Overexpression of copper zinc superoxide dismutase impairs human trophoblast cell fusion and differentiation

The syncytiotrophoblast is the major component of the human placenta, invol ved in feto-maternal exchanges and secretion of pregnancy-specific hormones . Multinucleated syncytiotrophoblast arises from fusion of mononuclear cyto trophoblast cells. In trisomy 21-affected placentas, we recently have shown that there is a defect in syncytiotrophoblast formation and a decrease in the production of pregnancy-specific hormones. Due to the role of oxygen fr ee radicals in trophoblast cell differentiation, we investigated the role o f the key antioxidant enzyme, copper/zinc superoxide dismutase, encoded by chromosome 21 in in vitro trophoblast differentiation. We first observed th at overexpression of superoxide dismutase in normal cytotrophoblasts impair ed syncytiotrophoblast formation. This was associated with a significant de crease in mRNA transcript levels and secretion of hCG and other hormonal ma rkers of syncytiotrophoblast. We confirmed abnormal cell fusion by overexpr ession of green fluorescence protein-tagged superoxide dismutase in cytotro phoblasts. In addition, a significant decrease in syncytin transcript level s was observed in superoxide dismutase-transfected cells. We then examined superoxide dismutase expression and activity in isolated trophoblast cells from trisomy 21-affected placentas. Superoxide dismutase mRNA expression (P <0.05), protein levels (P<0.01), and activity (P<0.05) were significantly h igher in trophoblast cells isolated from trisomy 21-affected placentas than in those from normal placentas. These results suggest that superoxide dism utase overexpression may directly impair trophoblast cell differentiation a nd fusion, and superoxide dismutase overexpression in Down's syndrome may b e responsible at least in part for the failure of syncytiotrophoblast forma tion observed in trisomy 21-affected placentas.