1 Introduction
In the 1990s, the British scholar Barker firstly proposed the hypothesis
of increased incidence of metabolic syndrome in adults with low birth
weight and the developmental origin of adult diseases based on the
results of a large-scale epidemiological survey. Over the past three
decades, scholars from many countries have carried out evidence-based
research on prenatal adverse environment, fetal birth weight, and adult
chronic diseases, and put forward a new concept of the origin of human
diseases called the Developmental Origins of Health and Disease (DOHaD).
To date, fetal development programming has become an essential theory
for understanding healthy development programming throughout the life
cycle (Fleming et al. , 2018).
Dexamethasone is one of synthetic
glucocorticoids that can promote fetal lung maturation, reduce the
occurrence of neonatal respiratory distress syndrome and perinatal
mortality, so it is widely used for preterm delivery and related
pregnancy diseases (Porto et al. ,
2011; Crowther et al. , 2015). The
World Health Organization (WHO) reported that the prevalence of prenatal
synthetic glucocorticoid treatment for premature labor at 22–36 weeks
of pregnancy is 54% in the maternal and child health survey data of 359
institutions in 29 countries and is as high as 91% in some countries
(Vogel et al. , 2014).
However, the use of prenatal
dexamethasone is a double-edged sword. A large number of studies have
confirmed that repeated
dexamethasone treatment has fetal developmental toxicity, which can
cause low birth weight, multiple organ development abnormalities, and
susceptibility to chronic diseases in adulthood
(Asztalos et al. , 2010;
Elfayomy et al. , 2014).
As the terminal effector of the hypothalamic-pituitary-adrenocortical
(HPA) axis, the adrenal gland is the organ with the earliest and fastest
growth of the HPA axis in utero . The adrenal gland is the organ
of glucocorticoid synthesis and secretion. Accumulating studies suggest
that basic glucocorticoid levels in utero play an important role
in fetal maturity and postnatal fate
(Moisiadis et al. , 2014a), and its
alteration caused by adverse environments during pregnancy can lead to
change in insulin-like growth factor 1 (IGF1) level in fetal blood
(Fowden, 2003), catch-up growth of the
IUGR progeny and the occurrence of metabolic diseases
(Mericq et al. , 2017). Therefore,
the development of the adrenal gland is the key to determine the
postnatal fate. IGF1 expression in the adrenal gland begins in the
second trimester of pregnancy, occurring only later than in the liver,
and IGF1 can regulate adrenal development and functional differentiation
(Han et al. , 1988). IGF1 and IGF1R
are widely expressed in the adrenal cortex, upregulating steroid
synthase through phosphorylation of the PI3K/Akt pathway to promote
steroidogenesis (Raha et al. ,
2007; Sirianni et al. , 2007). Our
previous research found that prenatal dexamethasone exposure (PDE) could
cause adrenal dysplasia in offspring mice, accompanied by decreased
serum corticosterone levels in maternal and fetal mice
(Xu et al. , 2011). However, is
this adrenal developmental dysfunction in offspring associated with
changes in maternal adrenal function? Is IGF1 involved in PDE-induced
programming alteration of adrenal development in
offspring?
We have not seen relevant reports
so far.
“Intrauterine programming” is the process of permanent alterations in
fetal tissue morphology and function caused by intrauterine environment
changes. And it is also the pathophysiological basis for the occurrence
of fetal-originated adult diseases
(Moisiadis et al. , 2014a).
Epigenetics
can lead to heritable changes in gene function that do not involve
changes in the DNA sequence, including DNA methylation, histone
modification, and non-coding RNA (such as miRNAs). Numerous studies have
suggested that glucocorticoid-induced intrauterine programming
alterations are related to abnormal expression of some critical genes
regulated by miRNAs (Clayton et al. ,
2018), and miRNAs can regulate histone acetylation and expression
levels of downstream target genes by targeting histone deacetylase
(Gao et al. , 2018;
Xing et al. , 2019). Our recent
studies have confirmed that abnormal histone acetylation modification
was involved in multi-organ development programming and related disease
susceptibility caused by PDE (Liu et
al. , 2018; Xiao et al. , 2018;
Li et al. , 2019). Therefore, we
speculate that low levels of maternally derived glucocorticoid caused by
PDE may regulate IGF1 histone acetylation and expression through miRNAs
in fetal adrenal, thereby resulting in its abnormal function development
in offspring.
In this study, based on a stable PDE rat model established in our
laboratory, we firstly confirmed the phenomenon of the low level of
maternally derived glucocorticoid
in fetal blood. Then, a programming alteration of GC-IGF1 axis was
explored by detecting blood corticosterone, adrenal IGF1 expression and
steroidogenesis function before and after birth, as well as its effects
after chronic stress in adults. Finally, the histone acetylation
regulating mechanism of glucocorticoid-dependent IGF1 expression was
elucidated in combination with human adrenocortical cells in
vitro . This study will elucidate the programming effect of maternal
glucocorticoid for offspring adrenal development programming and
homeostasis alterations, and provide an essential theoretical and
experimental basis for explaining the intrauterine development origin of
PDE-induced multi-organ dysplasia and related disease occurrence and
development in adults.