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ASPartOfMe
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15 Jul 2021, 8:26 am

The potential role of genetic and environmental interaction in autism spectrum disorder

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Researchers at Johns Hopkins Bloomberg School of Public Health have shown in a brain organoid study that exposure to a common pesticide synergizes with a frequent autism-linked gene mutation.

The results represent one of the clearest pieces of evidence yet that genetic and environmental factors may be that genetic and environmental factors may be able to combine to disturb neurodevelopment.

The brain organoid model, developed by the Bloomberg School researchers, consists of balls of cells that are differentiated from human stem cell cultures and mimic the developing human brain. The researchers found in the study that chlorpyrifos, a common pesticide alleged to contribute to developmental neurotoxicity and autism risk, dramatically reduces levels of the protein CHD8 in the organoids. CHD8 is a regulator of gene activity important in brain development. Mutations in its gene, which reduce CHD8 activity, are among the strongest of the 100-plus genetic risk factors for autism that have so far been identified.

The study, which appears online July 14 in Environmental Health Perspectives, is the first to show in a human model that an environmental risk factor can amplify the effect of genetic risk factor for autism.

How environmental factors and genetic susceptibilities interact to increase risk for autism spectrum disorder remains mostly unknown, in part because these interactions have been difficult to study. Traditional experiments with laboratory animals are expensive and, especially for disorders involving the brain and cognition, of limited relevance to humans.

Advances in stem cell methods in the past decades have allowed researchers to use human skin cells that can be transformed first into stem cells and then into almost any cell type and studied in the lab. In recent years, scientists have expanded beyond simple lab-dish cell cultures to make cultures of three-dimensional organoids that better represent the complexity of human organs.

For their study, the researchers used brain organoids to model the effects of a CHD8 gene disruption combined with exposure to chlorpyrifos. A group led by co-author Herbert Lachman, MD, professor at Albert Einstein College of Medicine, engineered the cells that make up the organoids to lack one of the two normal copies of the CHD8 gene. This modeled a substantial, but less-than-total, weakening of the CHD8 gene's activity, similar to that seen in people who have CHD8 mutations and autism. The researchers then examined the additional effect of exposure to chlorpyrifos, which is still widely used on agricultural produce in the U.S. and abroad.

"High-dose, short-term experimental exposures do not reflect the real-life situation, but they give us a starting point to identify genetic variants that might make individuals more susceptible to toxicants," says Smirnova.

The researchers found that the brain organoids with just one copy of the CHD8 gene had only two-thirds the normal level of CHD8 protein in their cells, but that chlorpyrifos exposure drove CHD8 levels much lower, turning a moderate scarcity into a severe one.


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Fnord
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15 Jul 2021, 8:31 am

"... a common pesticide synergizes with a frequent autism-linked gene mutation."

One should be cautious; this is only one study on one specific pesticide and one specific mutation.  Further studies are needed to provide validity to the original study's conclusions.

However, it should not be surprising if this turns out to be true.


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ASPartOfMe
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15 Jul 2021, 9:27 am

Fnord wrote:
"... a common pesticide synergizes with a frequent autism-linked gene mutation."

One should be cautious; this is only one study on one specific pesticide and one specific mutation.  Further studies are needed to provide validity to the original study's conclusions.

However, it should not be surprising if this turns out to be true.

Agreed


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Professionally Identified and joined WP August 26, 2013
DSM 5: Autism Spectrum Disorder, DSM IV: Aspergers Moderate Severity

“My autism is not a superpower. It also isn’t some kind of god-forsaken, endless fountain of suffering inflicted on my family. It’s just part of who I am as a person”. - Sara Luterman