The Effects of Olanzapine on Trophoblast Invasion

Abstract

Olanzapine (OLN) is one of the most commonly taken antipsychotics during pregnancy. Exposure of the fetus to OLN during gestation leads to altered birth weight. This is of concern because altered fetal growth increases the risk of metabolic syndrome later in life, which negatively impacts an individual’s quality of life, lifespan, and increases the burden on the healthcare system. However, the mechanisms of how antipsychotics, such as OLN, contribute to fetal growth effects have yet to be determined. The placenta plays a critical role in modulating the in utero environment to promote optimal fetal growth and is dysfunctional in pregnancies complicated by fetal growth restriction. However, no previous work has examined the direct effect of OLN on the placenta. We assessed whether OLN can impact the placenta by exposing a human trophoblast cell line (HTR-8/SVneo cells) to OLN and determining its effects on trophoblast invasion. Altered invasion is heavily implicated in adverse pregnancy outcomes such as preeclampsia, and intrauterine growth restriction. This thesis demonstrates that OLN increases trophoblast cell invasion, as well as integrin gene expression and the amount of active extracellular MMPs, which are important for invasion. Although the cellular signaling pathway(s) by which OLN mediates these effects remains unclear, it may involve OLN’s ability to decrease the maximal activity of the mitochondrial electron transport chain complexes. These findings provide the first evidence that OLN has the potential to affect placentation. This thesis contributes to the current understanding of how antipsychotic drugs can result in adverse fetal outcomes and allows healthcare providers to better predict and manage fetal outcomes of women taking OLN during pregnancy.