Study shows environmental influences may cause autism in some cases

May 29, 2014, Albert Einstein College of Medicine
Quinn, an autistic boy, and the line of toys he made before falling asleep. Repeatedly stacking or lining up objects is a behavior commonly associated with autism. Credit: Wikipedia.

Research by scientists at Albert Einstein College of Medicine of Yeshiva University may help explain how some cases of autism spectrum disorder (ASD) can result from environmental influences rather than gene mutations. The findings, published online today in PLOS Genetics, shed light on why older mothers are at increased risk for having children with ASD and could pave the way for more research into the role of environment on ASD.

The U.S. Centers for Disease Control and Prevention announced in March that one in 68 U.S. has an ASD—a 30 percent rise from 1 in 88 two years ago. A significant number of people with an ASD have gene mutations that are responsible for their condition. But a number of studies—particularly those involving identical twins, in which one twin has ASD and the other does not—show that not all ASD cases arise from mutations.

In fact, a major study of more than 14,000 children with ASDs published earlier this month in the Journal of the American Medical Association concluded that gene abnormalities could explain only half the risk for developing ASD. The other half of the risk was attributable to "nongenetic influences," meaning environmental factors that could include the conditions in the womb or a pregnant woman's stress level or diet.

Media reports on the causes of ASD have focused on the fact that older fathers (40 and over) are more likely than younger fathers to have children with an ASD, probably because of gene mutations that accumulate over the years in sperm-making . Yet older mothers (35 and over) face a similar risk that is entirely independent of their partners' age. But for older mothers, scientists know very little about why this risk exists. The Einstein researchers looked for genetic as well as environmental influences that might account for older mothers' increased risk for having children with ASD.

Their study, led by Esther Berko, an M.D./Ph.D. student in the lab of John Greally, M.B., B.Ch., Ph.D., involved 47 children with ASD and 48 typically developing (TD) children of women 35 and over. Unlike other ASD studies, this one included a significant number of minority children (Hispanic and African-American) from the Bronx. Brain cells––the obvious cells to examine for evidence of genetic and environmental differences between ASD and TD children—obviously could not be used. Instead, the researchers realized that if such differences existed, they should also occur in a readily available type of cell: the buccal epithelial cells that line the cheek.

"We hypothesized that whatever influences lead to ASD in children of older women probably are already present in the reproductive cells that produce the embryo or during the very earliest stages of embryonic development—in cells that give rise to both the buccal epithelium and the brain," said Dr. Greally, the study's senior author. "This would mean that whatever abnormalities we found in the cheek cells of children with an ASD versus TD children should exist in their brain cells as well." Dr. Greally is professor of genetics, of medicine and of pediatrics, director of the Center for Epigenomics and the Ruth L. and David S. Gottesman Faculty Scholar for Epigenomics at Einstein and attending physician, pediatrics at The Children's Hospital at Montefiore.

Small brushes were used to painlessly harvest cheek cells from children with an ASD and TD children living in the Bronx and throughout the U.S., as well as in Chile and Israel. Since the eggs of older mothers are prone to having abnormal numbers of chromosomes, the researchers first analyzed the cells for abnormal chromosome numbers as well as other chromosomal defects that might account for ASD. No such problems were found in the cells of ASD or TD children.

The researchers next examined the children's cells for evidence of environmental effects.

"If environmental influences were exerted during embryonic development, they would encode a "memory" in cells that we can detect as chemical alterations of genes," said Dr. Greally. "Most of these so-called epigenetic alterations are in the form of that chemically bind to DNA. Such methyl groups are vital for controlling gene activity, but changes in methylation patterns can dysregulate cell function by altering gene expression or by silencing genes entirely."

Dr. Greally and his colleagues carried out several types of genome-wide methylation analyses on the cheek cells of the ASD and TD children, looking for epigenomic differences that would suggest environmental influences at work. (Just as "genome" is defined as the genetic material of an organism, "epigenome" includes the patterns of methyl groups that have attached to an organism's entire genome.)

This was the largest epigenome-wide association study of ASD to date involving a single pure cell type. Using just one cell type—epithelial cheek cells in this case—helps prevent misleading results that can occur when epigenomic studies combine several different subpopulations of cells. "We were extremely careful in how we conducted this study, to ensure that whatever we found was as scientifically valid as possible," said Dr. Greally.

The researchers detected two groups of genes that were epigenetically distinctive in children with ASD compared with TD children. Moreover, these genes are known to be expressed in the brain and code for proteins involved in nerve transmission functions previously shown to be impaired in ASD. (Interestingly, these two groups of epigenetically distinctive genes weren't present in all the cells of children with ASD but only in a subset of them—a phenomenon called mosaicism.) In addition, these two gene groups tended to interact with genes already known to be mutated in individuals with ASD.

"Genes interact with each other to create molecular pathways that carry out important functions," said Dr. Greally. "Our findings suggest that, at least in some individuals with an ASD, the same pathways in the brain seem to hit by both mutations and epigenetic changes. So the severity of someone's ASD may depend on whether or not a is accompanied by epigenetic alterations to related genes."

Are environmental influences responsible for the epigenetic changes that dysregulate these genes? "We were able to eliminate some other possible causes of ASD such as chromosomal abnormalities, so our findings are consistent with that notion," said Dr. Greally. "In the case of at risk for having children with ASDs, one possible environmental influence might the aging process itself, which could disturb epigenetic patterns in their eggs, but there are other possibilities as well. Although much more work is needed, our study reveals a plausible way that —which we know are important in ASD—might be exerting their effects."

Explore further: Can chemicals produced by gut microbiota affect children with autism?

More information: The study is titled "Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder."

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1 / 5 (3) May 29, 2014
"Genes interact with each other to create molecular pathways that carry out important functions," said Dr. Greally. "Our findings suggest that, at least in some individuals with an ASD, the same pathways in the brain seem to hit by both mutations and epigenetic changes. So the severity of someone's ASD may depend on whether or not a gene mutation is accompanied by epigenetic alterations to related genes."

I've been wondering how serious scientists were going to portray the change from mutations and natural selection to ecological variation and ecological adaptations that sometimes fail due to the epigenetic effects of nutrient stress and social stress on cell type differentiation, which result from changes in the microRNA/messenger RNA balance.

The theorists have forced their pseudoscientific nonsense on us all for so long that even the serious scientists must tread lightly or risk repercussions from those who know nothing about conserved molecular mechanisms.
1 / 5 (3) May 29, 2014

Article excerpt: "OR2L13 has been found in two previous studies to demonstrate either altered DNA methylation in blood [9] or gene expression in brain [32] in individuals with ASD."

My comment: It's an olfactory receptor (OR), which means it can link the epigenetic landscape to the physical landscape of DNA in the organized genome as ORs do in every other species of invertebrate and vertebrate. That means it also links nutrient-stress and social stress to their epigenetic effects on prenatal and postnatal brain development via changes in the microRNA/messenger RNA balance that alter cell type differentiation from fertilization forward. There's a model for that!
The model links the conserved molecular mechanisms of cell type differentiation in species from microbes to man to morphological and behavioral phenotypes that include a link from OR2L13 to at least one amino acid substitution and at least one ectodermal receptor in the brain.
Fabio P_
5 / 5 (2) May 30, 2014
@JVK, you really have a one-track mind, don't you?
1 / 5 (3) May 30, 2014
Yes, thanks for asking. My focus has been on olfaction and olfactory receptors for more than 30 years, and that led to this conclusion (from my 2012 review)

"Socioaffective neuroscience and psychology may progress more quickly by keeping these apparent facts in mind: Olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans (Keller et al., 2007; Kohl, 2007; Villarreal, 2009; Vosshall, Wong, & Axel, 2000)."

Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors. http://www.ncbi.n...24693349

When I see an article that clearly links an olfactory receptor gene to ASDs, I cannot help but bring what is currently known about biophysically constrained cause and effect to the attention of others who are still trying to link mutations and natural selection to ASDs.

See also our 1996 review: http://www.ncbi.n.../9047261
1 / 5 (3) May 30, 2014
Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
Links nutrient-dependent DNA methylation to the de novo Creation of an olfactory receptor gene and sex differences in ASDs via epigenetic effects of food odors and pheromones on transgenerational epigenetic inheritance of ecological factors that distinguish the differentiation cell types. Controlled differentiation of cell types distinguishes epigenetically-effected dysregulation from mutations. The dysregulation occurs at the level of GnRH, not serotonin and oxytocin, which feedback on the GnRH neuronal system during prenatal and postnatal brain development.

That was a response to posting of "Switching brain serotonin with oxytocin" http://www.pnas.o...tml?etoc to the ISHE's human ethology group.

The moderator, best described as a bird-watcher -- edited out my content and left only the link to the article.
Fabio P_
5 / 5 (2) May 30, 2014
If you have to resort to advertising your research in the comment section of, that probably says something about the quality of your research in the first place? A search on PubMed and Web of Science only yields a handful of hits. Most of them are either as sole author or in conference proceedings. Care to share a full list of publications? At what institution are you employed?
1 / 5 (3) May 30, 2014
If you must resort to anonymous attacks on my credibility after noting that I have a series of published works that back up my claims, you should share your full list of publications and tell us where you are employed.

The issue is not my credibility, but one that involves academic suppression of accurate information about biophysically-constrained cause and effect that we attributed to alternative splicings of pre-mRNA in our 1996 review (in a section on molecular epigenetics).

The fact that Jay R. Feierman continues to attempt suppression of this information more than 18 years after we published with his uncle: Milton Diamond, is one that should be noted by those interested in autism research -- if only due to Diamond's reputation.

From Fertilization to Adult Sexual Behavior http://www.hawaii...ion.html

"Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA..."
1 / 5 (3) May 30, 2014
More advertising??

Nutrient-dependent/pheromone-controlled adaptive evolution: a model.

"Should we anticipate a problem with brain-directed social behavior in children of mother's who adopt the new dietary choline recommendation? Could additional choline epigenetically alter brain development and cause too much prenatal synaptogenesis, too little synaptolysis, or altered apoptosis? Could sex differences in the mother–infant bond which are correlated with nutrient intake and pheromone production (Nguyen, Gesquiere, Alberts, & Altmann, 2012) and with oxytocin secretion (Donaldson & Young, 2008) be altered by a child whose mother ingested too much choline?"

"What if maternal choline intake causes prenatal and postnatal variations in myelination and neurotransmission associated with brain imagery in autism spectrum disorders? What if choline interacts with glucose and lipid metabolism to cause neurodegenerative diseases later in life..."
Fabio P_
5 / 5 (2) May 30, 2014
I think I asked very simple and legitimate questions. Where are you employed, and where can I see a full list of publications. Pasting excerpts from papers in a rather incoherent fashion only makes you look a little desperate. And yes, your credibility is very much the issue. Crying academic suppression is usually a telltale sign of lack of credibility. Creationists and climate change deniers all do the very same thing.
1 / 5 (3) May 30, 2014
Internet trolls do exactly what you do. I am clearly identified as James V. Kohl, which means you can continue to attack my credibility, like anonymous fools and idiot minions who have been taught to believe in the pseudoscientific nonsense of invented theories have done during the past two decades.

Most of the idiot minions claim that anyone who doesn't believe what they do is a Creationist. However, they could simply read my published works to learn that Dobzhansky was a Creationist who also knew, albeit more than 50 years ago, that amino acid substitutions differentiate the cell types of different species. Thus, the only difference between him and today's Creationists is that they have learned more about biologically-based cause and effect as experimental evidence of it became readily available to serious scientists:

"...the only worthwhile biology is molecular biology. All else is "bird watching" or "butterfly collecting." http://icb.oxford...citation
1 / 5 (3) May 30, 2014
Others may want to discuss ASDs, rather than attack me. If so, here's a start:

A symbiotic liaison between the genetic and epigenetic code

Abstract excerpt: "...the model is further extendable to virtually all traceable molecular traits.

The extension of Laws of Biology to virtually all traceable molecular traits via nutrient-dependent pheromone-controlled ecological adaptations is made possible because gene duplication is epigenetically effected by nutrient uptake and pheromones control the physiology of reproduction.

However, social scientists continue to approach the epigenetic regulation and dysregulation of morphological and behavioral phenotypes in species from microbes to man as if mutations and natural selection were somehow involved in perturbed protein folding that they think somehow leads to increasing organismal complexity and also to ASDs.
1 / 5 (3) May 30, 2014
Titles of a few papers published by serious scientists during the past 3 months that attest to the accurate representations of cause and effect in my model.
Molecular mechanisms for the inheritance of acquired characteristics - exosomes, microRNA shuttling, fear and stress: Lamarck resurrected?
Transgenerational Epigenetic Inheritance: Myths and Mechanisms
Epigenetic control of mobile DNA as an interface between experience and genome change
Mapping posttranscriptional regulation of the human glycome uncovers microRNA defining the glycocode
Nuclear compartmentalization of odorant receptor genes
Postnatal Odorant Exposure Induces Peripheral Olfactory Plasticity at the Cellular Level
The Molecular and Systems Biology of Memory
Long term functional plasticity of sensory inputs mediated by olfactory learning
Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles
1 / 5 (3) May 30, 2014
Sex pheromone biosynthetic pathways are conserved between moths and the butterfly Bicyclus anynana

Hypothalamic response to the chemo-signal androstadienone in gender dysphoric children and adolescents

Chemosensory Communication of Gender through Two Human Steroids in a Sexually Dimorphic Manner

Odor Valence Linearly Modulates Attractiveness, but Not Age Assessment, of Invariant Facial Features in a Memory-Based Rating Task

Anyone willing to read any of these published works is welcome to attack me here, or elsewhere -- unless they are unable to provide experimental evidence of biologically based cause and effect to substantiate their attack. I'm tired of attacks by butterfly-collectors and bird-watchers who have also attacked others during the past 50 years (since Dobzhansky told everyone amino acid substitutions might be important to cell type differentiation).
Captain Stumpy
5 / 5 (1) Jun 02, 2014
I cannot help but bring what is currently known about biophysically constrained cause and effect to the attention of others who are still trying to link mutations and natural selection to ASDs
as if mutations and natural selection were somehow involved in perturbed protein folding that they think somehow leads to increasing organismal complexity and also to ASDs
lets examine your position here: In the past, I asked
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
(this is the DEFINITION of Mutation) to which you answered
--Thanks for asking
need the link again?
so we KNOW that your model creates mutations... and now you are here arguing that mutations are not possible and your "model" is the answer, which means that either you are severely mentally incapacitated or being blatantly stupid. who is the idiot minion troll here?
Captain Stumpy
5 / 5 (1) Jun 02, 2014
If you have to resort to advertising your research in the comment section of, that probably says something about the quality of your research in the first place? A search on PubMed and Web of Science only yields a handful of hits
@Fabio P_

jvk (to which I refer to as jk as it is more applicable to his status here) is the guy that sells that pheromone perfume
go to his site and you can find that he is a glorified lab tech selling perfume and trying to eradicate the use of the word mutation because he doesn't like it. Mostly it has to do with his definition of species... he definitely doesn't like single-mutation-speciation, but also doesn't know/comprehend that the lexicon of a field is used for clarity of communication, and doesn't comprehend his model creates mutations.
see also:http://freethough...s-place/

Myers denounces jk's stupidity
1 / 5 (2) Jun 02, 2014
Human pheromones: integrating neuroendocrinology and ethology

Won the same award that Jaak Panksepp's group won the following year for:

Comparative approaches in evolutionary psychology: molecular neuroscience meets the mind

Anyone attempting to denounce my stupidity is merely displaying their ignorance. PZ Myers and his idiot minions did this better than any group of people who have attacked me anywhere else. Myers then blocked my comments after labeling me a homophobe. My other award-winning publication was:

The Mind's Eyes: Human pheromones, neuroscience, and male sexual preferences

I used the same model (and examples) to explain the development of heterosexual and homosexual preferences.
not rated yet Jun 02, 2014
I have wondered for a while whether the increase in autism spectrum disorders has anything to do with with the increased acidity of the atmosphere. (Both from SOx and CO2.) I'm not a researcher, I'm a statistician by training, and now retired. The potential link to OR2L13 is interesting. I've only tried to look at the correlation between air pollution, increased CO2 levels and ASD. The problem of course is that geographical data is difficult to control for local trends in ASD diagnosis. And of course, the temporal increase in both ASD and global CO2 levels may be correlated, but that does not prove cause and effect.

I've also wondered about soot. In homes heated by wood burning, and in older polluted cities, there was plenty of soot in the environment. Some would have been ingested and could affect gut bacteria, but even more ends up in nasal passages. Lots of soot may be bad, while lower levels may be beneficial. Do you feel better after a camping trip? Hmmm.

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