Lasting effects of common herbicide on brain health

In a groundbreaking new study, Arizona State University researcher Ramon Velazquez and his colleagues at the Translational Genomics Research Institute (TGen), part of City of Hope, demonstrate that mice exposed to the herbicide glyphosate develop significant brain inflammation, which is associated with neurodegenerative disease. The findings suggest the brain may be much more susceptible to the damaging effects of the herbicide than previously thought. Glyphosate is one of the most pervasive herbicides used in the U.S. and worldwide.

The research, which appears today in the Journal of Neuroinflammation, identifies an association between glyphosate exposure in mice and symptoms of neuroinflammation, as well as accelerated Alzheimer's disease-like pathology. This study tracks both the presence and impact of glyphosate's byproducts in the brain long after exposure ends, showing an array of persistent, damaging effects on brain health.

Glyphosate exposure in mice also resulted in premature death and anxiety-like behaviors, which replicates findings by others examining glyphosate exposure in rodents. Further, the scientists discovered these symptoms persisted even after a 6-month recovery period during which exposure was discontinued.

Additionally, the investigation demonstrated that a byproduct of glyphosate -- aminomethylphosphonic acid -- accumulated in brain tissue, raising serious concerns about the chemical's safety for human populations.

"Our work contributes to the growing literature highlighting the brain's vulnerability to glyphosate," Velazquez says. "Given the increasing incidence of cognitive decline in the aging population, particularly in rural communities where exposure to glyphosate is more common due to large-scale farming, there is an urgent need for more basic research on the effects of this herbicide."

Velazquez is a researcher with the ASU-Banner Neurodegenerative Disease Research Center at the ASU Biodesign Institute and an assistant professor with the School of Life Sciences. He is joined by first author Samantha K. Bartholomew, a PhD candidate in the Velazquez Lab, other ASU colleagues, and co-senior author Patrick Pirrotte, associate professor with the Translational Genomics Research Institute (TGen) and researcher with the City of Hope Comprehensive Cancer Center in California.

According to the Centers for Disease Research, farm laborers, landscape workers, and others employed in agriculture are more likely to be exposed to glyphosate through inhalation or skin contact. Additionally, the new findings suggest that ingestion of glyphosate residues on foods sprayed with the herbicide potentially poses a health hazard. Most people living in the U.S. have been exposed to glyphosate during their lifetime.

"My hope is that our work drives further investigation into the effects of glyphosate exposure, which may lead to a reexamination of its long-term safety and perhaps spark discussion about other prevalent toxins in our environment that may affect the brain," Bartholomew says.

The team's findings build on earlier ASU research that demonstrates a link between glyphosate exposure and a heightened risk for neurodegenerative disorders.

The previous study showed that glyphosate crosses the blood-brain barrier, a protective layer that typically prevents potentially harmful substances from entering the brain. Once glyphosate crosses this barrier, it can interact with brain tissue and appears to contribute to neuroinflammation and other harmful effects on neural function.

The EPA considers certain levels of glyphosate safe for human exposure, asserting that the chemical is minimally absorbed into the body and is primarily excreted unchanged. However, recent studies, including this one, indicate that glyphosate, and its major metabolite aminomethylphosphonic acid, can persist in the body and accumulate in brain tissue over time, raising questions about existing safety thresholds and whether glyphosate use is safe at all.

Herbicide may attack more than weeds

Glyphosate is the world's most heavily applied herbicide, used on crops including corn, soybeans, sugar beets, alfalfa, cotton and wheat. Since the introduction of glyphosate-tolerant crops (genetically engineered to be sprayed with glyphosate without dying) in 1996, glyphosate usage has surged, with applications predominately in agricultural settings.

The U.S. Geological Survey notes approximately 300 million pounds of glyphosate are used annually in the United States alone. Although glyphosate levels are regulated on foods imported into the United States, enforcement and specific limits can vary. Due to its widespread use, the chemical is found throughout the food chain. It persists in the air, accumulates in soils, and is found in surface and groundwater.

Despite being considered safe by the EPA, the International Agency for Research on Cancer classifies glyphosate as "possibly carcinogenic to humans," and emerging research, including this study, points to its potential role in worsening neurodegenerative diseases by contributing to pathologies, like those seen in Alzheimer's disease.

The chemical works by inhibiting a specific enzyme pathway in plants that is crucial for producing essential amino acids. However, its impact extends beyond the intended weed, grass and plant targets, negatively affecting the biological systems in mammals, as demonstrated by its persistence in brain tissue and its role in inflammatory processes.

"Herbicides are used heavily and ubiquitously around the world," says Pirrotte, associate professor in TGen's Early Detection and Prevention Division, director of the Integrated Mass Spectrometry Shared Resource at TGen and City of Hope, and senior author of the paper. "These findings highlight that many chemicals we regularly encounter, previously considered safe, may pose potential health risks. However, further research is needed to fully assess the public health impact and identify safer alternatives."

Is glyphosate safe to use at all?

The researchers hypothesized that glyphosate exposure would induce neuroinflammation in control mice and worsen neuroinflammation in Alzheimer's model mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. Amyloid-β and Tau are key proteins that comprise plaques and tau tangles, the classic diagnostic markers of Alzheimer's disease. Plaques and tangles disrupt neural functioning and are directly linked to memory loss and cognitive decline.

The experiments were conducted over 13 weeks, followed by a six-month recovery period. The main metabolite, aminomethylphosphonic acid, was detected in the brains of both normal and transgenic mice with Alzheimer's pathology. Transgenic mice are genetically modified to carry genes that cause them to develop Alzheimer's-like symptoms as they age. This allows researchers to study the progression and effects of the disease in a controlled laboratory setting.

The researchers tested two levels of glyphosate exposure: a high dose, similar to levels used in earlier research, and a lower dose that is close to the limit used to establish the current acceptable dose in humans.

This lower dose still led to harmful effects in the brains of mice, even after exposure ceased for months. While reports show that most Americans are exposed to glyphosate daily, these results show that even a short period could potentially cause neurological damage.

Glyphosate caused a persistent increase in inflammatory markers in the brain and blood, even after the recovery period. This prolonged inflammation could drive the progression of neurodegenerative diseases, including Alzheimer's, indicating even temporary glyphosate exposure can lead to enduring inflammatory processes that affect brain health.

The data emphasizes that glyphosate exposure may be a significant health concern for human populations. The researchers stress the need for continued vigilance and intensified surveillance of glyphosate neurological and other long-term negative health effects.

"Our goal is to identify environmental factors that contribute to the rising prevalence of cognitive decline and neurodegenerative diseases in our society," Velazquez says. "By unveiling such factors, we can develop strategies to minimize exposures, ultimately improving the quality of life for the growing aging population."

The National Institutes on Aging, National Cancer Institute of the National Institutes of Health, and ASU Biodesign Institute funded this study.