Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Embryonic osteocalcin signaling determines lifelong adrenal steroidogenesis and homeostasis in the mouse.

Through their ability to regulate gene expression in most organs, glucocorticoid (GC) hormones influence numerous physiological processes and are therefore key regulators of organismal homeostasis. In bone, GC hormones inhibit expression of the hormone Osteocalcin for poorly understood reasons. Here, we show that in a classical endocrine feedback loop, osteocalcin in return enhanced the biosynthesis of GC as well as mineralocorticoid hormones (adrenal steroidogenesis) in rodents and primates. Conversely, inactivation of osteocalcin signaling in adrenal glands significantly impaired adrenal growth and steroidogenesis in mice. Embryo-made osteocalcin was necessary for normal Sf1 expression in fetal adrenal cells and adrenal cell steroidogenic differentiation and therefore determined the number of steroidogenic cells present in the adrenal glands of adult animals. Embryonic, not postnatal, osteocalcin also governed adrenal growth, adrenal steroidogenesis, blood pressure, electrolyte equilibrium, and the rise in circulating corticosterone levels during the acute stress response in adult offspring. This osteocalcin-dependent regulation of adrenal development and steroidogenesis occurred even in the absence of a functional hypothalamus/pituitary/adrenal axis and explains why osteocalcin administration during pregnancy promoted adrenal growth and steroidogenesis and improved the survival of adrenocorticotropic hormone signaling-deficient animals. This study reveals that a bone-derived embryonic hormone influences lifelong adrenal functions and organismal homeostasis in the mouse.

Early-Life Stress Reprograms Stress-Coping Abilities in Male and Female Juvenile Rats.

Prenatal stress (PS) is a major risk factor for the development of emotional disorders in adulthood that may be mediated by an altered hypothalamic-pituitary-adrenal axis response to stress. Although the early onset of stress-related disorders is recognized as a major public health problem, to date, there are relatively few studies that have examined the incidence of early-life stressors in younger individuals. In this study, we assessed PS impact on the stress-coping response of juvenile offspring in behavioral tests and in the induced molecular changes in the hippocampus. Furthermore, we assessed if pregnancy stress could be driving changes in patterns of maternal behavior during early lactation. We found that PS modified stress-coping abilities of both sex offspring. In the hippocampus, PS increased the expression of bdnf-IV and crfr1 and induced sex difference changes on glucocorticoids and BDNF mRNA receptor levels. PS changed the hippocampal epigenetic landscape mainly in male offspring. Stress during pregnancy enhanced pup-directed behavior of stressed dams. Our study indicates that exposure to PS, in addition to enhanced maternal behavior, induces dynamic neurobehavioral variations at juvenile ages of the offspring that should be considered adaptive or maladaptive, depending on the characteristics of the confronting environment. Our present results highlight the importance to further explore risk factors that appear early in life that will be important to allow timely prevention strategies to later vulnerability to stress-related disorders.

Periconceptional ethanol exposure alters hypothalamic-pituitary-adrenal axis function, signalling elements and associated behaviours in a rodent model.

Alcohol consumption throughout pregnancy has been associated with mental illness, hyperactivity and social difficulties in offspring. This may be due in part to programmed disruption of the hypothalamic-pituitary-adrenal axis (HPA) activity and responsiveness. However, it is unknown if the HPA is affected and similar behavioural outcomes occur following alcohol exposure limited to the time around conception, the periconceptional (PC) period. Female Sprague-Dawley rats were treated with PC:EtOH (12.5 % v/v EtOH liquid diet) or a control diet from four days before conception, until embryonic day 4. Offspring at 3-months of age underwent the forced swim test (FST) and social interaction test. HPA reactivity tests (combined dexamethasone suppression test (DST) and corticotropin-releasing hormone test (CST), 30-minute restraint stress) were performed at 5 months of age and then pituitary and adrenal glands were collected for expression of genes involved in HPA regulation. PC:EtOH exposure significantly increased immobility (p < 0.05) in both sexes in the FST. PC:EtOH also increased the duration of affiliative behaviour (p < 0.05) within the social interaction test in female offspring. PC:EtOH programmed HPA hyperactivity in both sexes during the DST/CST test (p < 0.05); however, there was no impact of PC:EtOH on plasma corticosterone concentration in response to restraint stress. There was no significant impact of PC:EtOH on mRNA expression in glucocorticoid signalling genes in the pituitary gland or the steroidogenic pathway in the adrenal gland. This study suggests that alcohol exposure, even when limited to a short period around conception, can program mental illness-like phenotypes, and this was associated with alterations in HPA responsiveness. This study further highlights that consumption of alcohol even prior to implantation may impact the long-term health of offspring.

Programming of a developmental imbalance in hypothalamic glutamatergic/GABAergic afferents mediates low basal activity of the hypothalamic-pituitary-adrenal axis induced by prenatal dexamethasone exposure in male offspring rats.

This study was intended to demonstrate that prenatal dexamethasone exposure (PDE) can induce low basal activity of the hypothalamic-pituitary-adrenal axis (HPAA) in male offspring rats and explore the underlying mechanism. Pregnant rats were subcutaneously administered 0.2 mg/kg/d dexamethasone from gestational day (GD) 9 to GD20. Male GD20 fetuses and postnatal day 85 adult male offspring rats were sacrificed under anesthesia. Hypothalamic cells were from GD20∼postnatal day (PD) 7 fetal male rats, treated with different concentrations of dexamethasone and the glucocorticoid receptor (GR) antagonist mifepristone for 5 days. The results suggested that dexamethasone enhanced the expression of hypothalamic L-glutamic acid decarboxylase (GAD) 67 by activating GR, further stimulating the conversion of glutamate to gamma-aminobutyric acid (GABA) and inducing an imbalance in glutamatergic/GABAergic afferents in the hypothalamic paraventricular nucleus (PVN). This imbalance change was maintained postnatally, leading to the inhibition of parvocellular neurons, and mediating the low basal activity of the HPAA in PDE offspring rats, which was manifested by decreased levels of blood adrenocorticotropic hormone and corticosterone as well as reduced expression levels of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus. Programming of a developmental imbalance in glutamatergic/GABAergic afferents in the PVN is a potential mechanism responsible for low basal activity of the HPAA in male PDE rats.

Neurogenesis and antidepressant action.

A theoretical framework is proposed to gain insight into the pathogenesis of major depressive disorder (MDD). Despite being a relatively weak argument, the neurogenesis theory is suggested to compensate for the limitations of the monoamine theory. In the adult hippocampus, neurogenesis is functionally related to regulation of the hypothalamic-pituitary-adrenal (HPA) axis, inflammatory processes, cognitive functions and other aspects that contribute to etiological factors that lead to MDD and promote recovery from MDD. Despite a lack of investigation into neurogenesis and antidepressant action, it is proposed that chronic administration of antidepressant(s) can induce the recruitment and integration of newborn neurons into the dentate gyrus and, ultimately, lead to the remission of MDD. The extant body of literature indicates that the suppression of neurogenesis per se may be associated with an impaired response to antidepressant treatment rather than with the induction of depressive-like behaviors. Moreover, recent studies have shown that increasing the survival rate and incorporation of new neurons can alleviate depressive-like behaviors and promote stress resilience. According to the neurogenic reserve hypothesis, hippocampal neurogenesis supports specific cortical functions, including executive functions, pattern separation and contextual information processing, control over the HPA axis and behavioral coping mechanisms in response to stressful situations. Therefore, hippocampal neurogenesis may be a promising biological indicator of stress resilience and antidepressant response in patients with MDD.

The epigenetics of the hypothalamic-pituitary-adrenal axis in fetal development.

The hypothalamic-pituitary-adrenal (HPA) axis is an important hormonal mechanism of the human body and is extremely programmable during embryonic and fetal development. Analyzing its development in this period is the key to understanding in fact how vulnerabilities of congenital diseases occur and any other changes in the phenotypic and histophysiological aspects of the fetus. The environment in which the mother is exposed during the gestational period can influence this axis. Knowing this, our objective was to analyze in recent research the possible impact of epigenetic programming on the HPA axis and its consequences for fetal development. This review brought together articles from two databases: ScienceDirect and PUBMED researched based on key words such as "epigenetics, HPA axis, cardiovascular disease, and circulatory problems" where it demonstrated full relevance in experimental and scientific settings. A total of 101 articles were selected following the criteria established by the researchers. Thus, it was possible to verify that the development of the HPA axis is directly related to changes that occur in the cardiovascular system, to the cerebral growth and other systems depending on the influence that it receives in the period of fetal formation.

The Hypothalamic-Pituitary-Adrenal Axis and the Fetus.

Glucocorticoids (GCs), cortisol in humans, influence multiple essential maturational events during gestation. In the human fetus, fetal hypothalamic-pituitary-adrenal (HPA) axis function, fetal adrenal steroidogenesis, placental 11ß- hydroxysteroid dehydrogenase type 2 activity, maternal cortisol concentrations, and environmental factors impact fetal cortisol exposure. The beneficial effects of synthetic glucocorticoids (sGCs), such as dexamethasone and betamethasone, on fetal lung maturation have significantly shifted the management of preterm labor and threatened preterm birth. Accumulating evidence suggests that exposure to sGCs in utero at critical developmental stages can alter the function of organ systems and that these effects may have sequelae that extend into adult life. Maternal stress and environmental influences may also impact fetal GC exposure. This article explores the vulnerability of the fetal HPA axis to endogenous GCs and exogenous sGCs.

A time-course transcriptional kinetics of the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes in zebrafish eleutheroembryos after exposure to norgestrel.

The objective of the present study was to investigate the effects of norgestrel on the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes in zebrafish eleutheroembryos. Zebrafish embryos were exposed to different concentrations of norgestrel (0 ng L(-1) , 5 ng L(-1) , 50 ng L(-1) , and 100 ng L(-1) ) for 144 h post fertilization (hpf), and the transcriptional profiles of the HPG and HPA axes were examined every day. Norgestrel modulated the expression of Pgr and Vtg1 messenger (m)RNAs mainly at 96 hpf for all treatment groups. In addition, norgestrel strongly altered the expression of Cyp11a1 mRNA above 5 ng L(-1) (significant upregulation from 48 hpf to 120 hpf and significant downregulation for 144 hpf). Norgestrel treatment could significantly induce expression of Cyp19a1a, Cyp11b, Gnrh2, Gnrh3, and Lhb mRNAs but inhibit transcripts of Hsd11b2 and Crh genes above 5 ng L(-1) at different time points. The transcriptional expression levels of Esr1, Ar, Star, Hsd17b3, Fshb, and Pomc were also mediated by 5 ng L(-1) norgestrel or higher during different exposure periods. Taken together, the overall results imply that the transcriptional changes in zebrafish eleutheroembryos may pose a potential effect on embryonic development, in particular in the brain and gonadogenesis.

Fetal and Neonatal HPA Axis.

Stress is an integral part of life. Activation of the hypothalamus-pituitary-adrenal (HPA) axis in the adult can be viewed as mostly adaptive to restore homeostasis in the short term. When stress occurs during development, and specifically during periods of vulnerability in maturing systems, it can significantly reprogram function, leading to pathologies in the adult. Thus, it is critical to understand how the HPA axis is regulated during developmental periods and what are the factors contributing to shape its activity and reactivity to environmental stressors. The HPA axis is not a passive system. It can actively participate in critical physiological regulation, inducing parturition in the sheep for instance or being a center stage actor in the preparation of the fetus to aerobic life (lung maturation). It is also a major player in orchestrating mental function, metabolic, and cardiovascular function often reprogrammed by stressors even prior to conception through epigenetic modifications of gametes. In this review, we review the ontogeny of the HPA axis with an emphasis on two species that have been widely studied-sheep and rodents-because they each share many similar regulatory mechanism applicable to our understanding of the human HPA axis. The studies discussed in this review should ultimately inform us about windows of susceptibility in the developing brain and the crucial importance of early preconception, prenatal, and postnatal interventions designed to improve parental competence and offspring outcome. Only through informed studies will our public health system be able to curb the expansion of many stress-related or stress-induced pathologies and forge a better future for upcoming generations.

Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.

The hypothalamic-pituitary-adrenal (HPA) axis is one of the most important neuroendocrine axes and plays an important role in stress defense responses before and after birth. Prenatal exposure to xenobiotics, including environmental toxins (such as smoke, sulfur dioxide and carbon monoxide), drugs (such as synthetic glucocorticoids), and foods and beverage categories (such as ethanol and caffeine), affects fetal development indirectly by changing the maternal status or damaging the placenta. Certain xenobiotics (such as caffeine, ethanol and dexamethasone) may also affect the fetus directly by crossing the placenta into the fetus due to their lipophilic properties and lower molecular weights. All of these factors probably result in intrauterine programming alteration of the HPA axis, which showed a low basal activity but hypersensitivity to chronic stress. These alterations will, therefore, increase the susceptibility to adult neuropsychiatric (such as depression and schizophrenia) and metabolic diseases (such as hypertension, diabetes and non-alcoholic fatty liver disease). The "over-exposure of fetuses to maternal glucocorticoids" may be the main initiation factor by which the fetal HPA axis programming is altered. Meantime, xenobiotics can directly induce abnormal epigenetic modifications and expression on the important fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein, et al) or damage by in situ oxidative metabolism of fetal adrenals, which may also be contributed to the programming alteration of fetal HPA axis.

Embryonic GABA(B) receptor blockade alters cell migration, adult hypothalamic structure, and anxiety- and depression-like behaviors sex specifically in mice.

Neurons of the paraventricular nucleus of the hypothalamus (PVN) regulate the hypothalamic- pituitary-adrenal (HPA) axis and the autonomic nervous system. Females lacking functional GABA(B) receptors because of a genetic disruption of the R1 subunit have altered cellular characteristics in and around the PVN at birth. The genetic disruption precluded appropriate assessments of physiology or behavior in adulthood. The current study was conducted to test the long term impact of a temporally restricting pharmacological blockade of the GABA(B) receptor to a 7-day critical period (E11-E17) during embryonic development. Experiments tested the role of GABA(B) receptor signaling in fetal development of the PVN and later adult capacities for adult stress related behaviors and physiology. In organotypic slices containing fetal PVN, there was a female specific, 52% increase in cell movement speeds with GABA(B) receptor antagonist treatment that was consistent with a sex-dependent lateral displacement of cells in vivo following 7 days of fetal exposure to GABA(B) receptor antagonist. Anxiety-like and depression-like behaviors, open-field activity, and HPA mediated responses to restraint stress were measured in adult offspring of mothers treated with GABA(B) receptor antagonist. Embryonic exposure to GABA(B) receptor antagonist resulted in reduced HPA axis activation following restraint stress and reduced depression-like behaviors. There was also increased anxiety-like behavior selectively in females and hyperactivity in males. A sex dependent response to disruptions of GABA(B) receptor signaling was identified for PVN formation and key aspects of physiology and behavior. These changes correspond to sex specific prevalence in similar human disorders, namely anxiety disorders and hyperactivity.

Glucocorticoids and fetal programming part 2: Mechanisms.

The lifelong health of an individual is shaped during critical periods of development. The fetus is particularly susceptible to internal and external stimuli, many of which can alter developmental trajectories and subsequent susceptibility to disease. Glucocorticoids are critical in normal development of the fetus, as they are involved in the growth and maturation of many organ systems. The surge in fetal glucocorticoid levels that occurs in most mammalian species over the last few days of pregnancy is an important developmental switch leading to fundamental changes in gene regulation in many organs, including the brain. These changes are important for the transition to postnatal life. Exposure of the fetus to increased levels of glucocorticoids, resulting from maternal stress or treatment with synthetic glucocorticoids, can lead to long-term 'programming' of hypothalamic-pituitary-adrenal function and behaviours. Glucocorticoids act at multiple levels within the fetal brain. Growing evidence indicates that they can exert powerful effects on the epigenome, including on DNA methylation, histone acetylation and microRNA, to influence gene expression. Such influences probably represent a critical component of the 'programming' process, and might be partly responsible for the transgenerational effects of antenatal glucocorticoid exposure on neurologic, cardiovascular and metabolic function.

Thyroid hormones in fetal growth and prepartum maturation.

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic-pituitary-thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4 and T3 bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.

Embryonic development of gonadotrope cells and gonadotropic hormones--lessons from model fish.

Pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are key regulators of vertebrate reproduction. The differential regulation of these hormones, however, is poorly understood and little is known about gonadotrope embryonic development. The different cell types in the vertebrate pituitary develop from common progenitor cells just after gastrulation. Proper development and merging of the anterior and posterior pituitary is dependent upon carefully regulated cell-to-cell interactions, and a suite of signaling pathways with precisely organized temporal and spatial expression patterns, which include transcription factors and their co-activators and repressors. Among the pituitary endocrine cell types, the gonadotropes are the last to develop and become functional. Although much progress has been made during the last decade regarding details of gonadotrope development, the coordinated program for their maturation is not well described. FSH and LH form an integral part of the hypothalamo-pituitary-gonad axis, the main regulator of gonad development and reproduction. Besides regulating gonad development, pre- and early post-natal activity in this axis is thought to be essential for proper development, especially of the central nervous system in mammals. As a means to investigate early functions of FSH and LH in more detail, we have developed a stable transgenic line of medaka with the LH beta subunit gene (lhb) promoter driving green fluorescent protein (Gfp) expression to characterize development of lhb-expressing gonadotropes. The lhb gene is maternally expressed early during embryogenesis. lhb-Expressing cells are initially localized outside the primordial pituitary in the developing gut tube as early as 32 hpf. At hatching, lhb-Gfp is clearly detected in the gut epithelium and in the anterior digestive tract. lhb-Gfp expression later consolidates in the developing pituitary by 2 weeks post-fertilization. This review discusses status of knowledge regarding pituitary morphology and development, with emphasis on gonadotrope cells and gonadotropins during early development, comparing main model species like mouse, zebrafish and medaka, including possible developmental functions of the observed extra pituitary expression of lhb in medaka.

Development and programming of the hypothalamus-pituitary-adrenal axis.

The fetal hypothalamus-pituitary-adrenal (HPA) axis plays a critical role in fetal development and physiology in utero: appropriate function of the fetal HPA axis is critical for preparation of the fetus for birth and survival in postnatal life. Because of the critical importance of appropriate physiological regulation of HPA activity in postnatal life, there has been intense interest in the possibility that fetal or neonatal stressors can permanently "program" the axis to hyperrespond or hyporespond to stimuli. This is a review of the literature relevant to normal development and "programming" of the HPA axis.

Prenatal maternal mood is associated with altered diurnal cortisol in adolescence.

BACKGROUND: Experimental animal work shows that prenatal stress has a persisting effect on the hypothalamic-pituitary-adrenal (HPA) axis of offspring. The implications of these findings for human health and development are not yet clear. METHODS: The data are based on the ALSPAC cohort, a prospective longitudinal study of a community sample that has followed mothers and children from pregnancy. When the children were aged 15 years, diurnal cortisol samples were collected at wake-up, 30 min post-awakening and at afternoon and evening times on up to three consecutive days on n=889 adolescents. Diurnal cortisol was predicted from prenatal anxiety and depression, obstetric, life-style, socio-demographic, and postnatal covariates. RESULTS: Multilevel model analysis indicated that maternal prenatal anxiety was associated with a modest alteration of diurnal cortisol, indexed by a reduced cortisol awakening response and flatter diurnal slope. The effects were independent of psychosocial and obstetric covariates and measures of maternal postnatal anxiety; effects were similar for prenatal maternal depression. There was no association between adolescent cortisol and paternal prenatal anxiety. CONCLUSIONS: There are small but persisting associations between maternal prenatal mood and diurnal cortisol in the child that persist into adolescence and may constitute a programming effect.

[Effects of the prenatal hypoxia on the hypothalamic-pituitary-adrenal axis function and working memory in rats].

A comparative analysis of the effects of severe hypobaric hypoxia in different prenatal periods on expression profiles of glucocorticoid receptors (GR) in dorsal (CA1) and ventral (dental gyrus) hippocampus and neocortex of rats, their stress reactivity and working memory has been performed in the present study for the first time. According to the data obtained, severe hypoxia in the prenatal period induces remarkable disturbances of GR expression in the neurons of neocortex of adult males but not females, that correlates to the disruption of working memory in adult males exposed to hypoxia on the prenatal 14-16th days. Elevation of stress plasma corticosterone levels have been observed only in the females subjected to hypoxia on the prenatal 17-19th days. Hypoxia in the females and males results in the differential changes in functions of hippocampus, as well as of other brain areas involved in learning.

Effects of early- and late-gestational maternal stress and synthetic glucocorticoid on development of the fetal hypothalamus-pituitary-adrenal axis in sheep.

Prenatal maternal stress (PMS) programs dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) in postnatal life, though time periods vulnerable to PMS, are still unclear. We evaluated in pregnant sheep the effect of PMS during early gestation [30-100 days of gestation (dGA); term is 150 dGA] or late gestation (100-120 dGA) on development of fetal HPAA function. We compared the effects of endogenous cortisol with synthetic glucocorticoid (GC) exposure, as used clinically to enhance fetal lung maturation. Pregnant sheep were exposed to repeated isolation stress twice per week for 3 h in a separate box with no visual, tactile, or auditory contact with their flock-mates either during early (n = 7) or late (n = 7) gestation. Additional groups received two courses of betamethasone (BM; n = 7; 2 × 110 µg kg(- 1) body weight, 24 h apart) during late gestation (106/107 and 112/113 dGA, n = 7) or acted as controls (n = 7). Fetal cortisol responses to hypotensive challenge, a physiological fetal stressor, were measured at 112 and 129 dGA, i.e. before and during maturation of the HPAA. Hypotension was induced by fetal infusion of sodium nitroprusside, a potent vasodilator. At 112 dGA, neither PMS nor BM altered fetal cortisol responses. PMS, during early or late gestation, and BM treatment increased fetal cortisol responses at 129 dGA with the greatest increase achieved in stressed early pregnant sheep. Thus, development of the HPAA is vulnerable to inappropriate levels of GCs during long periods of fetal life, whereas early gestation is most vulnerable to PMS.

Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease.

Adverse environments during the fetal and neonatal development period may permanently program physiology and metabolism, and lead to increased risk of diseases in later life. Programming of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key mechanisms that contribute to altered metabolism and response to stress. Programming of the HPA axis often involves epigenetic modification of the glucocorticoid receptor (GR) gene promoter, which influences tissue-specific GR expression patterns and response to stimuli. This review summarizes the current state of research on the HPA axis and programming of health and disease in the adult, focusing on the epigenetic regulation of GR gene expression patterns in response to fetal and neonatal stress. Aberrant GR gene expression patterns in the developing brain may have a significant negative impact on protection of the immature brain against hypoxic-ischemic encephalopathy in the critical period of development during and immediately after birth.