Long-term effects of prenatal synthetic glucocorticoid exposure on psychosocial stress reactivity and volitional control in children and adolescents

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Interactions between the developing individual and his or her developmental contexts are crucial for experience-dependent tuning of behavioural and brain development. Prenatal exposures to unfavorable events in the gestational environment, such as maternal stress or depression, glucocorticoids and substance abuse, are among the earliest adverse contextual influences on development. Of particular relevance to this project are long-term effects of prenatal synthetic glucocorticoid (sGC) exposure on the development of social stress reactivity and volitional control. Thus far, research on hypothalamus-pituitary-adrenal (HPA) axis functioning in humans exposed to antenatal sGC treatment is currently limited to the assessment of a single cortisol baseline measure and stress-induced cortisol secretion shortly after birth with preterm birth being an important confounder. Furthermore, although the HPA-axis is tightly linked to brain networks, such as the prefrontal circuitry, that subserve cognitive and motivational regulatory functions, long-term effects of antenatal sGC exposure on these regulatory functions in humans have been sparsely addessed and are mostly limited to behavioral assessments. To go beyond the current state of the art, this proposed project will assess long-term effects of antenatal sGC on psychosocial stress reactivity, behavioral and brain evoked potential measures of volitional control, using a retrospective longitudinal design. The proposed project has three aims: First, we plan to carry out a comprehensive assessment of hypothalamus-pituitary-adrenal (HPA) axis functioning in childhood and adolescence to explore (a) whether our previously observed effects of prenatal sGC exposure on stress reactivity in children would persist into adolescence and (b) whether these effects would generalize to measures of long-term changes in basal cortisol secretion. Second, by measuring electroencephalography (EEG) we aim to investigate the effects of antenatal sGC exposure on evoked brain potentials associated with cognitive monitoring, which are known to involve monoaminergic modulations and brain circuits that are tightly linked to the HPA-axis functions. A third goal of the current project is to investigate epigenetic modifications as a potential mechanism in mediating long-term effects of antenatal sGC on stress-related and cognitive measures. Other than the potential gain of understanding basic mechanisms that relate antenatal sGC exposure, monoaminergic modulation and cognition during child and adolescent development, a deeper understanding of long-term effects of antenatal sGC exposure is also of important clinical relevance given the widespread use of sGC (7 to 10% of women in Europe and North America) in obstetric care.