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.