Autism spectrum disorder (ASD) is diagnosed when individuals exhibit characteristic behaviors that include repetitive actions, decreased social interactions, and impaired communication. Curiously, many individuals with ASD also suffer from gastrointestinal (GI) issues, such as abdominal cramps and constipation.
Using the co-occurrence of brain and gut problems in ASD as their guide, researchers at the California Institute Technology (Caltech) are investigating a potentially transformative new therapy for autism and other neurodevelopmental disorders.
New Rochelle, NY, September 10, 2013—Use of stimulant medications to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and adolescents has increased significantly over the past several years. This trend toward increased use of prescription stimulants extends beyond ADHD to other types of neuropsychiatric disorders in children and teens as well, including Autism Spectrum Disorder (ASD), according to a study published in Journal of Child and Adolescent Psychopharmacology (JCAP), a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available on the JCAP website.
Søren Dalsgaard, MD, PhD, Helena Skyt Nielsen, PhD, and Marianne Simonsen, PhD, Aarhus University (Denmark), Lundbeck Foundation Initiative for Integrative Psychiatric Research (Denmark), and Hospital of Telemark (Norway), conducted a study of more than 850,000 children born in Denmark between 1990 and 2001. They found that 61% of children with ADHD, 16% of children with ASD, and 3% of those with other psychiatric disorders were treated with one or more medications typically prescribed for ADHD—methylphenidate, dexamphetamine, and atomoxetine. The data indicated significant increases in the prescription rates of these medications during the years 2003 to 2010.
“This study utilizes a population-based national cohort of children and adolescents, and assesses stimulant treatment in children and adolescents with ASD,” says Harold S. Koplewicz, MD, Editor-in-Chief of JCAP, and President, Child Mind Institute, New York, NY. “This is the largest and first prospective study to quantify the change in the use of treatment with ADHD medications over time.”
About the Journal
Journal of Child and Adolescent Psychopharmacology (JCAP) is an authoritative peer-reviewed journal published 10 times a year online with Open Access options and in print. The Journal is dedicated to child and adolescent psychiatry and behavioral pediatrics, covering clinical and biological aspects of child and adolescent psychopharmacology and developmental neurobiology. Complete tables of content and a sample issue may be viewed on the JCAP website.
About the Publisher
Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Cyberpsychology, Behavior, and Social Networking and Games for Health Journal. Its biotechnology trade magazine, Genetic Engineering & Biotechnology News (GEN), was the first in its field and is today the industry’s most widely read publication worldwide. A complete list of the firm’s over 80 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website.
Researchers identify risk factor for autism in a subset of children: Maternal Antibody-Related autism
Researchers with the UC Davis MIND Institute have found that prenatal exposure to specific combinations of antibodies found only in mothers of children with autism leads to changes in the brain that adversely affect behavior and development.
The researchers said that the highly specific immunoglobulin-G (IgG) autoantibodies cross the placenta during pregnancy to impact fetal brain development, resulting in a form of autism that the researchers now are calling maternal antibody-related (MAR) autism. The researchers said that MAR autism cases could represent as much as 23 percent of all autism cases.
The research is published online today in Translational Psychiatry, a Nature journal.
During gestation, maternal IgG antibodies normally cross the placenta and protect the fetus, conferring the mother’s immunities to the developing child. However, in addition to protective antibodies, autoantibodies that react to fetal proteins can also cross the placenta, essentially attacking fetal tissue.
The current study is an extension of an earlier study conducted in 2008. It explores the effects of the autism-specific IgG antibodies in a non-human primate model. Non-human primates live in complex social groups and use many forms of social communication. In addition, portions of the human brain, such as the prefrontal cortex, are poorly developed in other animal models, such as rodents, but are highly developed in the rhesus monkey.
For the study, a group of pregnant female monkeys were exposed to IgG purified from mothers of children with autism that exhibited fetal brain reactivity — the IgG-ASD group; a second group of pregnant female monkeys received IgG antibodies from the mothers of typically developing children. The third group included untreated animals that did not receive antibodies.
The study’s lead researcher is Melissa D. Bauman, UC Davis assistant adjunct professor in the UC Davis Department of Psychiatry and Behavioral Sciences, and a faculty member at the MIND Institute. To evaluate development in the IgG-ASD offspring, Bauman and her colleagues carried out a comprehensive evaluation of behavioral development and periodically conducted longitudinal magnetic resonance imaging (MRI) of the monkeys’ brain development during the first two years of life.
“The offspring of IgG-ASD antibody treated mothers consistently deviated from species-typical behavioral development of young rhesus monkeys,” Bauman said. Early in development, the monkey mothers treated with IgG-ASD antibodies were much more protective of their offspring. For example, the IgG-ASD treated mothers more frequently approached and contacted their infants and remained in close proximity to them.
The mothers may have detected behavioral abnormalities in their IgG-ASD offspring that were so subtle that they escaped the researchers’ attention, Bauman said. “The heightened protectiveness of the monkey mother’s was observed only when other animals were present, suggesting that the mothers perceived a greater risk to their IgG-ASD treated infants,” she said.
Other alterations in behavior were observed as the animals matured. For example, the offspring of the IgG-ASD antibody-treated animals more frequently approached other infants in their rearing group. “Even more strikingly, as they grew older, the IgG-ASD offspring increased their approaches to unfamiliar peers,” she said. “Inappropriately approaching a novel animal is highly unusual and potentially dangerous for young rhesus monkeys.”
Social interactions such as grooming or playing often occur when a young rhesus monkey approaches a peer. Despite the higher frequency of their approaches, the IgG-ASD offspring did not interact socially with peers more often than did the offspring whose mothers did not receive IgG-ASD antibodies. “In fact, there actually was a trend for the IgG-ASD offspring to receive less grooming from their same-age peers,” she said. “It is possible that there were subtleties in the demeanor of the IgG-ASD offspring that dissuaded their peers from interacting with them.”
These new behavioral findings build upon previous studies exploring the role of maternal antibodies in autism, including a pilot study conducted in non-human primates in 2008. During the past five years, study co-author Judy Van de Water and her colleagues have made substantial progress in characterizing which maternal antibodies are highly specific to autism. Van de Water with colleagues Rob Berman and Daniel Braunschweig recently reported that mouse offspring prenatally exposed to these autism-specific antibodies exhibit altered physical and social development, including anxiety and social behavior.
“The non-human primate study provides an exciting look at the pathologic effect of these autism-specific maternal antibodies,” said Judy Van de Water, who originally described the association between maternal antibodies to fetal brain proteins and ASD.
In addition to the behavioral changes, MRI analysis of the brains revealed altered patterns of neurodevelopment in the monkey offspring exposed to the IgG-ASD antibodies. The rate of brain growth was significantly faster in the male, but not female, IgG-ASD offspring, when compared with that of the control offspring. The total brain volume of the male IgG-ASD offspring also was significantly greater than normal, the researchers found.
While it is not clear why prenatal exposure to these antibodies only alters brain volume in the male offspring, a similar trajectory of abnormal brain development has been observed in male children with autism. Recent research from the MIND Institute has reported that boys with autism who were exposed prenatally to the same antibodies have significantly larger brains than boys with autism born to mothers without the IgG-ASD antibodies and typically developing control groups.
“The combination of brain and behavioral changes observed in the nonhuman primate offspring exposed to these autism-specific antibodies suggests that this is a very promising avenue of research.” Bauman adds that this unique interdisciplinary study requires a team of researchers with expertise in immunology, animal behavior and neuroscience thus “highlighting the collaborative efforts that characterize research at the UC Davis MIND Institute.”
David Amaral, research director of the MIND Institute and senior author of the paper, noted “that much research remains ahead of us to identify the mechanisms by which the antibodies affect brain development and behavior. But, this program of research is very exciting, because it opens pathways to potentially predicting and preventing some portion of future autism cases.”
Other study authors are Ana-Maria Iosif, Paul Ashwood, Daniel Braunschweig, Aaron Lee, Cynthia M. Schumann, Judy Van de Water and David G. Amaral, all of UC Davis.
This study was funded by the National Institute of Mental Health Grant # R01M H80218; the California National Primate Research Center Grant # RR00169. Human subject serum collection was supported by The UC Davis MIND Institute Pilot Grant Program and the National Center for Research Resources, National Institutes of Health, through Grant #UL1 RR024146.
Bacterial flora inhabiting the human gut have become one of the hottest topics in biological research. Implicated in a range of important activities including digestion, fine-tuning body weight, regulating immune response, and producing neurotransmitters affect that brain and behavior, these tiny workers form diverse communities. Hundreds of species inhabit the gut, and although most are beneficial, some can be very dangerous.
In new research appearing in the journal PLOS ONE, a team led by Rosa Krajmalnik-Brown, a researcher at Arizona State University’s Biodesign Institute, present the first comprehensive bacterial analysis focusing on commensal or beneficial bacteria in children with autism spectrum disorder (ASD).
After publishing earlier research exploring crucial links between intestinal microflora and gastric bypass, Krajmlanik-Brown convinced James Adams— director of the ASU Autism/Asperger’s Research Program—that similar high throughput techniques could be used to mine the microbiome of patients with autism. (Previously, Adams had been studying the relationship between the gut microbiome and autism using traditional culturing techniques.)
“One of the reasons we started addressing this topic is the fact that autistic children have a lot of GI problems that can last into adulthood,” Krajmalnik-Brown says. “Studies have shown that when we manage these problems, their behavior improves dramatically.”
Following up on these tantalizing hints, the group hypothesized the existence of distinctive features in the intestinal microflora found in autistic subjects compared to typical children. The current study confirmed these suspicions, and found that children with autism had significantly fewer types of gut bacteria, probably making them more vulnerable to pathogenic bacteria. Autistic subjects also had significantly lower amounts of three critical bacteria, Prevotella, Coprococcus, and Veillonellaceae.
Krajmalnik-Brown, along with the paper’s lead authors Dae-Wook Kang and Jin Gyoon Park, suggest that knowledge gleaned through such research may ultimately be used both as a quantitative e diagnostic tool to pinpoint autism and as a guide to developing effective treatments for ASD-associated GI problems. The work also offers hope for new prevention and treatment methods for ASD itself, which has been on a mysterious and rapid ascent around the world.
A disquieting puzzle
Autism is defined as a spectrum disorder, due to the broad range of symptoms involved and the influence of both genetic and environmental factors, features often confounding efforts at accurate diagnosis. The diseases’ prevalence in children exceeds juvenile diabetes, childhood cancer and pediatric AIDS combined.
Controversy surrounds the apparent explosive rise in autism cases. Heightened awareness of autism spectrum disorders and more diligent efforts at diagnosis must account for some of the increase, yet many researchers believe a genuine epidemic is occurring. In addition to hereditary components, Western-style diets and overuse of antibiotics at an early age may be contributing to the problem by lowering the diversity of the gut microflora.
In terms of severe developmental ailments affecting children and young adults, autism is one of the most common, striking about 1 in 50 children. The disorder—often pitiless and perplexing—is characterized by an array of physical and behavioral symptoms including anxiety, depression, extreme rigidity, poor social functioning and an overall lack of independence.
To date, studies of the gut microbiome in autistic subjects have focused primarily on pathogenic bacteria, some of which have been implicated in alterations to brain function. One example involves gram-negative bacteria containing lipopolysaccharides in their cell walls, which can induce inflammation of the brain and lead to the accumulation of high levels of mercury in the cerebrum.
A new approach
Krajmalnik-Brown and lead author Dae-Wook Kang are researchers in the Biodesign Institute’s Swette Center for Environmental Biotechnology, which is devoted to the use of microbial communities for the benefit of human and environmental health. Their new study is the first to approach autism from a different angle, by examining the possible role of so-called commensal or beneficial bacteria.
Up to a quadrillion (1014) bacteria inhabit the human intestine, contributing to digestion, producing vitamins and promoting GI health. Genes associated with human intestinal flora are 100 times as plentiful as the body’s human genes, forming what some have referred to as a second genome. Various environmental factors can destabilize the natural microbiome of the gut, including antibiotics and specific diets.
In the current study, a cohort of 20 healthy and 20 autistic subjects between 3 and 16 years of age were selected and their gut microflora from fecal samples analyzed by means of a technique known as pyrosequencing. Pyrosequencing is a high-throughput method, allowing many DNA samples to be combined as well as many sequences per sample to be analyzed.
Lower diversity of gut microbes was positively correlated with the presence of autistic symptoms in the study. The authors stress that bacterial richness and diversity are essential for maintaining a robust and adaptable bacterial community capable of fighting off environmental challenges. “We believe that a diverse gut is a healthy gut,” Krajmalnik-Brown says.
The new study detected decreased microbial diversity in the 20 autistic subjects whose fecal samples were analyzed. Specifically, three bacterial genera—Prevotella, Coprococcus and Veillonellaceae—were diminished in subjects with autism, when compared with samples from normal children. (Surprisingly, these microbial changes did not seem directly correlated with the severity of GI symptoms.)
The three genera represent important groups of carbohydrate-degrading and/or fermenting microbes. Such bacteria could be critical for healthy microbial-gut interactions or play a supportive role for a wide network of different microorganisms in the gut. The latter would explain the decreased diversity observed in autistic samples.
Bacteria: in sickness and in health
Among the fully classified genera in the study, Prevotella was the most conspicuously reduced in autistic subjects. Prevotella is believed to play a key role in the composition of the human gut microbiome. For this reason, the group undertook a sub-genus investigation of autistic subjects. They found that a species known as Prevotella copri occurred only in very low levels in the autistic samples. The species is a common component in normal children exhibiting more diverse and robust microbial communities.
“We think of Prevotella as a healthy, good thing to have,” Krajmalnik-Brown notes. (Michael Polan’s recent New York Times Magazine story on the microbiome points to the fact that he is proud that his gut microbiome is rich in Prevotella regarding it as a possible sign of a healthy non-Western diet.)
Jin Gyoon Park (the other lead author), who works in the Virginia G. Piper Center for Personalized Diagnostics, under Joshua LaBaer’s direction, conducted a rigorous bioinformatic and statistical analysis of the intestinal microflora. He believes that the microbiome can be mined in future work to find diagnostic biomarkers for autism and many other diseases. Quantitative diagnoses of this sort have so far been lacking for autism, a disease for which subjective behavior indices are typically used to identify the disorder.
In describing the next steps for the research group, Kang and Park point to more detailed, gene-level analyses aimed at probing bacterial function and further illuminating relationships between human health and the complexities of the microbiome. Additionally, the group will use the current results as a guide for new treatment studies for autism aimed at modifying bacterial composition in the gut.
A new, interdisciplinary consortium (Autism Microbiome Consortium) has been formed to investigate the underpinings of autism and the gut microbiome, bringing together the combined skills of neurologists, psychiatrists, neuroimmunologists, epidemiologists, pediatricians, geneticists, biochemists, microbiologists and others. In addition to Rosa Krajmalnik-Brown and James Adams, the group consists of:
Jack Gilbert (University of Chicago), Catherine Lozupone (University of Colorado), Rob Knight (University of Colorado and HHMI). Mady Hornig (Columbia University), Sarkis Mazmanian (California Institute of Technology), Tanya Murphy (University of South Florida), , Paul Patterson (California Institute of Technology), John Alverdy (University of Chicago), Janet Jansson (Lawrence Berkeley Lab), KImberly Johnson (University of Colorado).
Written by: Richard Harth Science Writer: Biodesign Institute email@example.com
(Santa Barbara, Calif.) –– Most infants respond to a game of peek-a-boo with smiles at the very least, and, for those who find the activity particularly entertaining, gales of laughter. For infants with autism spectrum disorders (ASD), however, the game can be distressing rather than pleasant, and they’ll do their best to tune out all aspects of it –– and that includes the people playing with them.
That disengagement is a hallmark of ASD, and one of the characteristics that amplifies the disorder as infants develop into children and then adults.
A study conducted by researchers at the Koegel Autism Center at UC Santa Barbara has found that replacing such games in favor of those the infant prefers can actually lessen the severity of the infants’ ASD symptoms, and, perhaps, alleviate the condition altogether. Their work is highlighted the current issue of the Journal of Positive Behavioral Interventions.
Lynn Koegel, clinical director of the center and the study’s lead author, described the game-playing protocol as a modified Pivotal Response Treatment (PVT). Developed at UCSB, PRT is based on principles of positive motivation. The researchers identified the activities that seemed to be more enjoyable to the infants and taught the respective parents to focus on those rather than on the typical games they might otherwise choose. “We had them play with their infants for short periods, and then give them some kind of social reward,” Koegel said. “Over time, we conditioned the infants to enjoy all the activities that were presented by pairing the less desired activities with the highly desired ones.” The social reward is preferable to, say, a toy, Koegel noted, because it maintains the ever-crucial personal interaction.
“The idea is to get them more interested in people,” she continued, “to focus on their socialization. If they’re avoiding people and avoiding interacting, that creates a whole host of other issues. They don’t form friendships, and then they don’t get the social feedback that comes from interacting with friends.”
According to Koegel, by the end of the relatively short one- to three-month intervention period, which included teaching the parents how to implement the procedures, all the infants in the study had normal reactions to stimuli. “Two of the three have no disabilities at all, and the third is very social,” she said. “The third does have a language delay, but that’s more manageable than some of the other issues.”
On a large scale, Koegel hopes to establish some benchmark for identifying social deficits in infants so parents and health care providers can intervene sooner rather than later. “We have a grant from the Autism Science Foundation to look at lots of babies and try to really figure out which signs are red flags, and which aren’t,” she said. “A number of the infants who show signs of autism will turn out to be perfectly fine; but we’re saying, let’s not take the risk if we can put an intervention in play that really works. Then we don’t have to worry about whether or not these kids would develop the full-blown symptoms of autism.”
Historically, ASD is diagnosed in children 18 months or older, and treatment generally begins around 4 years. “You can pretty reliably diagnose kids at 18 months, especially the more severe cases,” said Koegel. “The mild cases might be a little harder, especially if the child has some verbal communication. There are a few measures –– like the ones we used in our study –– that can diagnose kids pre-language, even as young as six months. But ours was the first that worked with children under 12 months and found an effective intervention.”
Given the increasing number of children being diagnosed with ASD, Koegel’s findings could be life altering –– literally. “When you consider that the recommended intervention for preschoolers with autism is 30 to 40 hours per week of one-on-one therapy, this is a fairly easy fix,” she said. “We did a single one-hour session per week for four to 12 weeks until the symptoms improved, and some of these infants were only a few months old. We saw a lot of positive change.”
Some Children Lose Autism Diagnosis: Small Group With Confirmed Autism Now On Par With Mainstream Peers
Jan. 15, 2013 — Some children who are accurately diagnosed in early childhood with autism lose the symptoms and the diagnosis as they grow older, a study supported by the National Institutes of Health has confirmed. The research team made the finding by carefully documenting a prior diagnosis of autism in a small group of school-age children and young adults with no current symptoms of the disorder.
The report is the first of a series that will probe more deeply into the nature of the change in these children’s status. Having been diagnosed at one time with an autism spectrum disorder (ASD), these young people now appear to be on par with typically developing peers. The study team is continuing to analyze data on changes in brain function in these children and whether they have subtle residual social deficits. The team is also reviewing records on the types of interventions the children received, and to what extent they may have played a role in the transition.
“Although the diagnosis of autism is not usually lost over time, the findings suggest that there is a very wide range of possible outcomes,” said NIMH Director Thomas R. Insel, M.D. “For an individual child, the outcome may be knowable only with time and after some years of intervention. Subsequent reports from this study should tell us more about the nature of autism and the role of therapy and other factors in the long term outcome for these children.”
The study, led by Deborah Fein, Ph.D., at the University of Connecticut, Storrs, recruited 34 optimal outcome children, who had received a diagnosis of autism in early life and were now reportedly functioning no differently than their mainstream peers. For comparison, the 34 children were matched by age, sex, and nonverbal IQ with 44 children with high-functioning autism, and 34 typically developing peers. Participants ranged in age from 8 to 21 years old.
Prior studies had examined the possibility of a loss of diagnosis, but questions remained regarding the accuracy of the initial diagnosis, and whether children who ultimately appeared similar to their mainstream peers initially had a relatively mild form of autism. In this study, early diagnostic reports by clinicians with expertise in autism diagnosis were reviewed by the investigators. As a second step to ensure accuracy, a diagnostic expert, without knowledge of the child’s current status, reviewed reports in which the earlier diagnosis had been deleted. The results suggested that children in the optimal outcome group had milder social deficits than the high functioning autism group in early childhood, but had other symptoms, related to communication and repetitive behavior, that were as severe as in the latter group.
The investigators evaluated the current status of the children using standard cognitive and observational tests and parent questionnaires. The optimal outcome children had to be in regular education classrooms with no special education services aimed at autism. They now showed no signs of problems with language, face recognition, communication, and social interaction.
This study cannot provide information on what percentage of children diagnosed with ASD might eventually lose the symptoms. Study investigators have collected a variety of information on the children, including structural and functional brain imaging data, psychiatric outcomes, and information on the therapies that the children received. Analysis of those data, which will be reported in subsequent papers, may shed light on questions such as whether the changes in diagnosis resulted from a normalizing of brain function, or if these children’s brains were able to compensate for autism-related difficulties. The verbal IQs of the optimal outcome children were slightly higher than those with high functioning autism. Additional study may reveal whether IQ may have been a factor in the transition they made.
“All children with ASD are capable of making progress with intensive therapy, but with our current state of knowledge most do not achieve the kind of optimal outcome that we are studying,” said Dr. Fein. “Our hope is that further research will help us better understand the mechanisms of change so that each child can have the best possible life.”
EEV: Highlights Although there are many potential causes. We chose to highlight HFCS, due to its toxin amplification.
1) Ca, Mg and Zn, or losses or displacement of any of these minerals from the consumption of HFCS
2) mercury (Hg) and fructose may both modulate PON1 activity
3) mercury (Hg) that may occur from the low Hg concentrations sometimes found in HFCS as a result of the manufacturing process
4) HFCS, may further enhance the toxic effects of lead (Pb) on cognitive and behavioral development in children
Initial Study date: 10 APR 2012
A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States
- * Corresponding author: Renee Dufault firstname.lastname@example.org
1 Food Ingredient and Health Research Institute, Ocean View, HI, USA
2 United Tribes Technical College, Bismarck, ND, USA
3 Department of Neuroscience and Ophthalmology, Louisiana State University Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
4 Shepherd University, Shepherdstown, WV, USA
5 Department of Health and Nutrition Sciences, Brooklyn College of City, University of New York, Brooklyn, NY, USA
6 Institute for Agriculture and Trade Policy, Minneapolis, MN, USA
7 Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
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Clinical Epigenetics 2012, 4:6 doi:10.1186/1868-7083-4-6
The electronic version of this article is the complete one and can be found online at: http://www.clinicalepigeneticsjournal.com/content/4/1/6
|Received:||9 December 2011|
|Accepted:||10 April 2012|
|Published:||10 April 2012|
© 2012 Dufault et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The number of children ages 6 to 21 in the United States receiving special education services under the autism disability category increased 91% between 2005 to 2010 while the number of children receiving special education services overall declined by 5%. The demand for special education services continues to rise in disability categories associated with pervasive developmental disorders. Neurodevelopment can be adversely impacted when gene expression is altered by dietary transcription factors, such as zinc insufficiency or deficiency, or by exposure to toxic substances found in our environment, such as mercury or organophosphate pesticides. Gene expression patterns differ geographically between populations and within populations. Gene variants of paraoxonase-1 are associated with autism in North America, but not in Italy, indicating regional specificity in gene-environment interactions. In the current review, we utilize a novel macroepigenetic approach to compare variations in diet and toxic substance exposure between these two geographical populations to determine the likely factors responsible for the autism epidemic in the United States.
Autism; DNA methylation; Environmental epigenetics; Heavy metals; HFCS; PON1; SAM; Zn
Introduction to macroepigenetics with autism as a case study
Autism is a developmental disorder defined by the American Psychiatric Association (APA) in the Diagnostic and Statistical Manual of Mental Disorders (DSM). The condition is considered a pervasive developmental disorder (PDD) that appears in the first three years of life and affects brain development impacting social and communication skills. Autism is defined by a common set of behaviors, including, but not limited to, observed deficits in nonverbal and verbal communication, lack of social reciprocity, and failure to develop and maintain appropriate peer relationships . Recent estimates suggest that 31% of children with Autism Spectrum Disorder (ASD) also meet diagnostic criteria for Attention-Deficit/Hyperactivity Disorder (ADHD) and another 24% of children with ASD exhibit sub-threshold clinical symptoms for ADHD . The number of children affected by this debilitating disorder remains unknown. As part of this review, we analyze the current United States (U. S.) Department of Education Special Education data to estimate the increase in autism prevalence from 2005 to 2010.
The cause(s) of autism also remain(s) unknown. D’Amelio et al. found paraoxonase-1 (PON1) gene variants associated with autism in subgroups of the U. S. population but not in Italy . They attributed the gene variation to greater household use of organophosphate (OP) pesticides in the U.S. compared to Italy. We think a more plausible explanation may lie in the U. S. food supply. As part of this investigation, we also reviewed and analyzed the U.S. Department of Agriculture (USDA) Food Availability Spreadsheets to identify which foods are most frequently consumed by Americans and of those which most frequently contain OP pesticide residue as reported by the U.S. Pesticide Data Program.
During this investigation, we conducted a literature review of all studies published on autism since we published our first Mercury Toxicity Model , which explains how mercury exposure, nutritional deficiencies and metabolic disruptions contribute to the development of autism. We evaluated all of the relevant studies and expanded our Mercury Toxicity Model. We then used the expanded model to compare the U.S. and Italian populations to determine what, if any, factors could explain the difference in PON1 gene variation and autism prevalence between the two countries. We propose the term “macroepigenetics” to describe the process of examining food supplies and their impact on body metabolism and gene function along with what is known about environmental exposures across populations.
In studying the larger factors outside the gene and human body that impact gene expression, we can better explain some of the gene-environment interactions that create disease conditions such as autism. There is agreement among many in the psychiatry profession that gene-environment interaction research is essential to understanding the etiology of autism and the other pervasive developmental disorders found in the ASD category . How the scientific community arrives at this understanding is key to solving the problem of rising autism prevalence. By demonstrating the macroepigenetic approach to determine the factors likely responsible for the autism prevalence in the U.S., we hope more scientists will follow our interdisciplinary lead and use macroepigenetics as a research strategy.
Current U. S. autism prevalence and special education trends
Before the 1980s the prevalence of autism in the U. S. was about 0.05% . In 2006, the Center for Disease Control and Prevention (CDC) reported that the estimated prevalence of autism had increased to between 0.6 and 0.7% of all children . Many scientists and parents believe the autism prevalence rate in the U.S. is much higher than these CDC statistics indicate. U.S. government scientists and collaborators published an article in 2007 indicating that 1.1% of U.S. children aged 3 to 17 years were currently diagnosed with ASD .
Special education data have been used in the past to estimate autism prevalence trends in the U.S. . In birth cohorts from 1975 to 1995, increases in autism were greatest for annual cohorts born from 1987 to 1992 . From 1992 to 1995, the autism prevalence increased with each successive year but the increases did not appear as great . Our review of the current special education data indicates the number of children ages 6 to 21 receiving special education services under the Autism category has increased 91% from 2005 to 2010. The number of children in the Developmental Delay category has increased 38% and the number of children receiving special education and related services under the Other Health Impaired (OHI) category has increased 26% from 2005 to 2010. Children with a diagnosis of ADHD are included in the OHI category. These increases are startling given that the overall number of children receiving special education services decreased by 5% from 2005 to 2010. Table 1 provides a graphical representation of the data obtained from the Data Accountability Center and analyzed during this review .
Table 1. Number of U.S. students ages 6 to 21 receiving special education services by disability category and year
Data from the 1997 to 2008 National Health Interview Surveys conducted by the CDC confirm these findings of increasing prevalence in autism and developmental disabilities associated with or sharing the diagnostic criteria for autism . Regardless of the source of data it seems clear that autism prevalence is rising in the U.S. compared to other countries, such as Italy, where the autism prevalence in the general population is estimated at only 0.1% . Because autism prevalence rates vary by country, population and geographic location, it is becoming more evident that gene-environment interactions are at play with dietary factors. The influence of environment factors on gene expression is primarily mediated by epigenetic mechanisms, including deoxyribonucleic acid (DNA) methylation along with methylation, acetylation, ubiquitination and phosphorylation of histones. Epigenetic regulation is particularly important during neurodevelopment .
A macroepigenetic model to explain gene-environment interactions in autism
In public health, epidemiology arguably has led the way in researching gene-environment interactions by studying how genotypes, environmental exposures and disorder outcomes occur in the human population . However, this epidemiological approach has often resulted in contradictory scientific conclusions when its practitioners do not consider the dietary factors that interact and modulate the molecular and genetic mechanisms underlying human metabolism and brain function . This has been the case despite the existence of literature from the field of “nutrigenomics”, which has specifically studied the effects of food and food ingredients on gene expression. In identifying the public health and the social and/or environmental determinants of disease, it seems invalid to study epidemiology without nutrigenomics, or vice versa. In other words, a more macro-level approach to unraveling the full range of environmental and genetic factors contributing to these kinds of neurological disorders ought to include nutrition factors as a component of the environment. By combining information derived from both nutrigenomic and epidemiology studies, a macroepigenetic model has already been developed to explain some of the gene-environment interactions with dietary factors that lead to the development of autism and ADHD .
Figure 1 shows the Mercury Toxicity model that provides a macroepigenetic explanation of how human neurodevelopment can be adversely impacted when gene expression is altered by dietary transcription factors such as zinc insufficiency or deficiency, or by exposure to toxic substances found in our environment, such as the heavy metals mercury and copper . Elimination of heavy metals requires the expression of the metallothionein (MT) gene, which synthesizes the Zn-dependent metal binding protein metallothionein . With dietary zinc (Zn) loss and copper (Cu) gain from the consumption of high fructose corn syrup (HFCS) , metabolic processes required to eliminate heavy metals are impaired in children with autism . Mercury has been found in samples of high fructose corn syrup and is allowable in trace amounts in certain food colors so long as the concentration does not exceed one part per million [17,18]. Mercury (Hg) and specific other heavy metals, including lead (Pb), copper (Cu), cadmium (Cd), silver (Ag) and bismuth (Bi), are capable of displacing the Zn atom in the MT protein molecule . This ‘pathogenic’ displacement of Zn impairs the MT molecule and its ability to pick up the heavy metal and carry it out of the body. If the diet is deficient in Zn or the absorption of Zn is impaired, then the body may not produce enough MT protein to carry and excrete the heavy metal load [19,20]. Children with autism may be Zn deficient and often have MT dysfunction [21–23]. Because of their diminished capacity to excrete toxic heavy metals, the severity of their condition is associated with their toxic metal burden . This macroepigenetic model proposes that autism prevalence is related to the consumption of HFCS and the overall exposure to Hg in the U.S. . However, other dietary factors associated with the consumption of HFCS may further contribute to the development of autism in the U.S.
Figure 1. The original Mercury Toxicity Model. The original Mercury Toxicity Model was published in 2009 by Dufault et al. in the Behavioral and Brain Functions journal. The model is a flow chart of what can happen in the body when there is exposure to mercury (Hg) from ingestion of foods (via HFCS, food colors and fish) or inhalation of air. Human neurodevelopment can be adversely impacted when MT gene expression is altered or suppressed by dietary transcription factors such as zinc (Zn) insufficiency or deficiency. Without proper MT expression and function, mercury excretion may not be possible and oxidative stress in the brain from mercury insult leads to reduced neuronal plasticity and impaired learning. Hg in fish is a problem when there is not enough selenium (Se) in the fish to counteract the Hg and the glutathione (GSH) system is disrupted leading to further oxidative stress.
Additional dietary factors associated with consumption of HFCS
U.S. per capita consumption of HFCS in 2009 was 35.7 pounds per year . The peak years for annual consumption of HFCS coincided with the peak growth rates of ASD in California, the only state that reports number of cases of ASD dating back to the mid-1980s . The Mercury Toxicity Model shows the HFCS characteristics most likely contributing to autism include the zinc-depleting effect that comes from consuming HFCS and certain food colors found in processed foods, and the additional Hg exposure that may occur from the low Hg concentrations sometimes found in HFCS as a result of the manufacturing process [4,17]. This model can be expanded to include additional adverse effects associated with the consumption of HFCS that likely contribute to the development of autism through PON1 gene modulation and lead intoxication.
U.S. Department of Agriculture (USDA) scientists warn that when dietary intake of magnesium (Mg) is low, consumption of HFCS leads to lower calcium (Ca) and phosphorus (P) balances adversely affecting macromineral homeostasis in humans . This is an unfortunate finding because there is evidence to suggest that dietary intake of Mg is low among Americans, most of whom consume a high fructose diet. In 2003, CDC scientists reported that substantial numbers of U.S. adults fail to consume adequate Mg in their diets . Children with autism were found to have significantly lower plasma Mg concentrations than normal subjects . Adams et al. found significant reductions in red blood cell (RBC) Ca, serum and white blood cell (WBC) Mg and an increase in RBC copper in autistic children as compared to controls . Recently, USDA scientists reported that the National Health and Nutrition Examination Survey (NHANES) data for 2005 to 2006 indicate that overall, nearly one half of all individuals one year and over had inadequate intakes of dietary Mg . With a substantial number of Americans consuming inadequate amounts of dietary Mg along with HFCS diets, one may predict that substantial numbers of Americans are likely experiencing a calcium (Ca) deficit as well.
Insufficient intake of dietary Ca, Mg and Zn, or losses or displacement of any of these minerals from the consumption of HFCS, may further enhance the toxic effects of lead (Pb) on cognitive and behavioral development in children . A significant and independent inverse relationship between dietary Ca intake and blood Pb concentrations was found in 3,000 American children examined as part of NHANES II . Elevated blood Pb levels are indicative of Pb intoxication, which is found in some children diagnosed with autism and associated with the development of ADHD [33,34]. It may be that inadequate intake of Ca or Mg combined with a HFCS zinc-depleting diet increases the risk of developing autism and ADHD from Pb intoxication.
Inadequate intake of Ca or Mg may further contribute to these developmental disorders by impacting human serum paraoxonase-1 (PON1) gene expression. PON1 is a calcium dependent enzyme responsible for OP pesticide detoxification as well as hydrolysis of the thiolactone form of homocysteine [35,36]. PON1 is synthesized in the liver and secreted in blood where it is incorporated into high density lipoproteins (HDL). The availability and catalytic activity of PON1 are impaired in many children with ASD making them more susceptible to the toxic effects of OP pesticide residues which are most frequently found in grain [37,38]. Figure 2 shows the expanded Mercury Toxicity Model that includes changes both in Pb toxicity and PON1 activity when dietary intake of Mg is low and consumption of HFCS leads to greater loss of calcium (Ca) and phosphorus (P), thereby adversely affecting macromineral homeostasis.
Figure 2. The expanded Mercury Toxicity Model. Figure 2 shows the expanding Mercury Toxicity Model that includes changes both in lead (Pb) toxicity and human serum paraoxonase (PON1) activity when dietary intake of Mg is low and consumption of high fructose corn syrup (HFCS) leads to lower calcium (Ca) and phosphorus (P) balances, adversely affecting macromineral homeostasis. With insufficient dietary intake of Ca and/or Mg, children become more susceptible to Pb intoxication and OP exposures with decreasing PON1 activity. Pb intoxication and OP exposures can both lead to oxidative stress in the brain reducing neuronal plasticity.
PON1 activity and organophosphate exposure in U.S
One can assert that with the consumption of a HFCS intensive diet and inadequate Mg intakes, PON1 activity may decrease, along with resulting Ca losses in genetically predisposed individuals. Although there are no human data yet to support this assertion, PON1 activity in rats decreased when fed a HFCS diet to mimic the human metabolic syndrome . PON1 activity has been extensively studied in humans and there are a number of factors known to modulate or alter PON1 expression including, but not limited to, Hg exposure, sex and age [40,41]. Age plays the most relevant role, as PON1 activity is very low before birth and gradually increases during the first few years of life in humans . In one study, scientists at UC Berkeley found the PON1 levels in many children may remain lower than those of their mothers for several years, especially those with genotypes associated with decreased PON1 activities . The scientists concluded that these children may be more susceptible to OP pesticides throughout their childhood and more vulnerable to conditions associated with oxidative stress such as autism . In a different study, scientists at UC Berkeley found that two-year-old children were less likely to display symptoms of PDD when their mothers had higher paraoxonase levels during their pregnancy . Proper function and adequate expression of the PON1 gene is essential both for prenatal development and child health because exposure to OP pesticides is a common occurrence in the U.S.
The CDC tracks exposure to OP pesticides or their metabolites through the National Biomonitoring Program (NBP). Exposure data are reported for the population as a whole and for subgroups. While most American groups are exposed to OP pesticides, children ages 6 to 11 have significantly higher exposures than adults and are at greatest risk from OP neurotoxicity . Harvard University researchers recently reported finding OP pesticide residues in a number of foods frequently consumed by children . The researchers expressed concern that the children were at times being exposed to multiple pesticide residues in single food commodities. OP pesticide exposures occur primarily from the consumption of foods containing pesticide residues.
It is well known that pesticide exposure can impair neurodevelopment in children, but recent studies have found that pesticide exposure during pregnancy can also cause delayed mental development in children . A review of epidemiological studies in 2008 found that prenatal and childhood exposure to OPs impairs neurobehavioral development . Higher concentrations of urinary dialkyl phosphate (DAP) measured during pregnancy was significantly associated with lower cognitive scores in children at seven years of age. Those children in the highest quintile of maternal DAP concentrations had an IQ score seven points lower than those children in the lowest quintile . In a group of newborns with the highest levels of the organophosphate chlorpyrifos measurable in their umbilical cord blood, birth weight averaged 150 grams less than the group with the lowest exposure . Prenatal pesticide exposure showed deficits consistent with developmental delays of 1.5 to 2 years .
Diet is the main source of OP exposure in children. Under the 1996 Food Quality Protection Act, the U.S. Secretary of Agriculture is directed to collect pesticide residue data on commodities frequently consumed by infants and children. USDA Pesticide Data Program (PDP) provides the residue data to comply with this law . We reviewed the PDP data from 2004 to 2008 and identified the foods most frequently found to contain organophosphate insecticide residues. In addition, we obtained the per capita availability data from the USDA to determine the amount of each food commodity the average American consumes . The results of our review indicate that wheat and corn are the commodities most likely contributing to OP exposure in U. S. children. Estimated per capita wheat consumption was approximately 95 pounds per year while estimated per capita corn consumption was approximately 23 pounds per year. The primary use of corn is for the production of corn sweeteners, such as HFCS; however, pesticide residue data were not gathered for this commodity by the PDP. Table 2 provides a complete breakdown of the results of this data review.
Table 2. PDP residue detections by year sampled wi th U.S. per capita consumption data
From Table 2 it is clear consumers are at risk of exposure to multiple OP pesticide residues from consuming the very same commodity. Cumulative exposures will continue to occur in the U.S. where OP pesticide use is widespread by the agricultural industry. Although OP pesticide use is equally widespread in other countries, there is genetic variation across populations that determine degree of susceptibility to OP exposure. The PON1 gene variants associated with autism in subgroups of the U.S. population but not in Italy could be attributed to the fact that HFCS consumption rarely occurs in Italy, thereby lessening the conditions for PON1 modulation.
HFCS consumption and PON1 modulation in autism in the U.S
In the 27-member European Union (EU), of which Italy is an original participant, HFCS is known as “isoglucose” and currently it is rarely consumed by Italians. Americans on the other hand consume on average 35.7 pounds per year, which may increase their overall Hg exposure [17,25]. Figure 3 shows U.S. per capita food consumption in pounds per year for HFCS beginning in the early 1970s and increasing throughout the 1980s to reach a peak between 1999 and 2002. In our previous publication, we reported the peak years for annual consumption of HFCS in the U.S. occurred within the same period as when the annual growth rates of autism peaked in California .
Figure 3. U.S. per capita consumption of high fructose corn syrup 1966-2004. Figure 3 shows the United States (US) per capita consumption of high fructose corn syrup (HFCS) in pounds per year as calculated by the United States Department of Agriculture (USDA)/Economic Research Service.
American per capita consumption of HFCS has exceeded 20 pounds per year since 1980 while Italians consume negligible amounts of the same ingredient. As was previously mentioned, mercury (Hg) and fructose may both modulate PON1 activity [39–41]. While excessive fructose exposure in the U.S. may primarily occur through the consumption of foods containing HFCS, mercury exposure may occur in a number of ways. A comparison of common sources of mercury exposure in the U.S. and Italy may offer a further explanation of the PON1 gene variation associated with autism in the U.S. but not in Italy.
In addition to HFCS, primary sources of inorganic and elemental Hg exposure may occur from consumption of food colors and preservatives made with mercury-cell chlorine or chlor-alkali products, seafood consumption, Hg in dental amalgam, thimerosal in vaccines, and depending on geographic location, inhalation of Hg contaminated air [4,51–54]. Children living near coal-fired power plants are often exposed to higher levels of Hg in their breathing air and have a higher prevalence of autism . Because Hg emissions from coal-fired power plants are not yet regulated in either the U.S. or Italy, this particular source of Hg exposure is unlikely to explain the overall difference in autism prevalence between these two countries. With respect to the consumption of seafood, use of Hg dental amalgam, thimerosal in vaccines or Hg-containing food colors and preservatives, there is also no appreciable difference between Italy and the U.S. [56–58]. The only remaining variable in our model is the excessive consumption of HFCS by Americans, which results in greater chronic exposures to both inorganic Hg and, by definition, fructose .
Inorganic Hg may interact with cysteine residues on PON1 preventing its activation in the liver and impairing the body’s ability to protect itself against OP pesticides and oxidative stressors involved in autism . As noted above, PON1 is responsible for hydrolysis of homocysteine thiolactone, and plasma PON1 activity is negatively correlated with homocysteine levels [36,59]. Homocysteine is a metabolic biomarker for oxidative stress and impaired methylation capacity. A recent study of the Inuit population found a significant inverse correlation between PON1 activity and Hg levels, as well as a direct correlation with selenium levels . With increasing Hg and fructose exposure and reductions in dietary Ca, one can expect to see reduced PON1 activity and increasing homocysteine levels in children with ASD.
Indeed, Pasca et al. recently reported finding that both PON1 arylesterase and PON1 paraoxonase activities were decreased in children with autism [61,62]. James et al. found that children with autism had higher plasma homocysteine levels than controls but demonstrated significant improvements in transmethylation metabolites and glutathione (GSH) after receiving folate and vitamin B12 . Patel and Curtis found that in addition to glutathione and B12 injections one to three times per week, children with autism and ADHD showed significant improvement in many areas of social interaction, concentration, writing, language and behavior when fed an organic diet low in fructose and free of food additives and food colors .
Mothers of autistic children in the U.S. were also found to have significant increases in mean plasma homocysteine levels compared to controls . Schmidt et al. found that women who took vitamin supplements during the periconceptional period reduced the risk of autism in their children . Those women who did not take vitamins during this period were more likely to have a child with autism and were at even greater risk when they had specific genetic variants within one-carbon metabolism pathways. This suggests that folate and other dietary methyl donors may alter epigenetic regulation of gene expression in their children, thereby reducing the risk of autism .
Methionine synthase links oxidation to epigenetics
Epigenetic regulation of gene expression is highly dependent upon methylation of both DNA and histones, and methylation capacity is in turn dependent upon activity of the folate and vitamin B12-dependent enzyme methionine synthase, which converts homocysteine to methionine. Lower methionine synthase activity decreases the level of the methyl donor S-adenosylmethionine (SAM) while simultaneously increasing the level of the methylation inhibitor S-adenosylhomocysteine (SAH) . The combined effect of changes in the SAM to SAH ratio, therefore, exerts a powerful influence over more than 200 methylation reactions, including DNA and histone methylation .
Methionine synthase activity is inhibited by oxidative stress, and its inhibition results in the diversion of homocysteine to produce the antioxidant glutathione (GSH), providing an important adaptive response . However, oxidative inhibition of methionine synthase leads to epigenetic effects via the resultant decrease in the SAM to SAH ratio and decreased DNA and histone methylation. Epigenetic changes in gene expression can recruit further adaptive responses to oxidative stress. Figure 4 illustrates how these changes may occur when the body is under oxidative stress from exposure to OP pesticides, heavy metals, and calcium depleting substances, such as HFCS. Decreased methionine synthase activity during oxidative stress also increases homocysteine thiolactone formation , raising the importance of PON1. As was previously mentioned, PON1 is essential for reducing homocysteine levels, which are thought to be harmful. Elevated plasma homocysteine (tHcy) levels are associated with genome-wide DNA hypomethylation that may carry over from one generation to the next, increasing the risk of autism . Epigenetic changes affecting germline cells can give rise to these transgenerational effects . James et al. found that parents share similar metabolic deficits in methylation capacity and glutathione-dependent antioxidant/detoxification capacity with their children with autism .
Figure 4. Methionine synthase links oxidative stress to epigenetic regulation. Figure 4 shows how exposure to toxic substances, such as OP pesticides, HFCS, or heavy metals, inhibits methionine synthase through effects of oxidative stress. As a result, decrease of SAM to SAH ratio will lead to a decrease in DNA methylation and consequently to altered PON1 gene expression.
Synergistic effect of multiple neurotoxins
Based upon the discussion above, it is clear that methionine synthase activity is crucial for translating changes in oxidative status into epigenetic effects, and this role is confirmed by the improved metabolic profile in autistic subjects given folate and vitamin B12 . This relationship has given rise to the “Redox/Methylation Hypothesis of Autism”, which proposed that oxidative insults arising from environmental exposures, such as Hg and pesticides, can cause neurodevelopmental disorders by disrupting epigenetic regulation . The macroepigenetic Mercury Toxicity Model expanded in this paper provides additional support for the “Redox/Methylation Hypothesis of Autism” while contributing important insight into the oxidative stress feedback mechanisms that may occur as a result of malnutrition resulting from dietary exposures to toxins. The delivery of children exhibiting autistic behaviors might be associated with the prenatal diet of their mothers. The severity of these behaviors can be further exacerbated by toxic dietary exposures of the children, which can improve with dietary changes aimed at eliminating these exposures. Children with autism could well be exhibiting an epigenetic response to several neurotoxic substances at once, including, but not limited to, inorganic Hg, Pb, OP pesticides and/or HFCS. The combined effect of these substances acting together is likely greater than the sum of the effects of the substances acting by themselves. This effect likely reduces neuronal plasticity and impairs learning capacity in autistic children.
The number of children ages 6 to 21 in the U.S. receiving special education services under the autism disability category increased 91% between 2005 to 2010 despite fewer children receiving special education services overall during the same time period. A comparison of autism prevalence between the U.S. and Italy using the Mercury Toxicity Model suggests the increase in autism in the U.S. is not related to mercury exposure from fish, coal-fired power plants, thimerosal, or dental amalgam but instead to the consumption of HFCS. Consumption of HFCS may lead to mineral imbalances, including Zn, Ca and P loss and Cu gain and is a potential source of inorganic mercury exposure. These mineral imbalances create multiple pathways for oxidative stress in the brain from exposure to OP pesticides and heavy metals, such as Pb or Hg. Inorganic mercury and fructose exposure from HFCS consumption may both modulate PON1 gene expression. With a reduction in PON1 activity, there is a potential for increasing homocysteine levels which are associated with genome-wide DNA hypomethylation that may carry over from one generation to the next, affecting both neurodevelopment and autism prevalence.
ADHD: Attention-Deficit-Hyperactivity-Disorder; Ag: Silver; APA: American Psychiatric Association; ASD: Autism Spectrum Disorder; Bi: Bismuth; Ca: Calcium; Cd: Cadmium; CDC: Center for Disease Control and Prevention; Cu: Copper; DAP: Dialkyl phosphate; DSM: Diagnostic and Statistical Manual of Mental Disorders; EU: European Union; GSH: Glutathione; HDL: High density lipoprotein; HFCS: High fructose corn syrup; Hg: Mercury; Mg: Magnesium; MT: Metallothionein; NBP: National Biomonitoring Program; NHANES: National Health and Nutrition Examination Survey; OHI: Other Health Impaired; OP: organophosphate pesticide; P: phosphorus; Pb: lead; PDD: Pervasive Developmental Delay; PDP: Pesticide Data Program; PON1: paraoxonase-1; RBC: red blood cell; SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; tHcy: total plasma homocysteine; USDA: United States Department of Agriculture; WBC: White blood cell; Zn: Zinc.
RDeth has in the past received compensation as an expert witness on the topic of autism. All of the other authors declare that they have no competing interests.
RDufault spearheaded the review and recruited interdisciplinary collaborators to contribute to the development of the manuscript. RDufault was the lead investigator and literature reviewer for the expansion of the mercury toxicity model. RDufault acquired, analyzed and interpreted the new data sets. WJL, RS and RDeth helped revise the manuscript critically for important intellectual content. RDeth provided Figure 4 and was the primary author of the methionine synthase section. All authors read and approved the final manuscript. RS validated all of the references. RC validated the data in Table 1 to ensure it was correctly gathered from existing data bases. RC also double checked the calculations in Table 1 to ensure they were error free. DW helped draft and edit the manuscript.
Lead author’s information
After retiring with honors from her position as an environmental health officer with the U.S. Public Health Service, R. Dufault obtained her teaching license and taught elementary special education for 3.5 years at which time she gained an understanding of how children with autism and ADHD in the U.S. receive special education services. As a volunteer, she currently teaches an epigenetics course on-line through the Food Ingredient and Health Research Institute.
The authors would like to thank Drs. Robert Lustig, Blaise LeBlanc and Steven Gilbert for the feedback each provided on this manuscript and/or the concepts therein. Funding for this research project was provided primarily by donations to the Food Ingredient and Health Research Institute. Research in the Lukiw laboratory is supported through Grant Number P20RR016456 from the National Center for Research Resources, a Translational Research Initiative Grant from LSU Health Sciences Center New Orleans, an Alzheimer Association Investigator-Initiated Research Grant IIRG-09-131729, and NIH NIA Grants AG18031 and AG038834.
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