Oxidative stress induced by tert-butylhydroperoxide interferes with the placental transport of glucose: in vitro studies with BeWo cells

Abstract

Increased oxidative stress is implicated in the onset and progression of prevalent pregnancy disorders (e.g. gestational diabetes and fetal growth restriction),and in programming the fetus to develop metabolic diseases later in life.Since the molecular mechanisms underlying these effects of oxidative stress are largely unexplored, we aimed to investigate if the placental transport of glucose – the main energetic substrate for the fetus and placenta – is altered by oxidative stress.In a human syncytiotrophoblast (STB)cell model, the BeWo cell line,oxidative stress was induced by treatment with 100 mM tert-butylhydroperoxide(tert-BOOH) for 24 h. Tert-BOOH decreased the steady-state intracellular accumulation (Amax) of[3H]2-deoxyglucose([3H]DG) mediated by both facilitative(GLUT) and non-facilitative(non-GLUT)glucose transporters.These effects were not associated with a change in the mRNA expression level of GLUT1, the major placental glucose transporter. Also,they seemed to be independent from phosphoinositide 3-kinase and protein kinase C signaling pathways and were unchanged either by inhibitors of free radical-generating enzymes or by free radical scavengers. In contrast, the dietary polyphenols quercetin, epigallocatechin-3-gallate and resveratrol completely reversed the inhibitory effect of tert-BOOH upon[3H]DG accumulation through a specific effect on GLUT-mediated transport. Finally, tert-BOOH induced an increase in the transepithelial permeability to [3H]DG in the apical-to-basal direction, apparently related to an increase in its paracellular transport. In conclusion, tert-BOOH-induced oxidative stress reduces STB accumulation of glucose associated with an increase in its transepithelial permeability. This effect may contribute to the deleterious consequences of pregnancy disorders associated with oxidative stress.