SP 6: Glucocorticoid-Induced Fetal Programming

Prof. Dr. med. Matthias Schwab

Clinic for Neurology, Senior Consultant,
Head of the Multiple Sclerosis Center,
Head of the interdisciplinary center for sleep and respiratory medicine

phone: +49 3641 9-323411
fax: +49 3641 9-323412

Research questions and aims

1. To determine in humans the effects of prenatal glucocorticoid (GC) exposure on RNA expression in relation to the GC, dose, and timing of exposure. 2. To examine in humans if these changes in RNA expression have a neurocognitive, behavioral or immunological phenotype. 3. To identify vulnerable periods during gestation in rats and to examine to what extent gene expression in blood leucocytes and/or mouth epithelial cells may be a proxy of that in neuronal tissues.

Scientific Background

GC-induced fetal programming of the activity of the HPA axis, structural and functional brain development and the associated cognitive and behavioral consequences have been shown in humans and several animal species (1, 2). The effects are paralleled by changes of DNA methylation of a multitude of genes whereas the phenotypically relevant changes and under which circumstances they occur is unknown (3, 4).

Own preceding work

We have a whole set of neurocognitive, behavioral and stress sensitivity measures as well as saliva and blood samples of two unique cohorts of children at the age of 10-14y exposed to prenatal GCs and their matched controls. In the first cohort, mothers received 2x8 mg betamethasone to induce fetal lung maturation in threatened preterm birth but babies were born at term (1). In the second cohort, mothers were exposed to 5x1000 mg methylprednisolone to treat relapses in multiple sclerosis (5). Preliminary results in MP-treated pilot children show a huge impact of prenatal GCs on RNA expression, in particular on cellular signaling, metabolism and immune responses. A large pool of blood and tissue samples from rats exposed to the weight-adapted clinical dose of betamethasone at different times during pregnancy and at different ages during later life is available (3).

Method spectrum, involvement of the Clinician Scientist

The scientist will use the Nanopore technology at the PromethION platform for RNA sequencing in collaboration with the Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Canada. Determination of a whole set of cytokines both in humans and rats has been established at the Department of Neurology in collaboration with the Institute of Clinical Chemistry and Laboratory Medicine.

Relevance for CEPRE and for Reproductive Health

Knowledge of mechanisms and periods vulnerable to the side effects of prenatal GCs on programming of offspring brain development and immunocompetency will help to improve indication for treatment. The findings might help to identify offspring at risk and can quickly be transferred into preventive measures.

References

1. Rakers F, Schleussner E, Muth I, Hoyer D, Rupprecht S, Schiecke K, Groten T, Dreiling M, Kozik V, Schwab M, Hoyer H, Ligges C. Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8- to 9-year-old children: A prospective observational study. Acta Obstet Gynecol Scand. 2022;101(9):996-1006.

2. Van den Bergh BRH, van den Heuvel MI, Lahti M, Braeken M, de Rooij SR, Entringer S, Hoyer D, Roseboom T, Raikkonen K, King S, Schwab M. Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy. Neurosci Biobehav Rev. 2020;117:26-64.

3. Huse K, Lausser L, Sass M, Agba OB, Bergmeier C, Jahn N, Groth M, Koch P, Dziegelewska M, Reichelt M, Gall M, Kramer M, Witte OW, Schwab M, Kestler H, Platzer M. Analysis of global LINE DNA methylation by next generation sequencing reveals tissue- and gender-specificity and age-dependent changes in rats. . Nucl Acid Res under review.

4. Cao-Lei L, van den Heuvel MI, Huse K, Platzer M, Elgbeili G, Braeken M, Otte RA, Witte OW, Schwab M, Van den Bergh BRH. Epigenetic Modifications Associated with Maternal Anxiety during Pregnancy and Children's Behavioral Measures. Cells. 2021;10(9).

5. Kozik V, Schwab M, Thiel S, Hellwig K, Rakers F, Dreiling M. Protocol for a Cross-Sectional Study: Effects of a Multiple Sclerosis Relapse Therapy With Methylprednisolone on Offspring Neurocognitive Development and Behavior (MS-Children). Front Neurol. 2022;13:830057.