Excessive glucocorticoid exposure may interfere with neuronal maturation in utero

Excessive exposure to glucocorticoids appears to impede neuronal maturation in utero, which can result in greater disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure, suggests a study.

“Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development,” the investigators said.

In this study, the investigators activated the glucocorticoid receptor (GR) using the synthetic glucocorticoid dexamethasone. They also mapped the effects using single-cell transcriptomics across development.

The GR was expressed in all cell types, and these expression levels saw an increase through development. Its activation prompted translocation to the nucleus and produced the expected effects on known GR-regulated pathways, while neurons and progenitor cells exhibited targeted regulation of differentiation- and maturation-related transcripts.

“Uniquely in neurons, differentially expressed transcripts were significantly enriched for genes associated with behaviour-related phenotypes and disorders,” the investigators said.

Such human neuronal glucocorticoid response profile was validated across organoids from three independent human pluripotent stem cell (hiPSC) lines reprogrammed from various source tissues from both male and female donors.

“A fine-tuned balance of GR activation is essential for organ formation, with disturbances influencing many health outcomes,” the investigators said. “In utero, glucocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects.”