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Environmental chemicals may boost brain inflammation

Environmental chemicals may boost central nervous system inflammation by modulating the function of brain astrocytes, a recent study shows. The researchers found that linuron, an herbicide, and methyl carbamate, a compound used by the textile, polymer and pharmaceutical industries, boosted inflammation in the astrocytes. They developed an approach that can be used to systematically evaluate the effects of hundreds of environmental factors on the development of neurological diseases. The findings were published in Cell.

Both genes and environmental factors are known to play a role in the development of neurological diseases. Astrocytes, on the other hand, play a crucial role in the development of the central nervous system and in maintaining brain chemistry balance. In neurological diseases, however, abnormal astrocyte function can boost inflammation.
“Comprehensive and systematic research addressing these factors has been challenging because the methods used haven’t been extensive enough,” says Programme Manager Merja Jaronen, PhD, from the University of Eastern Finland.

Jaronen participated in the study while working as a postdoctoral researcher at Harvard Medical School and at Brigham and Women’s Hospital in the US. The researchers developed an approach to systematically evaluate the effects of hundreds of environmental factors on the development of neurological diseases. This approach combines genome data, computer models, cell and animal models, and tissue samples from patients with multiple sclerosis. Using this model, the researchers explored the effects of environmental chemicals on central nervous system inflammation.

They used computer modelling to investigate 976 chemicals from multiple sources ranging from industrial and consumer products to food additives. Known as the ToxCast chemical inventory, this broad collection was established by the U.S. Environmental Protection Agency. Out of these chemicals, 75 were identified as compounds that affected signalling pathways previously linked to multiple sclerosis.

Using a novel zebrafish model of multiple sclerosis, the researchers analysed how these 75 compounds affect central nervous system inflammation. They also tested the compounds in mouse astrocytes. The researchers identified two compounds that boosted inflammation in the astrocytes: linuron, an herbicide, and methyl carbamate, a compound used by the textile, polymer and pharmaceutical industries. Linuron was banned in Europe in 2016, but it is still used elsewhere in the world.

Discovery of an inflammation-driving molecular pathway

The researchers also identified a molecular pathway through which linuron may drive inflammatory responses in astrocytes.  They showed that linuron boosts inflammatory responses in astrocytes by activating signalling through the Sigmar1 receptor, the IRE1a enzyme and the XBP1 protein.  This was shown to boost inflammation in the animal model of multiple sclerosis. The findings were also confirmed in human astrocytes. The researchers also observed increased activity of this molecular pathway in tissue samples from patients with multiple sclerosis.

The findings provide further insight into the role of Sigmar1 in the development of neurological disorders, as it has earlier been associated with amyotrophic lateral sclerosis (ALS), a disease that has long been thought to have environmental contributors.

“This study is an important step towards an increasingly comprehensive investigation of environmental chemicals at the systemic level and in order to understand the exposome, i.e., all of the environmental exposures people experience in their lifetime.  Our findings shed light on the role of environmental chemicals in central nervous system inflammation, laying the foundations for epidemiological studies that focus on the effects of different exposures on humans,” Jaronen says.

For further information, please contact:
Programme Manager Merja Jaronen, PhD, University of Eastern Finland, merja.jaronen (a) uef.fi,  tel. +358 50 5129116.

Research article:

Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.

Wheeler MA, Jaronen M, Covacu R, Zandee SEJ, Scalisi G, Rothhammer V, Tjon EC, Chao CC, Kenison JE, Blain M, Rao VTS, Hewson P, Barroso A, Gutiérrez-Vázquez C, Prat A, Antel JP, Hauser R, Quintana FJ. Cell. 2019 Jan 24;176(3):581-596.e18. doi: 10.1016/j.cell.2018.12.012. Epub 2019 Jan 17.

This news item is based on a release issued by Harvard Medical School, https://hms.harvard.edu/news/neuroenvironmental-connection