Cervantes, Elizabeth

Abstract Background and objective The placenta is crucial for fetal development; altered function is associated with complications and adverse neonatal outcomes. Our goal was to ascertain changes in the placental transcriptome in relation to neonatal outcome and fetal/placental sex. Study design Seventy-two mother-baby dyads were included. Demographic, obstetrical, neonatal, and infant health data were obtained through medical charts. Adverse neonatal outcome was defined as the presence of a pulmonary, cardiac, neurological or other health complication. Bulk RNA-sequencing of placental biopsies was obtained. P-value <0.05 was considered statistically significant. Results Neonates experiencing adverse outcomes were more likely to be premature or have lower birth weights. Analysis of the placental transcriptome revealed a predominant inflammatory profile in pregnancies associated with adverse neonatal outcomes with the top pathways being related to immune and inflammatory responses. Among differently expressed genes (DEGs), 1237 were upregulated and 239 were downregulated in adverse vs no adverse outcomes. Furthermore, sex-specific differences in gene expression were observed and indicated that male and female placentas displayed unique DEGs in association with adverse outcomes. Indeed, no DEG was observed in female placentas when comparing those without vs with adverse neonatal outcomes, as opposed to 1279 DEGs in male placentas, of which 91% were up-regulated in adverse subgroups. Conclusions These findings highlight that inflammatory pathways are upregulated in placentas in association with adverse neonatal outcomes, and showcase the importance of the fetal sex in understanding neonatal health. The placenta provides a unique tool for early identification of high-risk infants rapidly after delivery.

Preterm premature rupture of membranes (pPROM) is a leading cause of preterm birth (PTB) and is increasingly recognized for its association with neurodevelopmental disorders (NDDs). The disruption of fetal membrane integrity introduces potential infection and inflammation into the intrauterine environment, triggering immune responses that may affect fetal development. Placental inflammation plays a pivotal role in mediating these effects, exposing the fetus to cytokines, oxidative stress, and potential microbial insults that contribute to adverse neurodevelopmental outcomes. This review examines the current evidence of the mechanistic pathways linking pPROM-induced placental inflammation to NDDs, emphasizing the roles of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in the inflammatory responses. We discuss how these immune activations lead to immune cell recruitment and excessive (or uncontrolled) production of inflammatory mediators, leading to an overall inflammatory imbalance that has been linked to disrupted fetal brain development in animal models. Animal models provide critical insights into how both sterile and pathogenic placental inflammation alter fetal neurodevelopment, while human studies, though limited, highlight promising biomarkers and potential therapeutic targets. This review identifies critical knowledge gaps and outlines future directions to mitigate the impact of placental inflammation on long-term infant health.

Abstract The vertebrate stress response (SR) is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and contributes to generating context appropriate physiological and behavioral changes. Although the HPA axis plays vital roles both in stressful and basal conditions, research has focused on the response under stress. To understand broader roles of the HPA axis in a changing environment, we characterized an adaptive behavior of larval zebrafish during ambient illumination changes. The glucocorticoid receptor (nr3c1) was necessary to maintain basal locomotor activity in light and darkness. The HPA axis was required to adapt to light more efficiently but became dispensable when longer illumination was provided. Light adaptation was more efficient in dimmer light and did not require the mineralocorticoid receptor (nr3c2). Our findings show that the HPA axis contributes to the SR at various stages, facilitating the phasic response and maintaining an adapted basal state, and that certain adaptations occur without HPA axis activity.