👤 Patrick Pirrotte

Glyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that C57BL/6J mice dosed with glyphosate for 14 days showed glyphosate and its major metabolite aminomethylphosphonic acid present in brain tissue, with corresponding increases in pro-inflammatory cytokine tumor necrosis factor-⍺ (TNF-⍺) in the brain and peripheral blood plasma. Since TNF-⍺ is elevated in neurodegenerative disorders such as Alzheimer's Disease (AD), in this study, we asked whether glyphosate exposure serves as an accelerant of AD pathogenesis. Additionally, whether glyphosate and aminomethylphosphonic acid remain in the brain after a recovery period has yet to be examined. We hypothesized that glyphosate exposure would induce neuroinflammation in control mice, while exacerbating neuroinflammation in AD mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. We dosed 4.5-month-old 3xTg-AD and non-transgenic (NonTg) control mice with either 0, 50 or 500 mg/kg of glyphosate daily for 13 weeks followed by a 6-month recovery period. We found that aminomethylphosphonic acid was detectable in the brains of 3xTg-AD and NonTg glyphosate-dosed mice despite the 6-month recovery. Glyphosate-dosed 3xTg-AD mice showed reduced survival, increased thigmotaxia in the Morris water maze, significant increases in the beta secretase enzyme (BACE-1) of amyloidogenic processing, amyloid-β (Aβ) 42 insoluble fractions, Aβ 42 plaque load and plaque size, and phosphorylated tau (pTau) at epitopes Threonine 181, Serine 396, and AT8 (Serine 202, Threonine 205). Notably, we found increased pro- and anti-inflammatory cytokines and chemokines persisting in both 3xTg-AD and NonTg brain tissue and in 3xTg-AD peripheral blood plasma. Taken together, our results are the first to demonstrate that despite an extended recovery period, exposure to glyphosate elicits long-lasting pathological consequences. As glyphosate use continues to rise, more research is needed to elucidate the impact of this herbicide and its metabolites on the human brain, and their potential to contribute to dysfunctions observed in neurodegenerative diseases. Show less

Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy. Show less