Neurosteroid regulation of placental inflammation

ABSTRACT Diverse pregnancy pathologies, including preeclampsia and spontaneous preterm labor, share a broad phenotype of placental inflammation. Placental inflammation is also a known risk factor for impaired neurodevelopmental outcomes. It is characterized by elevated ratios of pro- to anti-inflammatory signaling molecules, as well as activation of inflammatory pathways that promote these responses, such as Toll-like receptor (TLR) and nuclear factor k B (NFkB) pathway activation. While investigating the impact of altered placental neurosteroid production on brain development, we found a correlation between placental allopregnanolone (ALLO) levels and molecular indicators of placental inflammation, an association not previously described. Our new preliminary data from mouse and human placenta support a negative correlation between placental ALLO levels and inflammatory status. We will leverage human placental biospies from the NICHD’s Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) cohort to define placental neurosteroid and cytokine levels across multiple pregnancy pathologies. We will pair this assessment with mechanistic manipulations in human placental explant (HPE) cultures from healthy, term pregnancies. The impact of endogenous and exogenous ALLO exposure on human placental inflammation and inflammatory signaling in both sexes will be assessed using state-of-the-art neurosteroid and cytokine analysis to: investigate the reciprocal interactions of endogenous placental ALLO with placental production of immune mediators (Aim 1) and determine whether treatment with exogenous ALLO or its analogs can prevent placental inflammatory responses. Since placental inflammation is a component of multiple pregnancy complications that result in preterm delivery and severe neonatal illness, as well as a significant contributor to short- and long-term neurodevelopmental risk in children, such as autism, we need to better understand the regulatory mechanism controlling the placental inflammatory milieu. The experiments proposed here will fill key knowledge gaps in understanding human placental endocrine and inflammatory function, point to possible circulating neurosteroid biomarkers for at-risk fetuses and potentially produce new therapies to reduce placental inflammation before it causes either acute or long-term injury to the fetus.