Common pesticide may increase autism risk, researchers find

autism
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Exposure to a common pesticide has been linked to a frequent autism-associated gene mutation, new research has found.

In a study conducted by researchers at Johns Hopkins Bloomberg School of Public Health, evidence was found that genetic and environmental factors may be able to combine to disturb neurodevelopment.

The findings of the study have been published in Environmental Health Perspectives.

For a long while, it has been thought that a combination of genetic and environmental factors may contribute to an increased risk of developing autistic spectrum disorder – a developmental disorder characterised by cognitive function, social, and communication impairments.

The researchers created a brain organoid model consisting of balls of cells that are differentiated from human stem cell cultures and mimic the developing human brain. They discovered 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 is the first to demonstrate in a human model that an environmental risk factor can amplify the effect of genetic risk factors for autism.

Study lead Lena Smirnova, PhD, a research associate in the Department of Environmental Health and Engineering at the Bloomberg School, said: “This is a step forward in showing an interplay between genetics and environment and its potential role for autism spectrum disorder.”

Quicker and more cost-effective research

Evidence for how environmental factors and genetic susceptibilities interact to increase the risk of autism spectrum disorder has been difficult to examine, and therefore remains mostly unknown. One of the main reasons for the lack of research in this area is that traditional experiments using laboratory animals are expensive, particularly for cognitive disorders, and are of limited relevance to humans.

The study’s use of brain organoids signals a quicker, less expensive, and more human-relevant alternative for experimentation in this field.

The research 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 modelled 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 US and abroad.

Smirnova said: “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.

“Now we can explore how other genes and potentially toxic substances interact.”

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. The exposure clearly demonstrated how an environmental factor can worsen the effect of a genetic one, likely worsening disease progression and symptoms.

As part of their study, the researchers compiled a list of molecules in blood, urine, and brain tissue that prior studies have shown to be different in autism spectrum patients. They found that levels of several of these apparent autism biomarkers were also significantly altered in the organoids by CHD8 deficiency or chlorpyrifos exposure, and more so by both.

“In this sense, we showed that changes in these organoids reflect changes seen in autism patients,” Smirnova says.

The findings, according to the researchers, pave the way for further studies of gene-environment interactions in disease using human-derived organoids.

“The use of three-dimensional, human-derived, brain-like models like the one in this study is a good way forward for studying the interplay of genetic and environmental factors in autism and other neurodevelopmental disorders,” Hartung says.

 

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