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.