclude that shared environmental influences are also at play.

Although twins share very similar pregnancy and birth environments, those environments aren’t exactly the same. For example, twins can have different positions in the womb or different placentas, and this can affect such environmental influences as blood and oxygen flow. Indeed, twins often have different birth weights, a known risk factor for autism.

It’s important to remember that “environmental” influences such as these don’t cause autism by themselves. Rather, if a child has a genetic predisposition for developing autism, these influences may further increase the risk.

Autism Speaks continues to fund and otherwise support research on both genetic and nongenetic risk factors for autism. EARLI is a network of researchers who follow mothers of children with autism beginning at the start of another pregnancy. IBIS is a study of early brain development in the younger siblings of children with autism. These studies depend on the participation and support of the autism community.  Please visit our Participate in Research page to learn more.

Importantly, these studies provide insights into the underlying biology of different types of autism. This in turn becomes a basis for developing ways to treat and possibly prevent autism. As always, the goal of the research we support is to improve the lives of all on the autism spectrum.

And thanks for the question. Please keep them coming.

What do scientists mean when they talk about ‘environmental factors’ that cause autism?

September 30, 2011 34 comments

This week’s “Got Questions?” response comes from Alycia Halladay, PhD, Autism Speaks’ director of research for environmental science.

Research has taught us that there’s no simple explanation for what causes autism. We know that genes play a role, but they aren’t the whole picture. Environment also matters.

However “environment” can be a tricky term, as pediatrician Perri Klass recently noted in her New York Times column. In autism research, we use the word to refer to pretty much any influence beyond inherited genes—not just exposure to pollutants or other toxic chemicals.

In fact, the environmental factors that research most strongly links to autism are influences such as maternal infection during pregnancy (especially rubella), birth complications (especially those involving oxygen deprivation), and parental age at time of conception (dad as well as mom). Parents who wait less than one year between pregnancies may be at a slightly higher risk for having a child with autism. (Conversely, there is strong evidence that mothers who take prenatal vitamins before conceiving reduce the odds that their children will develop autism.)

Clearly, countless fetuses and babies are exposed to “environmental risk factors” such as these without ever developing autism. But if a child is genetically predisposed to autism, it appears that these influences further increase the risk. For this reason, we say that environmental factors increase the risk of autism rather than cause it.

Research has suggested that many other environmental, or nongenetic, factors may increase the risk for autism. But scientists can’t yet say whether these involve direct (versus coincidental) links. Such factors include a pregnant woman’s exposure to certain chemicals such as pesticides and phthalates (commonly found in plastics) or certain drugs such as terbutaline (used to stop premature labor), valproic acid (to control seizures), and some antipsychotics and mood stabilizers. Of course, in the case of medications, any possible increased risk of autism must be balanced against a woman’s medical needs—which can likewise affect the health of her pregnancy and children.

In addition, most environmental factors associated with autism appear to increase risk only slightly and only in combination with other factors such as genetic predisposition.  So it is difficult, in most cases, to pinpoint any one environmental influence. For these reasons, Autism Speaks continues to fund research on a wide range of environmental risk factors. Importantly, the more we learn about how these influences affect brain development, the better we can help the children, adults and families who are affected by autism.

Want to learn more about the research Autism Speaks is funding? On our Science Grant Search page, you can browse studies by topic and location. Finally, if you or your child is affected by autism, please consider participating in one of our clinical studies. Thanks, and please keep sending us your questions.

‘Meta-analysis’ Clarifies Birth Conditions Associated with Autism

July 11, 2011 50 comments

Posted by Alycia Halladay, PhD, director of research for environmental science, Autism Speaks

For over four decades, autism researchers have been combing through birth records to look for events that might increase the risk that a newborn goes on to develop an autism spectrum disorder (ASD). Many clues have emerged regarding the influence of such factors as prematurity, low birth weight, method of delivery, or even the season in which conception or delivery occurs. But no one study was large enough to provide definitive answers, and inconsistent results between studies have caused confusion among scientists as well as parents trying to follow the science.

Today, the respected journal Pediatrics publishes a study that goes far in cutting through the confusion. Researchers from Harvard and Brown universities reviewed and analyzed the combined results of 40 studies that looked at potential autism risk factors during the birth (perinatal) and newborn (neonatal) period.

Such a “meta-analysis” study is a powerful tool in science, as it allows researchers to combine and compare findings from different sources to get a clearer, more reliable picture of the associations between potential risks and conditions such as autism. Importantly, the study confirmed an association between autism and such conditions as abnormal fetal presentation during delivery (for example, breech), fetal respiratory distress (breathing difficulties), birth injury or trauma, low 5-minute APGAR score (a 1-10 score for assessing newborn health after delivery), newborn seizures, low birth weight, multiple births (twins, triplets, etc.), anemia (low blood iron, and being born in the summer.

Of note, preterm birth was not found to be associated with ASD, of particular interest because there had been considerable differences on this count across earlier studies. Most importantly, perhaps, the researchers concluded that the evidence did not implicate any one perinatal or neonatal factor as causing autism by itself. Rather, the evidence suggests that a combination of these factors—reflecting generally poor conditions during and immediately after birth–may increase the risk that a child with an underlying genetic disposition will develop autism.

One common thread across several of these risk factors is that they result in a lack of adequate blood flow to the brain during the birth process. One hypothesis is that, when combined with a genetic predisposition, oxygen deprivation to the brain worsens abnormal brain development. Studying these and other environmental (versus genetic) risk factors for autism is important to increase our understanding of the biology of ASD and to provide practical guidance for physicians and parents on how to avoid or modify those risk factors that can be changed.

In addition, this meta-analysis strongly suggests that pediatricians and parents should closely monitor the development of babies born in difficult situations so that early intervention can be offered should developmental issues such as autism arise. What this study does not say is that difficult birth means a baby will go on to develop autism. Rather, these conditions and complications may increase the risk of autism among those who have a genetic predisposition for developing it.

As in my last post, I want to invite readers to explore the many environmental risk studies that Autism Speaks is supporting with donor dollars, scientific resources, and the participation of autism families in clinical studies. Please see our Grants Search and Participate gateways at www.autismspeaks.org. Thanks for being a vital part of our mission to improve the lives of all who struggle with autism. For more on the Pediatrics meta-analysis study, also see Autism Speaks news.

Twin Study Suggests Environmental Role in Autism: Now What?

July 7, 2011 31 comments

Posted by Alycia Halladay, PhD, director of research for environmental science, Autism Speaks

As reported last week, a large twin study supported by Autism Speaks compared the frequency with which identical and fraternal twins both share a diagnosis of autism. This approach enabled the investigators to use statistical techniques to calculate the degree to which environmental factors shared by twins contribute to their risk of developing autism. Such factors include conditions in the womb and during birth.

The results of the California Autism Twin study were game-changing because they revealed a much larger environmental influence than had previously been estimated—accounting for about 58% of the risk of developing autism. By contrast, much smaller twin studies had previously suggested that genes largely accounted  for a child’s risk of autism.

The results underscore the need to investigate the role that non-inherited risk factors play in the development of autism spectrum disorders (ASD). So what’s being done to help speed this research? And what role are Autism Speaks and its donor dollars playing in this effort?

Autism Speaks has funded over $21 million in the study of environmental risk factors, an initiative we call (obviously enough) the Environmental Factors of Autism Initiative. Already, we have a large body of evidence suggesting that it is not any one environmental factor, but many different factors working together, that elevate the risk and severity of autism in individuals with a genetic predisposition for this condition. In other words, autism is seldom caused by any one thing and neither is it an “all or nothing” condition.  Furthermore, different combinations of genetic and environmental risk factors contribute to individual cases of autism.

Within the Environmental Factors of Autism Initiative are ongoing studies focusing on environmental exposures that occur before and during pregnancy and throughout the first year of life—crucial periods for human brain development. These studies look at such possible risk factors as maternal and paternal age, socioeconomic status, season of birth, exposure to chemicals or toxic agents, nutrition and exposure to various pharmaceutical drugs during pregnancy, the difficulty of labor and delivery, and various other forms of prenatal stress.  The researchers we support are also investigating the mechanisms by which genes and the environment may interact (so-called epigenetics) and the role of the immune system.  We are also supporting large scale epidemiological studies that focus on pregnancy and the first year of life.  These include the EARLI study  and the IBIS study.

Are you interested in learning more about the studies Autism Speaks is funding with donor dollars? We are proud to debut the new Grant Search function on our website. Please use it to explore past and present research studies by topic or location. And if you or your family is affected by autism, please consider participating in one of our clinical studies.

Environmental Epigenomics and Susceptibility for Developmental Disorders: Findings from the Keystone Symposium

April 19, 2011 5 comments

By Guest Blogger, Jennifer T. Wolstenholme, PhD, Postdoctoral Fellow at the University of Virginia, Charlottesville, VA, working with two Autism Speaks-funded researchers, Emile Rissman, Ph.D. and Jennifer Connelly, Ph.D.

In recent work in our lab, we have established a mouse model for gestational exposure to an endocrine disrupting compound, bisphenol A (BPA), at human physiological levels. We asked if a low BPA dose ingested during pregnancy (20 ug BPA/kg body weight/day) would affect the social behaviors of the juvenile offspring mice. In addition, we continued to breed the mice from these litters to ask if these effects could be transmitted to future generations that were not directly exposed to dietary BPA. We also examined a handful of genes known to be affected by BPA or involved in social behaviors to determine if BPA also changed the expression of these genes in the brain during embryogenesis. The take home message is this: we do not know if exposure to endocrine disrupting chemicals causes any neurobiological disorders, including autism spectrum disorders (ASD).  However, the data are interesting enough to cause us and others to continue to test the hypothesis that exposure to BPA during gestation may result in modified social behaviors in juvenile mice.

Bisphenol A (BPA) is a man-made compound used to make polycarbonate plastics (i.e. food and water containers), epoxy resins (i.e. canned food linings) and thermal register receipts. Human exposure to this chemical is wide spread and nearly unavoidable as it has been detected in urine in 90% of all humans sampled [1, 2]. Public health concerns have been fueled by findings that BPA exposure can reduce sex differences both behaviorally and in the brain. In rats and mice, perinatal exposure to BPA is associated with aggressive behavior, cognitive impairments, increased novelty seeking and impulsivity [3-5].  BPA can also influence social interactions and anxiety in rodents [6-10]. This list of associations have suggested to some that BPA may be somehow related to human neurological disorders, such as ASD. However, such a conclusion at this time is premature.

Many laboratories have suggested that BPA exposure disrupts normal brain development and behaviors through its actions on the steroid receptors [18, 19].  BPA acts as an analog of steroid hormones.  Steroid hormones organize the brain during neonatal development [11-13]. BPA has steroid-like properties and binds estrogen receptors, (ERa, ERb [14]), as well as androgen and thyroid receptors [15-17].

In addition to steroid-related effects, BPA may have even more global actions as it can alter DNA methylation [20].  Dysregulation of DNA methylation during critical developmental windows could disrupt the normal progression of brain and endocrine system development causing robust changes in the developing embryo that can persist into adulthood or even beyond if effects extend to germ cells that later serve reproduction as sperm or egg cells. Embryonic development is a particularly sensitive period, specifically when the body’s germ line cells undergo epigenetic programming and experience a wave of DNA de-methylation and re-methylation.

Skinner et al. have shown trans-generational effects for several endocrine disrupting compounds, but at much higher doses than humans are typically exposed [21, 22]. Specifically, endocrine disruptors found in plastics, pesticides, hydrocarbons and herbicides can affect embryonic testes development and lead to deficits in sperm production in adulthood.  These effects are trans-generational in rodents directly exposed to these chemicals during gestation (F1 generation) and through to the great, great grandchildren (F2, F3 and F4 generations).

We use a paradigm in which inbred female mice are placed on control diet free of any phytoestrogens, or control diet with BPA (5mg BPA per kg diet). This diet produced BPA blood levels equivalent to those reported in humans. A week after the start of the diet females were mated. At birth, pups were fostered to control dams to limit BPA’s effect only to gestation. Three generations of offspring were tested for social behaviors at 21 days after birth.

BPA exposure had effects on several social and non-social behaviors and some of these differences between mice on control and BPA-containing diets persisted over generations. The great, great grandchildren of the BPA lineage (the F4 generation) were never directly exposed to dietary sources of BPA, yet social interactions resembled those of mice exposed during gestation. Some of these behavioral effects are correlated with different levels of gene expression in the brains of mice directly exposed to BPA compared to mice that were never exposed to dietary BPA. More work needs to be done to discover if the relationships between the affected genes and the behavioral changes are causal. Since exposure to BPA appears to alter social interactions in young mice, this compound may contribute to the risk of developing neurological disorders such as autism spectrum disorders, but further studies, especially in humans are needed to show a causal relationship. 

References

1.         Fujimaki, K., et al., [Estimation of intake level of bisphenol A in Japanese pregnant women based on measurement of urinary excretion level of the metabolite]. Nippon Eiseigaku Zasshi, 2004. 59(4): p. 403-8.

2.         vom Saal, F.S., et al., Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol, 2007. 24(2): p. 131-8.

3.         Kawai, K., et al., Aggressive behavior and serum testosterone concentration during the maturation process of male mice: the effects of fetal exposure to bisphenol A. Environ Health Perspect, 2003. 111(2): p. 175-8.

4.         Miyagawa, K., et al., Memory impairment associated with a dysfunction of the hippocampal cholinergic system induced by prenatal and neonatal exposures to bisphenol-A. Neurosci Lett, 2007. 418(3): p. 236-41.

5.         Tian, Y.H., et al., Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice. Synapse, 2010. 64(6): p. 432-9.

6.         Dessi-Fulgheri, F., S. Porrini, and F. Farabollini, Effects of perinatal exposure to bisphenol A on play behavior of female and male juvenile rats. Environ Health Perspect, 2002. 110 Suppl 3: p. 403-7.

7.         Negishi, T., et al., Behavioral alterations in response to fear-provoking stimuli and tranylcypromine induced by perinatal exposure to bisphenol A and nonylphenol in male rats. Environ Health Perspect, 2004. 112(11): p. 1159-64.

8.         Ryan, B.C. and J.G. Vandenbergh, Developmental exposure to environmental estrogens alters anxiety and spatial memory in female mice. Horm Behav, 2006. 50(1): p. 85-93.

9.         Cox, K., et al., Gestational exposure to bisphenol A and cross-fostering affect behaviors in juvenile mice. Horm Behav, 2010. 58(5): p. 754-61.

10.       Porrini, S., et al., Early exposure to a low dose of bisphenol A affects socio-sexual behavior of juvenile female rats. Brain Res Bull, 2005. 65(3): p. 261-6.

11.       McEwen, B.S. and S.E. Alves, Estrogen actions in the central nervous system. Endocr Rev, 1999. 20(3): p. 279-307.

12.       Phoenix, C.H., et al., Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology, 1959. 65: p. 369-82.

13.       Negri-Cesi, P., et al., Sexual differentiation of the brain: role of testosterone and its active metabolites. J Endocrinol Invest, 2004. 27(6 Suppl): p. 120-7.

14.       Kuiper, G.G., et al., Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology, 1998. 139(10): p. 4252-63.

15.       Sohoni, P. and J.P. Sumpter, Several environmental oestrogens are also anti-androgens. J Endocrinol, 1998. 158(3): p. 327-39.

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Meeting highlights environmental influences on genetic risk factors for ASD

March 15, 2011 19 comments

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.

Categories: Science Tags: , , ,

Feeling exposed? Insights from a new meeting on environmental impacts in autism

December 11, 2010 10 comments

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.

Read more about this meeting in The Daily Green.

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