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March 31, 2016

Autism-Like Changes in Gene Expression Caused by Common Pesticides

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    Heritability and epidemiological studies have linked autism and neurodegeneration risks to environmental factors such as pesticides. [Fig and Sage]

    Heritability and epidemiological studies have linked autism and neurodegeneration risks to environmental factors such as pesticides, but these studies have failed to resolve which chemicals merit extra scrutiny. This is a significant shortcoming, given that more than 80,000 chemicals are registered for use in the environment. Until potentially harmful chemicals are identified, additional questions—such as those concerning dosages and cumulative effects—cannot even be asked.

    To sharpen the investigation of environmental factors associated with autism and neurodegeneration risks, researchers based at the University of North Carolina (UNC) decided to interrogate molecular processes in neurons. In particular, they considered the effects of pesticides and fungicides on transcription. Ultimately, the researchers found that commonly used chemicals produced gene expression changes similar to those in people with autism and neurodegenerative conditions, including Alzheimer’s disease and Huntington’s disease.

    The details of this work appeared March 31 in the journal Nature Communications, in an article entitled, “Identification of Chemicals That Mimic Transcriptional Changes Associated with Autism, Brain Aging and Neurodegeneration.” The article described how the UNC researchers, led by cell biologist Mark Zylka, Ph.D., exposed mouse neurons to hundreds of chemicals commonly found in the environment and on food. Then the researchers sequenced RNA from these neurons to find out which genes were misregulated when compared to untreated neurons.

    “We find that rotenone, a pesticide associated with Parkinson’s disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age, and neurodegeneration,” wrote the article’s authors. “These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane.”

    Dr. Zylka cautioned that it is too early to say whether these chemicals cause these conditions in people. "Many additional studies,” he noted, “will be needed to determine if any of these chemicals represent real risks to the human brain.”

    These chemicals, however, were found to reduce the expression of genes involved in synaptic transmission. Also, the chemicals caused an elevated expression of genes associated with inflammation in the nervous system. This so-called neuroinflammation is commonly seen in autism and neurodegenerative conditions.

    Jeannie T. Lee, M.D., Ph.D., professor of genetics at Harvard Medical School and Massachusetts General Hospital, who was not involved in this research, said, "This is a very important study that should serve as a wake-up call to regulatory agencies and the general medical community. 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."

    In the course of their work, the researchers created hundreds of data sets of gene expression. Sifting through this data involved the use of computer programs to deduce which chemicals caused gene expression changes that were similar to each other.

    "Based on RNA sequencing, we describe six groups of chemicals," Dr. Zylka explained. "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."

    Dr. Zylka added, "The real tough question is: If you eat fruits, vegetables, or cereals that contain these chemicals, do they get into your bloodstream and at what concentration? That information doesn't exist." Also, given their presence on a variety of foodstuffs, might long-term exposure to these chemicals—even at low doses—have a cumulative effect on the brain?

    Dr. Zylka noted that conventionally grown leafy green vegetables such as lettuce, spinach, and kale have the highest levels of these fungicides. But due to each chemical's effectiveness at reducing fungal blights and rust, crop yields have increased and farmers are expanding their use of these chemicals to include many additional types of food crops.

    Dr. Zylka's team hopes their research 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," Dr. Zylka stated. "Yet these chemicals are being used at increasing levels on many of the foods we eat."

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