The impact of the herbicide glyphosate and its metabolites AMPA and MPA on the metabolism and functions of human blood neutrophils and their sex-dependent effects on reactive oxygen species and CXCL8/IL-8 production.

Significant levels of glyphosate, the world's most widely used herbicide, and its primary metabolites, AMPA and MPA, are detected in various human organs and body fluids, including blood. Several studies have associated the presence of glyphosate in humans with health problems, and effects on immune cells and their functions have been reported. However, the impact of this molecule and its metabolites on neutrophils, the most abundant leukocytes in the human bloodstream, is still poorly documented. We isolated neutrophils from human donor blood and investigated the effects of exposure to glyphosate, AMPA, and MPA on viability, energy metabolism, and essential antimicrobial functions in vitro. We observed that neutrophil viability was unaffected at the blood-relevant average concentrations of the general population and exposed workers, as well as at higher intoxication concentrations. Neutrophil energy metabolism was also not altered following exposure to the chemicals. However, while phagocytosis was unaffected, reactive oxygen species generation and CXCL8/IL-8 production were altered by exposure to the molecules. Alterations in function following exposure to glyphosate and metabolites differed according to the sex of the donors, which could be linked to glyphosate's known role as an endocrine disruptor. While ROS generation was increased in both sexes, male neutrophils exposed to glyphosate had increased intracellular production of CXCL8/IL-8, with no effect on female neutrophils. Conversely, exposure to the metabolites AMPA and MPA decreased extracellular production of this chemokine only in female neutrophils, with MPA also increasing intracellular production in male cells exposed to the chemoattractant N-formyl-methionine-leucyl-phenylalanine. Our study highlights the effects of glyphosate and its metabolites on the antimicrobial functions of neutrophils, which could be associated with health problems as future studies provide a better understanding of the risks associated with glyphosate use. Advances in knowledge will enable better and potentially stricter regulations to protect the public.

Metabolic regulation of neutrophil functions in homeostasis and diseases.

Neutrophils are the most abundant leukocytes in humans and play a role in the innate immune response by being the first cells attracted to the site of infection. While early studies presented neutrophils as almost exclusively glycolytic cells, recent advances show that these cells use several metabolic pathways other than glycolysis, such as the pentose phosphate pathway, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, which they modulate to perform their functions. Metabolism shifts from fatty acid oxidation-mediated mitochondrial respiration in immature neutrophils to glycolysis in mature neutrophils. Tissue environments largely influence neutrophil metabolism according to nutrient sources, inflammatory mediators, and oxygen availability. Inhibition of metabolic pathways in neutrophils results in impairment of certain effector functions, such as NETosis, chemotaxis, degranulation, and reactive oxygen species generation. Alteration of these neutrophil functions is implicated in certain human diseases, such as antiphospholipid syndrome, coronavirus disease 2019, and bronchiectasis. Metabolic regulators such as AMPK, HIF-1α, mTOR, and Arf6 are linked to neutrophil metabolism and function and could potentially be targeted for the treatment of diseases associated with neutrophil dysfunction. This review details the effects of alterations in neutrophil metabolism on the effector functions of these cells.