Translating basic research knowledge on the biological embedding of early-life stress into novel approaches for the developmental programming of lifelong health

Abstract

This review integrates scientific knowledge obtained over the past few decades on the biological mechanisms that contribute to the profound association between exposure to early adversity, including childhood trauma and prenatal stress, and the lifelong elevated risk to develop a broad range of diseases. We further discuss insights into gene-environment interactions moderating the association between early adversity and disease manifestation and we discuss the role of epigenetic and other molecular processes in the biological embedding of early adversity. Based on these findings, we propose potential mechanisms that may contribute to the intergenerational transmission of risk related to early adversity from the mother to the fetus. Finally, we argue that basic research knowledge on the biological embedding of early adversity must now be translated into novel intervention strategies that are mechanism-driven and sensitive to developmental timing. Indeed, to date, there are no diagnostic biomarkers of risk or mechanism-informed interventions that we can offer to victims of early adversity in order to efficiently prevent or reverse adverse health outcomes. Such translational efforts can be expected to have significant impact on both clinical practice and the public health system, and will promote precision medicine in pediatrics and across the lifespan.

Keywords: Developmental programming; Early life stress; Intergenerational transmission; Prenatal stress; Targeted intervention.

Fig. 1.. Early-Life Stress, Biological Consequences, and Risk for Disease.

Exposure to ELS robustly increases the lifelong risk for psychiatric disorders and chronic physical diseases. A core dysfunction at the neural, stress-physiological, immune and molecular levels promotes the pathophysiology of these disorders. The manifestation of symptoms or disease after ELS is moderated by allele variations in stress-regulatory genes and such gene-environment interactions are mediated in part by allelic and environmentally driven epigenetic programming of gene expression.

Fig. 2.. Intergenerational Transmission of the Effects of Early-Life Stress.

The transmission of maternal ELS to her child may occur during the sensitive prenatal and early postnatal periods of her offspring’s development. Maternal exposure to ELS can affect her long-term physical and mental health and these pathological conditions will likely endure when the mother becomes pregnant and after delivery. As a result, maternal ELS may be associated with an altered maternal-placental-fetal stress biology, which has the potential to affect the developing fetal brain. Maternal ELS experience may furthermore increase the risk of developing postpartum depression and parenting difficulties, which additionally impose a risk on the development of her offspring’s brain and increase vulnerability for adverse health outcomes.

Fig. 3.. A Vicious Cycle of Biological Embedding of Early-Life Stress, Disease Manifestation, and Transgernerational Transmission: Deriving Specific Targets for Intervention.

Exposure to ELS likely leads to immediate processes of biological embedding. This biological embedding of ELS with subsequent dysregulation of stress response systems, metabolic dysregulation, and inflammation, may lead to structural and functional changes in brain regions critical for stress, emotional, and energy homeostatic regulation, as well as accelerated cellular ageing. These biological embedding trajectories will eventually lead to manifestation of clinical phenotypes, including adverse mental and physical health outcomes. Additional stressors or developmental processes during puberty may accentuate risk. Genetic and social-protective factors, such as social support, may moderate outcomes. The phenotypic manifestation of the biological embedding of ELS may be transmitted into the next generation, perhaps already in the fetal phase, forming a vicious cycle of maltreatment and adverse health outcomes. This model may provide a framework for developing and testing novel intervention strategies that target different stages of this vicious cycle.