700. Stress and pharmacology during prenatal development: modelling environmental exposures in vitro

Abstract

Abstract Background Psychological distress like anxiety or depression and life events like trauma or natural disasters play important roles in maternal and fetal health in pregnancy. According to the developmental origins of health and disease hypothesis, and consistent with perinatal longitudinal studies, the interplay of genetic predispositions with a wide range of environmental exposures individual differences in developmental trajectories and health risk outcomes of offspring. This happens as early as the first weeks of pregnancy and likely impacts placenta development and function, shaping how this organ filters environmental exposures and supports the developing fetus. Importantly, the brain undergoes significant growth and plasticity during the first pregnancy trimester. Altered activation of the glucocorticoid receptor (GR) system is one factor mediating stress effects, likely through transcriptional and epigenetic dysregulation. Aims & Objectives There are significant knowledge gaps regarding the biological determinants of environmental exposures and their molecular and cellular function outcomes, especially in relation to maternal-fetal transmission of psychopathology. To investigate these processes from a human-specific perspective we used state-of-the art in-vitro induced pluripotent stem cell-derived 3-dimensional organoids to model critical periods and tissues. The work presented herein is aimed at investigating how prenatal exposures, particularly prenatal stress and psychopharmacological exposure, shape fetal neurodevelopment via the placenta-brain axis. Method To determine cell-type specific GR activation response, we profiled the transcriptomes of thousands of cells using single-cell transcriptomic analyses following GR activation. We used immunofluorescence high-content confocal microscopy to better understand protein, and cell morphology-level effects. We used and single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) analyses to understand cell-type-specific gene-level responses and to build gene-regulatory networks of lasting effects on specific cell populations. Results Chronic GR activation in cerebral organoids induced a robust cell-type-specific differential response from transcription factors involved in neuronal cell fate regulation. Lineage analyses identified an over-commitment toward inhibitory neurons, through modulation of lineage driver genes that directed the likelihood of individual cells’ commitment. In-vitro findings were consistent across diverse genetic backgrounds and supported by ex-vivo human fetal brain data. In the first trimester placenta and trophoblast organoid models of these key tissues, we identified additional cell-type specific mechanisms of GR activation and cortisol regulation, pointing to protective cellular mechanisms with vulnerability in conditions of excessive exposure. Discussion & Conclusions Both cerebral and trophoblast organoids show responsiveness to GR activation that is cell-type and critical period specific. In the brain, the likely outcome of aberrant overexposure is a lasting shift in neuron type distribution and consequently brain architecture. In the placenta, cortisol overexposure interacts with cell-type specific barrier mechanisms and shows evidence of placental dysfunction. This work sheds light on the mechanisms by which environmental stimuli like maternal stress or pharmacology could lead to lasting changes in prenatal health and subsequent atypical brain development, perhaps explaining aspects of mental illness vulnerability.