The Profound Impact of Prenatal Development on Lifelong Health: Exploring the DOHaD Hypothesis and the Role of Glucocorticoids

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The concept that prenatal development exerts a substantial influence on postnatal health has been progressively underscored by emerging scientific evidence. At the heart of this discourse is the “developmental origin of health and disease (DOHaD) hypothesis,” which posits that environmental factors during critical periods of prenatal development have enduring effects on cellular and tissue integrity, with notable implications for the central nervous system (CNS) and, by extension, lifelong human health. This hypothesis underscores the intricate link between prenatal environmental exposures and the subsequent risk of developing various diseases later in life.

Glucocorticoids (GCs), a class of steroid hormones, play a crucial role in the development of the CNS during pregnancy. These hormones are instrumental in regulating the development of fetal organs, particularly the lungs and brain. The physiological levels of GCs are meticulously regulated throughout gestation, following a species-specific pattern. In mice, for instance, corticosterone levels surge sharply towards the end of gestation. Conversely, in humans, cortisol levels—cortisol being the predominant GC—begin to rise gradually from the onset of the second trimester. This meticulous regulation underscores the critical role of GCs in developmental processes.

However, the therapeutic use of synthetic GCs (sGCs), as well as maternal endocrine and stress-related disorders, can lead to deviations from the physiological range and/or timing of GC levels, which may adversely impact fetal development. The placenta serves as a protective barrier against maternal GCs, but factors such as stress and depression can diminish its capacity to metabolize cortisol, leading to increased fetal exposure. sGCs, such as betamethasone or dexamethasone (dex), which readily cross the placenta, are commonly prescribed between 22 to 33 gestational weeks in high-risk pregnancies to promote fetal lung maturation and enhance survival rates in cases of imminent preterm delivery.

Preterm birth, defined as delivery before 37 gestational weeks, affects more than 1 in 10 babies globally, translating to approximately 15 million preterm births annually. Of these, around 615,000 occur extremely preterm (before 28 gestational weeks), underscoring the clinical and societal importance of prenatal sGC use in managing preterm delivery risks.

The deviation from the physiological range of prenatal GCs can have significant lasting effects on postnatal brain structure and behavior, as evidenced by large epidemiological studies. Animal model data further support the direct effects of GCs. Despite the well-characterized molecular and cellular effects of GCs on the term and adult brain in rodents, their impact on early brain development, particularly during the human neurogenic period (which extends until 28 gestational weeks), has remained largely unexplored until recently.

Recent research endeavors have sought to bridge this gap by employing a combination of experiments in human cerebral organoids (hCOs) and mouse embryos, coupled with human genetic analyses. These studies have mechanistically linked enhanced prenatal sGC exposure to alterations in human cortical neurogenesis, with lasting consequences for cognitive abilities and brain structure. This body of work not only reinforces the significance of the DOHaD hypothesis but also highlights the need for a nuanced understanding of prenatal environmental exposures, including the use of sGCs, in shaping lifelong health trajectories.

The exploration of the developmental origins of health and disease offers a vital framework for understanding the long-term health implications of prenatal environmental exposures. The role of glucocorticoids in this process elucidates the complex interplay between genetics, environmental factors, and developmental biology, underscoring the importance of targeted therapeutic interventions and preventative measures to mitigate the risk of adverse postnatal outcomes associated with prenatal disruptions.

The Role of Glucocorticoids in Neurogenesis: A Molecular Perspective on Prenatal Development and Neurodevelopmental Outcomes

The intricate choreography of gene expression, orchestrated by transcription factors (TFs), is essential for the correct progression of neurogenic processes. A spotlight on ZBTB16, a gene with species-specific expression patterns during development, reveals its critical role in these processes. In species like rodents, which are characterized by smooth brains (lissencephalic), Zbtb16 is notably absent during the phase of cortical neurogenesis. Contrastingly, in humans, which have folded brains (gyrencephalic), ZBTB16 marks its presence at early stages of neurogenesis, indicating a divergent biological function across species.

Glucocorticoids (GCs), a class of steroid hormones, are pivotal in sustaining the expression of ZBTB16 during the neurogenic period—a stage when it is physiologically absent. This action of GCs leads to an increased proliferation of Pax6+Eomes+ progenitor cells, underscoring their potency in amplifying gyrencephalic species-specific neurogenic processes. The ability of GCs to modulate or extend this sensitive developmental window for the production of brain progenitors (BPs) through ZBTB16 hints at a mechanism by which enhanced neurogenic potential is achieved. This specific mediation by ZBTB16 in the realm of neurogenesis, as evidenced by single-cell data, delineates a clear pathway through which GCs influence the brain’s developmental trajectory without interfering with other neuronal functions previously reported in the literature.

The clinical relevance of these findings becomes apparent when considering the context of premature births, where the administration of synthetic glucocorticoids (sGCs) is a common intervention to combat the risks associated with preterm delivery. With around 615,000 cases of extreme preterm pregnancies annually, the period of neurogenesis before the 28th gestational week becomes a critical window for sGC treatment. Such interventions, while crucial for survival, have been associated with long-term metabolic, endocrine, cardiovascular, and neurodevelopmental complications.

Recent studies and meta-analyses have begun to unravel the nuanced effects of sGC exposure, suggesting that the timing of administration significantly influences neurodevelopmental outcomes. Particularly, sGC treatments between 22 and 27 gestational weeks have been linked to a reduced risk of neurodevelopmental impairments in extremely preterm births, highlighting the importance of the neurogenic window in determining the impact of GC exposure on brain development.

Further investigation into the dichotomy of GC effects based on the timing of exposure during neurogenesis has revealed potential molecular and cellular pathways through which these impacts are mediated. The study of ZBTB16 as a critical mediator offers a molecular and cellular explanation for the observed differences in neurodevelopmental outcomes, suggesting that early sGC use might benefit behavioral and neurodevelopmental measures in extremely preterm infants.

However, the implications of increased neuron numbers resulting from GC-induced ZBTB16 expression during neurogenesis on postnatal brain function remain to be fully understood. While promising, the association between prenatal GC exposure, mediated by ZBTB16, and postnatal behavioral and structural outcomes requires careful interpretation.

In sum, the research into the role of GCs during neurogenesis not only sheds light on the molecular mechanisms underlying cortical development but also offers insights into how early interventions with sGCs might influence long-term neurodevelopmental and behavioral outcomes. These findings underscore the importance of timing in the administration of sGCs during pregnancy, paving the way for refined treatment guidelines that take into account the developmental windows of neurogenesis for optimizing both survival rates and quality of life in preterm infants.


reference link: https://doi.org/10.1016/j.neuron.2024.02.005

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