Role of genetic and environmental interactions in autism found in brain organoids
2021
Johns Hopkins University, Baltimore, USA
Using brain organoids differentiated from stem cells, exposure to a pesticide was shown to interact with a common gene mutation associated with autism.
Here, the pesticide chlorpyrifos, which has been reported to contribute to developmental neurotoxicity and autism risk, dramatically reduced the concentration of the protein CHD8 in the organoids. CHD8 is a regulator of gene activity that is important for brain development. Mutations in its gene that reduce CHD8 activity are among the strongest of the more than 100 genetic risk factors for autism identified to date.
In the study, the cells that make up the organoids were altered to lack one of the two normal copies of the CHD8 gene. This resulted in a significant, but not complete, weakening of the CHD8 gene's activity, similar to that seen in people who have CHD8 mutations and autism.
The researchers found that brain organoids with only one copy of the CHD8 gene had only two-thirds of the normal level of CHD8 protein in their cells, but that exposure to chlorpyrifos significantly lowered CHD8 levels, turning a moderate deficiency into a severe deficiency. The exposure clearly demonstrated how an environmental factor can exacerbate the effect of a genetic factor, likely worsening disease progression and symptoms.
The researchers also compiled a list of molecules in blood, urine and brain tissue that previous studies have shown to be different in autism spectrum patients.
They found that concentrations of several of these apparent autism biomarkers were also significantly altered in organoids by CHD8 deficiency or chlorpyrifos exposure, and to a greater extent by both.
According to the researchers, the findings pave the way for further studies of gene-environment interactions in disease using human-derived organoids.
Gene–environment interactions in developmental neurotoxicity: a case study of synergy between Chlorpyrifos and CHD8 knockout in human brainspheres
Lena Smirnova
Added on: 07-29-2021
[1] https://ehp.niehs.nih.gov/doi/10.1289/EHP8580
