Summary: Prenatal stress can leave lasting epigenetic marks that influence an individual’s vulnerability to stress and mental health conditions later in life. Adult children of mothers who experienced stress, anxiety, depression, or medically induced glucocorticoid exposure during pregnancy show molecular changes linked to altered stress responsiveness.
Source: Simon Fraser University
Simon Fraser University assistant professor Nadine Provençal and collaborators at the Max Planck Institute of Psychiatry have identified a form of “cellular memory” that helps explain how exposure to stress in the womb can shape how the brain responds to stress later in life.
“The prenatal period is one of the most dynamic and sensitive phases of human development,” says Nadine Provençal. “Stress experienced by the mother during pregnancy can affect both her health and the developing fetus. Our work links an epigenetic marker—a cellular memory—to an increased sensitivity to stress hormones, which may explain why some people are more vulnerable to stress as adults.”
In laboratory experiments, the research team exposed human hippocampal progenitor cells, which model developing neurons, to high levels of stress hormones comparable to those present during episodes of prenatal stress. They found that this exposure produced changes in DNA methylation—an epigenetic modification—on thousands of genomic sites. Crucially, many of these methylation changes remained after the hormones were removed, indicating a persistent cellular memory of early exposure.
Beyond the cell culture findings, the scientists examined umbilical cord blood from newborns whose mothers experienced prenatal stress, including clinical depression and anxiety, as well as cases where women received glucocorticoid analogues to reduce the risk of premature birth. The team detected a significant overlap between the epigenetic marks seen in the laboratory neurons and those present in the newborns’ cord blood, supporting the translational relevance of the cell-based model.
These enduring DNA methylation changes did not always correspond to stable shifts in gene expression. Instead, many of the lasting epigenetic marks appeared to prime genes to respond more strongly to subsequent stress challenges. In other words, early glucocorticoid exposure can reset the set point for how genes react to future stress, increasing transcriptional responsiveness when the system is re-exposed to stress hormones.
Functionally, lasting methylation changes localized to specific genomic regions associated with poised or bivalent enhancers—regulatory elements that can modulate gene activity during development. The researchers grouped differentially methylated sites into trajectories across neuron differentiation, identifying both transient and persistent patterns. A subset of persistent sites was also detectable in peripheral blood, enabling the creation of a polyepigenetic score that predicted prenatal glucocorticoid exposure in newborns’ cord blood DNA.
Taken together, these results illuminate a biological pathway by which prenatal stress can alter neurodevelopmental trajectories and recalibrate stress-response systems throughout life. Understanding these molecular mechanisms helps explain increased psychiatric risk following prenatal adversity and may guide early identification of individuals at higher risk. Ultimately, this knowledge could contribute to prevention strategies or interventions designed to reduce the likelihood that early stress leads to later mental illness.
Source:
Simon Fraser University
Media Contacts:
Nadine Provençal – Simon Fraser University
Image Source:
The image is in the public domain.
Original Research: Closed access
“Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation”. Nadine Provençal, Janine Arloth, Annamaria Cattaneo, Christoph Anacker, Nadia Cattane, Tobias Wiechmann, Simone Röh, Maik Ködel, Torsten Klengel, Darina Czamara, Nikola S. Müller, Jari Lahti, PREDO team, Katri Räikkönen, Carmine M. Pariante, and Elisabeth B. Binder. PNAS. doi: 10.1073/pnas.1820842116
Abstract
Prenatal exposure to stress is linked to a higher risk of psychiatric disorders later in life, potentially mediated by increased exposure to glucocorticoids (GCs) that affect neurogenesis. This study investigated long-lasting epigenetic mediators of those effects using a human hippocampal progenitor cell model. Glucocorticoid exposure during neurogenesis induced DNA methylation changes at tens of thousands of CpG sites and altered the expression of thousands of transcripts. Some methylation changes were transient, while others persisted and were enriched at regulatory enhancer regions. Persistent methylation differences did not necessarily produce stable expression changes but were associated with a stronger transcriptional response to a subsequent GC challenge. A subset of these persistent sites was also responsive in peripheral blood, allowing a polyepigenetic score that predicted prenatal exposure in newborn cord blood DNA. These data suggest early glucocorticoid exposure can shift the set point for future transcriptional responses to stress, which may underlie variable vulnerability to stress-related disorders later in life.