NADPH oxidase is the major source of placental superoxide in early pregnancy: association with MAPK pathway activation.

First-trimester placenta (<10 gestational weeks (GW)) develops in a low oxygen environment (≈2%). Early oxygen exposure can cause oxidative damage leading to pregnancy disorders. The aim of this work was to determine the major sources of placental superoxide during early pregnancy - more specifically before 10 GW - and to study redox adaptation to increased oxygen pressure after 12 GW. Our results show that NADPH oxidase (Nox) is the main source of superoxide in first-trimester chorionic villi. Its activity is higher before 10 GW and concomitant with the location on the syncytiotrophoblast apical pole of p47phox, the Nox organizer subunit. After the increase in pO pressure (12-14 GW), the activities of the antioxidant enzymes SOD1, catalase and GPX1 are increased. The redox-sensitive MAPK pathways show increased phosphorylated-p38 expression, but no variation in the phosphorylation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) during first trimester, suggesting a physiological redox adaptation, whilst ERK1/2 phosphorylation is higher after 12 GW. Nox is the major superoxide source in early pregnancy (<10 GW). Increased superoxide production at 7-9 GW is associated with p38 MAPK pathway activation, suggesting that it is involved in physiological placental function and healthy early development of the placenta, through MAPK pathways.