Placental Malaria Induces Oxidative Stress in Human Syncytiotrophoblast.

Abstract

BACKGROUND Placental malaria is characterized by the accumulation of Plasmodium falciparum-infected erythrocytes and maternal inflammation in the intervillous spaces of the placenta. These features are associated with placental damage and fetal compromise. However, understanding of the mechanisms that lead to poor pregnancy outcome and interventions targeting excessive host responses to placental malaria are still lacking. The syncytiotrophoblast, a cell of fetal origin, is known to be responsive to malaria-infected erythrocytes as well as the malaria toxin, hemozoin, but its susceptibility to oxidative stress and how this might contribute to placental damage and dysfunction has not yet been directly investigated. METHODS The characteristics and key drivers of the syncytiotrophoblast response to oxidative stress were investigated using ex vivo human placental tissues and primary trophoblasts isolated from healthy pregnant women. Primary syncytiotrophoblast was exposed to hemozoin and tumor necrosis factor, a critical inflammatory cytokine, to model conditions found in human placental malaria. RESULTS The data show remarkable lipid peroxidation in human placental samples from a malaria endemic setting and evidence of a modulated antioxidant response at the transcriptional level. Likewise, primary human syncytiotrophoblast exposed to hemozoin, tumor necrosis factor, and tumor necrosis factor combined with hemozoin in vitro exhibited increased markers of an anti-oxidative response, and, with hemozoin alone, oxidation of lipids and DNA. CONCLUSIONS These results suggest that oxidative stress in syncytiotrophoblast is promoted by both hemozoin exposure and maternal inflammatory responses to placental malaria and contribute to an increased understanding of placental dysfunction and compromise in this infection.