The Impact of Early Life Exposure to Glyphosate

Eosinophilic esophagitis (EoE) is a chronic immune mediated disease that affects populations of all ages. It is characterized by eosinophilic inflammation of the esophageal mucosa, decreased epithelial integrity, and lamina propria fibrosis. Clinically, the symptoms of EoE can range from mild (dysphagia, abdominal pain, vomiting), to severe (food impaction, inability to thrive), to complete loss of esophageal function in extreme cases. This disease, first described in 1993, is rising in incidence and prevalence. Unfortunately, the reason for disease emergence is unknown and environmental triggers have been postulated as a potential source. The role of environmental toxins, specifically herbicides, has never been examined in the pathophysiology of atopic disease. Glyphosate, the active ingredient in Roundup, is the most used herbicide in the United States, and is frequently used as a desiccant prior to harvest. Residual amounts can be detected in harvested crops and downstream food products, potentially leading to a diet of chronic exposure. Herein we sought to determine the effects of early life glyphosate treatment and the consequences of exposure on the development of eosinophilic esophagitis and the maintenance of epithelial integrity. We exposed mice to physiologic levels of glyphosate in utero and throughout their life cycle to simulate glyphosate consumption in the typical American diet. We then induced EoE in mice using our established protocol and evaluated epithelial integrity and inflammation. Interestingly, we found that chronic glyphosate treatment alone induced a 2-fold increase in esophageal eosinophils over baseline, similar to mice undergoing EoE. Secondarily, we exposed primary human esophageal and intestinal organoids to short term glyphosate treatment. We observed no changes in the esophageal organoids. However, we found increased gene expression of mucin 2 (MUC2) in organoids derived from terminal ileum and proximal colon. Taken together these results suggest that there is increased inflammation in the glyphosate treated mice and this may be due, in part, to a response generated in the small intestine by glyphosate exposure.