A new study from NIEHS grantees at the University of North Carolina at Chapel Hill (UNC), published March 31 in the journal Nature Communications, reported that some commonly used fungicides produce changes in mouse brain cells that look strikingly similar to those in people with autism and neurodegenerative conditions, including Alzheimer’s disease and Huntington’s disease.
The changes affect gene expression, which means they affect how genes are transcribed without altering the genetic sequence.
New approach to identifying effects on brain function
The study describes a new way to pinpoint chemicals that have the potential to affect brain functions. Mark Zylka, Ph.D., senior author of the study and associate professor of cell biology and physiology at UNC, and his team exposed mouse neurons to approximately 300 different chemicals. The researchers sequenced RNA from these neurons to find out which genes were misregulated compared with untreated neurons.
This work created hundreds of data sets of gene expression, and Zylka’s team used computer programs to determine which chemicals caused gene expression changes that were similar to each other.
“Based on RNA sequencing, we describe six groups of chemicals,” Zylka said. “We found that chemicals within each group altered expression in a common manner. One of these groups of chemicals altered the levels of many of the same genes that are altered in the brains of people with autism or Alzheimer’s disease.”
That group, which contains certain pesticides and a new class of fungicides that includes pyraclostrobin, trifloxystrobin, fenamidone, and famoxadone, reduced the expression of genes involved in synaptic transmission — the connections important for communication between neurons.
Additional brain changes observed
These substances caused an elevated expression of genes associated with inflammation in the nervous system. Neuroinflammation is commonly seen in autism and neurodegenerative conditions, although Zylka cautioned that more study was needed to determine the causes of those conditions in people.
Another change observed by the researchers was increased production of particles that can damage the basic building blocks of cells, called free radicals, which have been implicated in certain brain diseases.
The chemicals also disrupted neuron microtubules. “Disrupting microtubules affects the function of synapses in mature neurons and can impair the movement of cells as the brain develops,” Zylka said. “We have not yet evaluated whether these chemicals impair brain development in animal models or people.”
“This is a very important study that should serve as a wake-up call to regulatory agencies and the general medical community,” said Jennie Lee, M.D., Ph.D., a Harvard University molecular biologist who was not involved in this research. “The work is timely and has wide-ranging implications not only for diseases like autism, Parkinson's, and cancer, but also for the health of future generations. I suspect that a number of these chemicals will turn out to have effects on transgenerational inheritance.”
The researchers hope their study will encourage other scientists and regulatory agencies to take a closer look at these fungicides and follow up with epidemiological studies. “Virtually nothing is known about how these chemicals impact the developing or adult brain,” Zylka said. “Yet these chemicals are being used at increasing levels on many of the foods we eat.”
Citation: Pearson BL, Simon JM, McCoy ES, Salazar G, Fragola G, Zylka MJ. 2016. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration. Nat Commun (7):11173.
(This story is based on a UNC press release by Mark Derewicz.)