Metallothionein protects against severe oxidative stress-induced apoptosis of human trophoblastic cells.
Oxidative stress induces cellular apoptosis. Many agents producing intracellular oxidative stress, including H(2)O(2) and steroid hormones, have also been found to induce metallothionein (MT) expression. Recently, MT has been recognized as potentially having antioxidant activity. This action may be essential for survival of terminally differentiated cells subject to oxidative stress, such as syncytiotrophoblasts, placental cells producing pregnancy hormones and forming the maternal-fetal barrier. We previously demonstrated an inverse relationship between basal MT expression and apoptotic incidence in the trophoblastic cell line, JEG-3. Using JEG-3 cells transfected with MT in sense or antisense orientation, we have examined here the effect of altered basal MT levels on trophoblastic function and apoptosis following treatment with H(2)O(2) or diethylstilbestrol (DES). Induction of MT mRNA was observed in control and transfected JEG-3 cells following exposure to severe oxidative stress. Changes in the localization of MT protein, however, were apparent after a low oxidative stress challenge. Exposure to H(2)O(2) resulted in a dose-dependent decrease in human chorionic gonadotropin secretion in all JEG-3 cultures regardless of basal MT expression, whereas no change was detected following DES treatment. With respect to apoptosis, a significant protective effect was observed proportional to the basal MT level. These results suggest that although MT does not ameliorate oxidative stress-induced perturbation of some trophoblastic functions, its expression is critical for protection of these cells from severe oxidative stress-induced apoptosis. MT thus appears to act as an anti-apoptotic antioxidant in trophoblastic cells.
McAleer
M F
MF
Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Tuan
R S
RS
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004054:Diethylstilbestrol / Q000633:toxicity*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D066298:In Vitro Techniques; D008668:Metallothionein / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014327:Trophoblasts
D012333:RNA, Messenger; D004054:Diethylstilbestrol; D008668:Metallothionein; D006861:Hydrogen Peroxide