EPIGENETIC SIGNATURE OF CHRONIC MATERNAL STRESS
LOAD DURING PREGNANCY MIGHT BE A POTENTIAL
BIOMARKER FOR SPONTANEOUS PRETERM BIRTH
Rogac M, Peterlin B
*Corresponding Author: Mihael Rogac, M.D., Ph.D., Clinical Institute of Medical Genetics, University
Medical Center Ljubljana, Slajmerjeva 4, 1000 Ljubljana, Slovenia. Tel: +386-1-522-6171.
Fax: +386-1-540-1137. E-mail: mihael.rogac@kclj.si
page: 27
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INTRODUCTION
The rate of preterm birth, defined as birth before
37 weeks’ gestation, is rising worldwide. It accounts for
75.0% of perinatal mortality and more than half the longterm
morbidity. The frequency and severity of adverse
outcomes are rising with decreasing gestational age and
decreasing quality of care. The preterm birth rate has also
risen in most industrialized countries, despite increasing
knowledge of risk factors and mechanisms related to preterm
birth, and the introduction of many public health and
medical interventions designed to reduce preterm birth [1].
The frequency of preterm birth is about 12.0-13.0% in the
USA and 5.0-9.0% in many other developed countries [2].
Spontaneous preterm birth accounts for at least 50.0%
of all preterm birth. A previous spontaneous preterm birth
is the greatest risk factor for spontaneous preterm birth [2].
Chronic maternal stress is increasingly recognized as one of
the contributing risk factors for spontaneous preterm birth
[3-5]. Thus, preterm birth and chronic maternal stress load
during pregnancy are closely connected. We have not, as
yet, found the biological mechanisms of stress that relate
to the triggering of preterm births, but we can identify
several risk factors and behaviors that are connected to
spontaneous preterm birth and chronic maternal stress. For
example, these are previous trauma in childhood, anxiety
and depression, experiences with previous labor, low socioeconomic
status, low education, and nutrition.
Measures of stressful life events, the perception of
stress, depressive symptoms, and levels of pregnancy-related
anxiety are commonly used to indicate maternal adversity.
Chronic maternal stress load has been a sum of adverse
mother’s life events since her birth. Epigenetic biomarkers
of several specific genetic loci could be a reliable measure
of this chronic maternal stress load. These epigenetic
biomarkers may reveal mother’s stress bioprofile or stress diathesis. Studies showed that there is no strong scientific
proof for either the role of abnormal response of corticotropin-
releasing hormone (CRH), cytokines or for the role of
catecholamines in the pathogenesis of preterm birth [6,7].
Epigenetic modifications interacting with genetic variation to
precipitate disease [8] can provide a hypothetical explanation
for stress-related disorders such as preterm birth.
DNA methylation changes are tissue-specific. Evidence
show that blood/leucocytes might be a possible
surrogate through which to investigate stress related conditions
that act through the central nervous system (CNS).
We suggest that methylation changes of DNA isolated from
blood leucocytes are a reliable enough measure of stress
related changes that occur in the brain.
Understanding the molecular physiology of chronic
maternal stress load in preterm birth has important implications
for the development of preventive and treatment
measures for preterm birth and for decreasing mortality
and morbidity in preterm newborns. Additionally, such
understanding could also enable us to develop simple assays
based on epigenetic changes, thus providing us with
a process that also enables the measurement of chronic
stress load in expectant mothers.
Chronic Maternal Stress Load and Preterm Birth.
Almost 60 years ago, previous research already revealed that
women who were considered as emotionally well-adjusted
had a relatively low incidence of difficult labor [9]. Wortis
and Freedman [10] found that the endemic nature of premature
delivery in women of low social class was similarly
related to the stress of life experiences. Women who react
with greater sensitivity and less resilience to their life situations
also appear more likely to deliver prematurely [10].
Chronic or recurrent stress that occurs with maternal under
nutrition, immune system response, early-life events or
maternal psychopathology, leads to cascading, potentially
irreversible changes in biological stress-regulatory systems
[11]. Accumulated stress appears to negatively impact our
ability to respond to stress, and also affects how we perceive
stress in relation to our emotional response to environment.
Adaptation to stress has its own consequences, including
outcomes such as preterm birth.
Early life experiences appear to increase human susceptibility
for anxiety and depression that are known risk
factors for preterm birth [12-14]. Chronic stressors are
recognized for being particularly salient among poor and
minority women, that is, women who also correspondingly
experience the highest rates of adverse birth outcomes.
Expectant mothers from lower socio-economic groups are
often exposed to a higher incidence of incomplete families,
poor housing, low educational level, high mobility,
dysfunctional families and social pathology [10]. We know
that for individual subjects within this group, such factors
often represent an accumulation of psychological stresses.
Evaluating relationship between chronic maternal stress
load and spontaneous preterm birth, Manuck et al. [15]
identified nine potential spontaneous preterm birth clinical
phenotypes based on clinical data. Evidence of any type
of maternal stress was associated with 59.8% in a group
of very early spontaneous preterm birth and with 55.4%
in a group of early spontaneous preterm birth.
Chronic Maternal Stress Load and Epigenetics.
We now explain how DNA methylation is involved in regulating
the human organism’s stress response. The hypothalamic-
pituitary-adrenal (HPA) axis is a major component
of human stress response and its vulnerability is a key
factor in the pathogenesis of many chronic diseases of
adulthood. The HPA axis vulnerability is related to the velocity,
amplitude and duration of mother’s stress response.
We suggest describing this as HPA axis hyper-sensibility,
as stress response is often quick, strong and too long in
mothers with chronic stress loads (Figure 1). Most commonly
studied genes related to stress response are NR3C1 which encodes an enzyme to regulate the transmission of
cortisol to the fetus at the maternal-fetal boundary; FKBP5
which encodes FK506, a negative regulator of cortisol
response; BDNF, which influences neuronal development;
and, serotonin transporter SLC6A4 which encodes 5-HTT
protein, an important regulator of emotional behavior responses
in early life experiences.
Existing studies have primarily investigated the
role of glucocorticoid receptor expression and sensibility,
which is related to the promoter NR3C1 methylation
changes [16-20]. DNA methylation of few other genes such
as FKBP5, BDNF, 11B-HSD2, and serotonin transporter
SLC6A4 could also be involved. Perhaps these stressrelated
molecules also influence the activity of HPA axis
and/or human organism’s response to stress [21-23]. For
example, a deficiency of 11B-HSD2 leads to overexposure
of the fetus to cortisol and lower birth weight [24]. Placental
11BHSD2 is dynamically regulated by proinflammatory
cytokines, malnutrition, and maternal stress or
anxiety [25]. We suggest that DNA methylation changes
in these genes occur after increased exposure to cortisol,
especially in fetal and infant periods of life. Why and how
these changes occur is still a topic of discussion.
In animals, however, maternal licking/grooming (LG)
behavior has effect on offspring stress responses by increasing
HPA axis responses to stress. This kind of mother’s
behavior increases glucocorticoid receptor expression and
negative feedback. These changes in the offspring result from
epigenetic alterations, including DNA demethylation and increased
histone acetylation [2]. Subsequent studies in humans
expanded on the findings in rats. Turecki and Meaney [27]
systematically reviewed the effects of the social environment
and stress on GR gene methylation. They found that nine
out of 10 human studies examining exon 1F methylation (17
homologue in rats) reported increased promoter methylation
with early life adversity. Early life adversity is a known
cause of anxiety and depression in pregnancy. Glucocorticoid
receptor DNA methylation is an important step in organism
susceptibility to stress and is involved in interaction between
early life stressors and higher stress reactivity.
Nevertheless, these processes are related to the placenta
physiology and to the role of 11BHSD2 gene methylation,
that is the anatomical and physiological connection
between mother and fetus. This connection may either
protect or be detrimental to the fetus or embryo. DNA
methylation changes in other genes such as FKBP5, BDNF
and serotonin transporter SLC6A4, could also be a part of
mother’s stress bioprofile and could have a role in explaining
biological mechanisms of preterm birth.
Paquette et al. [23,28] studied in 509 infants the influence
of placental FKBP5 epigenetic variation at intron 7,
which is associated with infant neurobehavioral outcome
in the neonatal intensive care unit (NICU). FKBP5 also
regulates cortisol response within the placenta. Infants
who were born with an elevated expression of FKBP5
showed elevated stress abstinence at the time of birth. DNA
methylation changes of the BDNF gene were studied in
cases of early-life adversity and in psychiatric conditions
[29-31]. Montirosso et al. [32] and Provenzi et al. [22]
evaluated serotonin transporter SLC6A4 in pain-related
stress during NICU stays and its effect on infants’ temperament
at 3 months of age. Preterm birth per se was
not found to be associated with epigenetic alterations of
the SLC6A4, whereas higher levels of pain-related stress
exposure in NICU stays may alter transcriptional activity
of the serotonin transporter gene. Hillman et al. [33]
investigated the feto-placental genome and its interaction
with the maternal in utero environment leading to poor
placental development and fetal growth restriction. They
found that growth-restricted neonates have distinct DNA
methylation profiles in preterm placenta and in cord blood
at birth. Sparrow et al. [34] revealed that preterm birth is
associated with alterations in the methylome at sites that
influence neural development and function.
Epigenetic changes of several specific genetic loci
may comprise parts of the larger metabolic network, where
hypersensibility of the HPA axis is just one side of the
story (Figure 2). Hypersensibility of the HPA axis is not
necessarily manifested by increased cortisol concentration
in the blood, but may be related to receptor changes in the
hormones and neurotransmitters related to human stress
response. Preterm birth may, therefore, be identifiable as a
clinical symptom of chr onic maternal stress load that has accumulated since mother’s birth and is part of mother’s
stress bioprofile. Studies involving preterm birth and DNA
methylation changes in specific genetic loci can, therefore,
provide us with new opportunities and research challenges.
Epigenetics and Preterm Birth. Several studies
have examined the associations between the epigenome
and preterm birth. In support for this hypothesis, Vidal
et al. [8] found that maternal stress may be associated
with epigenetic changes at MEST DMR, a gene relevant
to maternal care and obesity. Reduced prenatal stress may
support the epigenomic profile of a healthy infant [8].
Three studies have investigated CpG sites connected
to preterm birth using neonatal blood [35-37]. Parets et
al. [35] found 29 CpG sites associated with development
and the Notch signaling pathway that were associated to
preterm birth in a case control study of 50 African American
neonates. These sites were independent of gestational
age [35]. Cruickshank et al. [36] also investigated blood
of premature neonates, and they identified 1555 CpG sites
associated with preterm birth; no specific type of preterm
birth was defined. These differences were no longer detectable
at age 18 [36]. Fernando et al. [37] identified 1855
sites associated with spontaneous preterm birth from cord
blood, and 196 were independent of gestational age and
none of these overlapped with the 29 preterm birth associated
sites from the previous study of Parets et al. [35].
There have been few studies examining DNA methylation
differences in mothers who deliver preterm. Parets
et al. [38] found that neonatal methylation could be predicted
from maternal methylation and these CpG sites were
enriched in biological pathways implicated in preterm birth
and chronic diseases. Heng et al. [39] examined 469 genes
that were differentially expressed in 106 women delivering
preterm compared to 48 women with threatened preterm
birth. These genes were correlated with several pathways,
including stress response and mRNA processing [39].
Many other studies examined other types of biomarkers
for preterm birth such as cytokines and other metabolites
in maternal serum, but biomarkers that examine DNA
methylation changes may allow for earlier identification
of those at increased risk for preterm birth. DNA methylation
changes are also more suitable to screening with
next-generation sequencing panels that utilize standardized
chemistry, and are able for more rapid and reproducible
assessment of multiple biomarkers. However, evidence
of preterm birth’s epigenetic signature is still scarce and
studies are so far inconclusive.
Epigenetic Signature in Blood as a Biomarker for
Preterm Birth. A limitation of studies that evaluate epigenetic
biomarkers for stress related clinical conditions is
that DNA methylation changes were investigated in the
blood and not in the brain. It is certainly not necessary that
a potentially useful biomarker detected in peripheral blood
resembles expression of the same analyte in the brain. To
date, most relevant studies have focused specifically on
the correspondence of the “methylome” (all methylated
sites) across tissues.
Measuring DNA methylation changes in single genes,
as in promoter I and IV of BDNF and FKBP5 genes, and
comparing blood and brain tissue, indicate that blood is
a good proxy for brain in terms of cytosine methylation
measured at the genome wide level [40,41]. For example,
in schizophrenia patients, Murphy et al. [42] found nearly
identical patterns of CpG site-specific methylation across
the blood and brain samples analyzing promoter region
of a single catechol-O-methyltransferase (COMT) gene.
These data adequately indicate the correlation between
DNA methylation in peripheral blood leukocytes and CNS
samples.
Researchers mostly studied the whole methylome
across various tissues. Fan and Zhang [43] reported
strong positive correlations in CpG-island methylation
status across all somatic tissues but they did not included
brain tissue in the study. Davies et al. [44] observed that
CpG sites within islands were more correlated across the
cortex, the cerebellum and blood than sites within island
shores or coding sequencing. Van der Oord et al. [45] found
that when they analyzed DNA extracted from 1408 blood
samples and 66 postmortem brain samples of schizophrenia
cases and controls, that of the CpG single nucleotide
polymorphism (SNP) methylated in brain, 94.0% were
also methylated in the blood. A review of the epigenomic
literature by Tylee et al. [46] revealed that CpG-island
methylation levels are generally highly correlated (r =
0.90) between blood and brain, and their review of the
transcriptome studies suggest that between 35.0 and 80.0%
of known transcripts are present in both brain and blood
tissue samples.
Recent studies also suggest that certain blood cells
such as lymphocytes and monocytes are a reliable source of
DNA methylation changes in the blood. And these changes
are correlated with DNA methylation changes in the brain.
An increasing body of evidence suggests that there is a
close relationship between the CNS and the immune system.
Lymphocytes appear to play a central role in this
communication. Numerous studies have shown similarities
between receptor expression and mechanisms of the
transduction processes of cells in the nervous system and
lymphocytes. In several neuropsychiatric disorders such as
depression, stress, Alzheimer’s disease and schizophrenia,
researchers found alterations of metabolism and cellular
functions in the CNS as well as main neurotransmitter and
hormonal systems that are similar to altered function and
metabolism of blood lymphocytes [47-49]. The presence of sympathetic fibers in lymphoid tissues suggests that
direct contact occurs for neural signaling cascades with
the immune system [50].
An important limitation in all of these studies was that
brain DNA methylation changes were studied in postmortem
tissue. Because taking a blood sample is a minimally
invasive procedure, it is typically considered as a practical
surrogate. For the present, however, such a practice affords
a reliable enough procedure for the examination of DNA
methylation changes in peripheral blood for evaluating the
risk of preterm birth as one kind of various stress-related
disorder.
Implications. Our analyses suggest that DNA methylation
changes of specific genetic loci cause increased
vulnerability and sensitivity of the human stress response.
This exaggerated stress response can also manifest in
preterm birth. It is possible that part of an exaggerated
response to stress in preterm birth lies in the DNA methylation
pattern of specific genes involved in cortisol signaling
and neurotransmitter systems such as serotonin.
Finding epigenetic biomarkers of increased stress
susceptibility for preterm birth or mother’s stress bioprofile
would be a first step in characterizing that group
of women with preterm births. Based on the results of a
blood sample, we could begin preventive and therapeutic
measures to decrease chronic maternal stress load in this
group of women. Preventive measures could involve cognitive
behavior therapy support, social assistance for underprivileged
groups of women, and mind-body therapies
for stress reduction. Therapeutic measures such as drugs
that change DNA methylation patterns are also underway.
Nutrition, too, might play a role as a preventive measure
against chronic stress accumulation.
Investigating chronic maternal stress load and risk for
preterm birth is also important in identifying epigenetic
mechanisms of human stress response, and fetal programing.
Again, in doing so, we may then be able to develop
simple assays based on epigenetic changes in order to
measure chronic stress load in expectant mothers.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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