Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFα: implications for neurodegenerative disorders

Abstract

Background Herbicides are environmental contaminants that have gained much attention due to the potential hazards they pose to human health. Glyphosate, the active ingredient in many commercial herbicides, is the most heavily applied herbicide worldwide. The recent rise in glyphosate application to corn and soy crops correlates positively with increased death rates due to Alzheimer’s disease and other neurodegenerative disorders. Glyphosate has been shown to cross the blood–brain barrier in in vitro models, but has yet to be verified in vivo. Additionally, reports have shown that glyphosate exposure increases pro-inflammatory cytokines in blood plasma, particularly TNFα. Methods Here, we examined whether glyphosate infiltrates the brain and elevates TNFα levels in 4-month-old C57BL/6J mice. Mice received either 125, 250, or 500 mg/kg/day of glyphosate, or a vehicle via oral gavage for 14 days. Urine, plasma, and brain samples were collected on the final day of dosing for analysis via UPLC–MS and ELISAs. Primary cortical neurons were derived from amyloidogenic APP/PS1 pups to evaluate in vitro changes in Aβ40-42 burden and cytotoxicity. RNA sequencing was performed on C57BL/6J brain samples to determine changes in the transcriptome. Results Our analysis revealed that glyphosate infiltrated the brain in a dose-dependent manner and upregulated TNFα in both plasma and brain tissue post-exposure. Notably, glyphosate measures correlated positively with TNFα levels. Glyphosate exposure in APP/PS1 primary cortical neurons increases levels of soluble Aβ40-42 and cytotoxicity. RNAseq revealed over 200 differentially expressed genes in a dose-dependent manner and cell-type-specific deconvolution analysis showed enrichment of key biological processes in oligodendrocytes including myelination, axon ensheathment, glial cell development, and oligodendrocyte development. Conclusions Collectively, these results show for the first time that glyphosate infiltrates the brain, elevates both the expression of TNFα and soluble Aβ, and disrupts the transcriptome in a dose-dependent manner, suggesting that exposure to this herbicide may have detrimental outcomes regarding the health of the general population.

The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling

“…In our studies, we hypothesized that glyphosate in GBH causes neuroin ammation to impair cognitive function. It has been recently shown that oral administration of glyphosate to mice (125, 250 and 500 mg/kg for 14 days) elevates glyphosate levels (10-50 ng/mg) and tumor necrosis factor-(TNFα) in the brain (Winstone et al, 2022). This study has two important implications: orally administered glyphosate in ltrates the CNS and elevates pro-in ammatory cytokines in the CSF.…”

Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review

“…Brain imaging studies have also found that the areas of the brain most vulnerable to the toxic effects of chemicals and other environmental toxins are the pre- and post-central gyri, temporal transverse gyrus, and the calcarine regions. While epidemiologic associations between environmental chemical exposure and AD are still limited, the risk of developing AD in older adults due to neurologic impairments caused by environmental toxins is well established [ 199 , 210 , 211 , 212 , 213 ].…”

“…Studies in cell and animal models have revealed alterations in neural pathways and metabolism associated with AD. Neuro-imaging studies have reported associations between exposure to toxic chemicals and white matter volume reduction [ 213 , 214 , 215 ]. Other reported effects include reduced gray matter, larger ventricular volume, and smaller corpus callosum.…”

"Ameliorative Potential of Astaxanthin on Glyphosate- Induced Neurocognitive Functional Changes in Adult Zebrafish Via Acid Phosphatase and Annexin A2 Dysfunction"

“…In the neuronal tissue, GYP enhances neuronal excitation and loss of neuronal plasticity leads to neurodegenerations [6]. Furthermore, it affects cellular metabolism and causes mitochondrial dysfunctions via free radical generation, release of pro-inflammatory cytokines, and enhance the synthesis & release of glutamate molecules [7,8]. Subsequently, it also causes the dysfunction of the blood-brain barrier (BBB) [9].…”