ABSTRACT
Endocrine disruptors (EDs) pose significant risks to human and environmental health, with potential implications for neurotoxicity. This study investigates the synergistic neurotoxic effects of perfluorooctane sulfonate (PFOS) and glyphosate (GLY), two ubiquitous EDs, using SHSY5Y neuronal and C6 astrocytic cell lines. While individual exposures to PFOS and glyphosate at non-toxic concentrations did not induce significant changes, their combination resulted in a marked increase in oxidative stress and neuroinflammatory responses. Specifically, the co-exposure led to elevated levels of interleukin-6, tumor necrosis factor alpha, and interferon gamma, along with reduced interleukin-10 expression, indicative of heightened neuroinflammatory processes. These findings underscore the importance of considering the synergistic interactions of EDs in assessing neurotoxic risks and highlight the urgent need for further research to mitigate the adverse effects of these compounds on neurological health.
Subject(s)
Alkanesulfonic Acids , Endocrine Disruptors , Fluorocarbons , Glycine , Glyphosate , Glycine/analogs & derivatives , Glycine/toxicity , Fluorocarbons/toxicity , Endocrine Disruptors/toxicity , Humans , Alkanesulfonic Acids/toxicity , Oxidative Stress/drug effects , Cell Line, Tumor , Cell Line , Animals , Neurons/drug effects , Neurons/metabolism , Astrocytes/drug effects , Astrocytes/metabolism , Herbicides/toxicity , Cytokines/metabolism , Cell Survival/drug effects , RatsABSTRACT
BACKGROUND: The formation of the NLRP3 inflammasome in the heart during acute myocardial infarction amplifies the inflammatory response and mediates further damage. Glyburide has NLRP3 inhibitory activity in vitro but requires very high doses in vivo, associated with hypoglycemia. The aim of this study was to measure the effects on the NLRP3 inflammasome of 16673-34-0, an intermediate substrate free of the cyclohexylurea moiety, involved in insulin release. METHODS AND RESULTS: We synthesized 16673-34-0 (5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)ethyl]benzamide) that displayed no effect on glucose metabolism. HL-1 cardiomyocytes were treated with lipopolysaccharide and ATP to induce the formation of the NLRP3 inflammasome, measured as increased caspase-1 activity and cell death, and 16673-34-0 prevented such effects. 16673-34-0 was well tolerated with no effects on the glucose levels in vivo. Treatment with 16673-34-0 in a model of acute myocardial infarction because of ischemia and reperfusion significantly inhibited the activity of inflammasome (caspase-1) in the heart by 90% (P < 0.01) and reduced infarct size, measured at pathology (by >40%, P < 0.01) and with troponin I levels (by >70%, P < 0.01). CONCLUSIONS: The small molecule 16673-34-0, an intermediate substrate in the glyburide synthesis free of the cyclohexylurea moiety, inhibits the formation of the NLRP3 inflammasome in cardiomyocytes and limits the infarct size after myocardial ischemia-reperfusion in the mouse, without affecting glucose metabolism.
