Introduction: Prenatal stress has been shown to increase the susceptibility to adverse neonatal outcomes as well as psychopathology including anxiety and depression and the effects of exposure to prenatal stress can generate transgenerationally inheritable epigenetic and transcriptomic signatures linked to impaired mental and physical health. The objective of this study is to investigate the mechanistic effects of transgenerational and multigenerational exposure to prenatal stress on the developing fetal brain and placenta.
Methods: Four generations of Long-Evans rats were bred for this study. The parental (F0) generation gestating rats were exposed to stress during gestational days 12-18. The transgenerational lineage was bred to the F3 generation without any further stress exposure. The F3 generation multigenerational lineage experienced three successive generations of the stress paradigm. Control, transgenerational, and multigenerational lineage fetuses and placentas were collected at G21. Both the fetal cortex and placenta of the F1-F3 generations were used for DNA methylation, miRNA, and mRNA analyses in order to assess epigenomic and transcriptomic changes.
Results: Results demonstrated that ancestral transgenerational and multigenerational exposure to prenatal stress did not appear to have a strong effect on the F1 generation but caused significant changes in DNA methylation, mRNA, and miRNA expression in the placenta and embryonic cortex of the F2 and F3 generations. Transgenerational changes included alteration of gene pathways associated with neurological diseases and placental dysfunction. Interestingly, there was an overlap in epigenomic and transcriptomic changes between the placenta and fetal cortex, suggesting that the placenta may be used for a potential biomarker to predict molecular changes in the brain correlated with pathologies in adulthood.
Conclusion: The discovery of early predictive and prognostic biomarkers of neurological disease associated with ancestral exposure to prenatal stress is critical for early life therapeutic interventions that prevent and mitigate psychological and neurological diseases as well as improving public health outcomes.
Olena Babenko– Graduate Student, Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge
Yaroslav Ilnytskyy– Research Associate, Department of Biological Sciences, University of Lethbridge
Igor Kovalchuk– Professor, Department of Biological Sciences, University of Lethbridge
Gerlinde Metz– Professor, Canadian Centre for Behavioral Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, Canada T1K 3M4, Department of Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, Canada, T1K 3M4 , Southern Alberta Genome Sciences Centre, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, Canada T1K 3M4