The aryl receptor inhibitor epigallocatechin-3-gallate protects INS-1E beta-cell line against acute dioxin toxicity.
The aim of this research was to investigate the mechanism(s) underlying the acute toxicity of dioxin in pancreatic beta cells and to evaluate the protective effects of epigallocatechin-3-gallate (EGCG), the most abundant of the green tea's catechins and a powerful inhibitor of the aryl hydrocarbon receptor (AhR). Using the insulin-secreting INS-1E cell line we have explored the effect of 1h exposure to different concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alone or in the presence of EGCG, on: (a) cell survival; (b) cellular ultrastructure; (c) intracellular calcium levels; (d) mitochondrial membrane potential; (e) glucose-stimulated insulin secretion and (f) activation of MAP kinases. Our results demonstrate that TCDD is highly toxic for INS-1E cells, suggesting that pancreatic beta cells should be considered a relevant and sensitive target for dioxin acute toxicity. EGCG significantly protects INS-1E cells against TCDD-induced toxicity in terms of both cell survival and preservation of cellular ultrastructure. The mechanism of this protective effect seems to be related to: (a) the ability of EGCG to preserve the mitochondrial function and thus to prevent the TCDD-induced inhibition of glucose-stimulated insulin secretion and (b) the ability of EGCG to inhibit the TCDD-induced activation of selected kinases, such as e.g. ERK 1/2 and JNK. Our results clearly show that EGCG is able to protect pancreatic beta cells against dioxin acute toxicity and indicate the mitochondrion as the most likely target for this beneficial effect.
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, I-56126 Pisa, Italy.
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L
Martino
M
M
Masini
M
M
Novelli
D
D
Giacopelli
P
P
Beffy
P
P
Masiello
V
V
De Tata
D000975:Antioxidants / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
D000975:Antioxidants; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D002392:Catechin; C045651:epigallocatechin gallate
Diabetes; Dioxin; Epigallocatechin-3-gallate; Insulin secretion; Pancreatic beta cells