Melatonin: the watchdog of villous trophoblast homeostasis against hypoxia/reoxygenation-induced oxidative stress and apoptosis

Abstract

Human placenta produces melatonin and expresses its receptors. We propose that melatonin, an antioxidant, protects the human placenta against hypoxia/reoxygenation (H/R)-induced damage. Primary term villous cytotrophoblasts were cultured under normoxia (8% O2) with or without 1mM melatonin for 72h to induce differentiation into the syncytiotrophoblast. The cells were then cultured for an additional 22h under normoxia or subjected to hypoxia (0.5% O2) for 4h followed by 18h reoxygenation (8% O2) with or without melatonin. H/R induced oxidative stress, which activated the Bax/Bcl-2 mitochondrial apoptosis pathway and the downstream fragmentation of DNA. Villous trophoblast treatment with melatonin reversed all the negative effects induced by H/R to normoxic levels. This study shows that melatonin protects the villous trophoblast against H/R-induced oxidative stress and apoptosis and suggests a potential preventive and therapeutic use of this indolamine in pregnancy complications characterized by syncytiotrophoblast survival alteration.

Keywords: Antioxidant; CAT; GPx; H/R; HIF-1; HPRT1; Mitochondrial apoptosis; NF-κB; PARP; PPIA; ROCK-1; ROS; RT; Reactive oxygen species; SOD1 or Cu, ZN–SOD; SOD2, Mn–SOD; STBM; TNF-α; Villous trophoblast; XDH; XO; catalase; glutathione peroxidase; hypoxanthine phosphoribosyltransferase 1; hypoxia inducible factor 1; hypoxia/reoxygenation; nuclear factor-κB; peptidylprolyl isomerase A; poly(ADP-ribose) polymerase; quantitative polymerase chain reaction; reactive oxygen species; real-time PCR, qPCR; reverse-transcription; rho-associated coiled-coil protein kinase 1; sFlt-1; soluble fms-like tyrosine kinase 1; superoxide dismutase 1; superoxide dismutase 2; syncytiotrophoblast microparticles; tumor necrosis factor α; xanthine dehydrogenase; xanthine oxidase.