Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

Abstract

Walk, Sheffield S10 2SF 7 ‡ Corresponding author (a.fazeli@sheffield.ac.uk) 8 Abstract 9Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of 10 stress mechanisms -particularly psychiatric disorders -represent a significant global health problem. 11While it has long been observed that levels of stress experienced in the periconception period may 12 greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations 13are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-14 down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis 15 of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how 16 dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in 17 glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of 18 knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance 19 is then extensively discussed, including the role of chromatin remodelling associated with specific HPA 20 axis-related genes, and the possible role of regulatory RNAs as messengers of environmental stress both 21 in the intrauterine environment, and across the germ line. Furthering our understanding of the role of 22 stress on embryonic development is crucial if we are to increase our predictive power of disease risk 23 and devise effective treatments and intervention strategies. 24

Maternal and Neonatal Hair Cortisol Levels Are Associated with Infant Neurodevelopment at Six Months of Age

“…Our findings regarding hair cortisol levels during the first trimester offer an additional value supporting the importance of assessing stress levels during the periconception period [42]. In this respect, stress levels during the periconception period can have long-term effects on infant development [43].…”

“…Strengths of this study include the longitudinal design that allowed assessing cortisol levels during the first, second, and third trimester, and postpartum in pregnant women, along with neonate cortisol levels. Additionally, the use of hair to assess cortisol levels through a non-invasive method provides a retrospective stress status of pregnant women during the periconception period and gives the opportunity to estimate fetal cortisol [42,43,46]. Moreover, infant neurodevelopment was assessed at the early age of six months which may allow the detection of potential associations between maternal and neonate hair cortisol levels and infant development at early stages.…”

Maternal mental health and infant emotional reactivity: a 20-year two-cohort study of preconception and perinatal exposures

“…One recent study linked maternal abuse in childhood to increased placental hormone production during later pregnancies, providing preliminary evidence that maternal stress before conception may influence offspring neurodevelopment through changes to the in utero environment (Moog et al ., 2016). We assessed antenatal maternal depressive symptoms in the third trimester and may not have captured periconceptional exposure including during embryogenesis and implantation, both sensitive to environmental influence including maternal stress (Ord et al ., 2017). Brain regions integral to stress response regulation and susceptible to excess exposure to maternal hormones are identifiable by eight weeks gestation (Gunnar and Davis, 2013).…”

Premature birth stunts early growth and is a possible driver of stress‐induced maternal effects in the guppy Poecilia reticulata

“…As aspects of the environment such as resources, competition and predation stress are in constant flux, it is essential for organisms to respond plastically to environmental changes. Frequently, these changes exceed the reach of homeostasis and induce stress, necessitating adaptive responses to restore balance (Barton, ; Chrousos, ; Ord et al ., ). Appropriate stress response physiology is essential for survival and plasticity in response to stressful conditions is well‐documented (Schulte, ).…”