4.1 The basis of establishing a PDE rat model and the significance of offspring’s abnormal adrenal function in the occurrence of fetal-derived diseases
Dexamethasone is often given to treat pregnant women at risk of premature delivery in the second and third trimester of pregnancy (Gilstrap et al. , 2001). The classic clinical application of dexamethasone in the treatment of premature infants is an intramuscular injection every 12 h, 6 mg each time, for a total of 4 times. However, approximately 1/3 of pregnant women change from preventive to continuous administration due to the difficulty in early diagnosis of preterm delivery and the inefficacy of a single course in some pregnant women, resulting in multiple courses of treatment, sometimes more than 11 courses (Quinlivan et al. , 1998; Murphy et al. , 2008). Accumulating animal experiments showed that multi-course treatment could cause a series of long-term adverse effects (Elfayomy et al. , 2014). The National Institutes of Health (NIH) suggested that more animal experiments were needed to explore the long-term effects of multi-course treatment.
In humans, the adrenal fetal zone and permanent zone gradually forms a transitional zone in the 16th-20thweeks during pregnancy, which has some typical characteristics of the adrenal cortex (Mesianoet al. , 1993). In rats, the development of the adrenal cortex starts from the migration of corpus callosum epithelial cells of the urogenital system from GD 9 (Hatanoet al. , 1996). The vital organs that sustain life have also developed and have corresponding functions in the second and third trimesters of pregnancy. Besides, prenatal treatment with dexamethasone in rats at 0.2 mg/kg·d in this study is comparable with that used in humans at 0.03 mg/kg·d. And the standard dose of dexamethasone in clinical settings during pregnancy is 0.05-0.2 mg/kg·d (Moisiadis et al. , 2014b). Therefore, we subcutaneously administrated 0.2 mg/kg·d dexamethasone on GD9-20 to establish the PDE rat model based on the clinical treatment status and the characteristics of adrenal development.
Glucocorticoids are involved in regulating the biosynthesis and metabolism of sugar, fat, and protein in the body, which play a vital role in the occurrence and development of various chronic diseases (Goodwin et al. , 2012). Longitudinal studies reported that repeated antenatal dexamethasone treatment could cause adverse effects on the growth and development of offspring (Frenchet al. , 1999), such as cognitive and behavioral disorders (French et al. , 2004). Recently, we confirmed multi-organ developmental abnormalities in offspring and susceptibilities to various diseases after birth, such as osteoporosis (Xiao et al. , 2018), neurobehavioral disorders (Huang et al. , 2019), glomerular sclerosis (Liet al. , 2019) in the PDE rat model. In this study, we used the same PDE rat model and found that the adrenal steroidogenic function persistently reduced in the offspring. These findings have significance to understand the occurrence and development of various chronic diseases in adult PDE offspring.