Chorioamnionitis disrupts erythropoietin and melatonin homeostasis through the placental-fetal-brain axis during critical developmental periods

• DOI: 10.3389/fphys.2023.1201699
• Publication Date: 2023-07-20T17:31:22Z
• Authors: Yuma Kitase; Nethra K. Madurai; Sarah Hamimi; Ryan L. Hellinger; O. Angel Odukoya; Sindhu Ramachandra; Sankar Muthukumar; Vikram Vasan; Riley Sevensky; Shannon E. Kirk; Alexander Gall; Timothy Heck; Maide Ozen; Benjamin C. Orsburn; Shenandoah Robinson; Lauren L. Jantzie
• Keywords: Erythropoietin receptor; Hypoxia; Chorioamnionitis

Introduction: Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer a singular etiology. Most experience cumulative insults prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, postnatal stressors such as sepsis seizures. Accordingly, tailoring of therapeutic regimens endogenous repair or neuro-immunomodulatory agents for individuals requires more precise understanding ligand, receptor-, non-receptor-mediated regulation essential developmental hormones. Given the recent clinical focus on neurorepair PBI, we hypothesized that there would be injury-induced changes in erythropoietin (EPO), receptor (EPOR), melatonin (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, hypoxia inducible factors (HIF1α, HIF2α). Specifically, predicted EPO, EPOR, MLTR1, SIRT1, HIF1α HIF2α alterations after chorioamnionitis (CHORIO) reflect relative observed human preterm infants. Similarly, expected unique reveal potential clues mechanisms timing inflammatory oxidative CHORIO could inform future development treat PBI. Methods: To induce CHORIO, laparotomy was performed embryonic day 18 (E18) rats transient uterine artery occlusion plus intra-amniotic injection lipopolysaccharide (LPS). Placentae fetal brains were collected at 24 h. Brains also 2 (P2), P7, P21. levels quantified using electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT liquid chromatography mass spectrometry. Results: Examination MLTR1 h showed while placental EPO mRNA decreased acutely cerebral EPOR increased compared control. Notably, P2 SIRT1 deficient despite normalized presence elevated serum levels. Uniquely, shifted P7 P21, prominent CHORIO-induced expression. Reductions P21 concomitant controls variable Discussion: These data commensurate robust inflammation through maternal placental-fetal axis, impacts MLT, HIF signal transduction defined by dynamic mRNA, protein. ligand-receptor mismatch, tissue compartment differential regulation, signaling highlight importance, complexity nuance neural immune cell provide As placenta, cells, cells share many common, developmentally regulated pathways, further studies needed clarify dynamics capitalize therapies target mechanisms.