Abstract
Prenatal dexamethasone exposure (PDE) induces developmental toxicities of multiple organs in offspring. Here, we verified the intergenerational effect of low peak bone mass induced by PDE and investigated its intrauterine programming mechanism. Pregnant rats were injected subcutaneously with 0.2 mg/kg/d dexamethasone from gestation day (GD) 9 to 20. Some pregnant rats were killed for the fetuses on GD20, and the rest went on to spontaneous labor to produce the first-generation (F1) offspring. The adult F1 male offspring were mated with normal females to produce the F2 offspring. In vivo, PDE leads to low peak bone mass in F1 male offspring rats at postnatal week (PW) 28. Furthermore, PDE reduced the bone mass in F1 male offspring from GD20 to PW12. Meanwhile, the osteogenic differentiation was suppressed and the local renin–angiotensin system (RAS) was activated continuously by PDE. Moreover, the histone 3 lysine 27 acetylation (H3K27ac) level in angiotensin-converting enzyme (ACE) promoter region was increased by PDE from GD20 to PW12. Likewise, PDE induced the low peak bone mass and the activated local RAS in F2 male offspring. Meaningfully, the H3K27ac level of ACE was increased by PDE in the F2 offspring. In vitro, dexamethasone inhibited bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation and promoted RAS activation. Furthermore, dexamethasone recruited CCAAT/enhancer-binding protein α and p300 into the BMSCs nucleus by activating glucocorticoid receptor, which cooperatively increased the H3K27ac level in the ACE promoter region. In conclusion, PDE induced the low peak bone mass and its intergenerational effect, which was mediated by sustained activation of RAS via increasing H3K27ac level of ACE.
Highlights
Dexamethasone, as a kind of synthetic glucocorticoids, can promote fetal lung maturity, reduce neonatal respiratory distress syndrome, and decrease perinatal mortality[1,2]
The results showed that prenatal dexamethasone exposure (PDE) reduced the bone mass at PW28 (Fig. 2a), which was manifested as the decreased BV/TV, Tb.N and Tb.Th, and increased Tb
The results showed that the Md.Ar and B.Pm in primary ossification center were significantly decreased by PDE, which indicated that PDE reduced the fetal bone mass in F1 male offspring (Fig. 2c, d)
Summary
Dexamethasone, as a kind of synthetic glucocorticoids, can promote fetal lung maturity, reduce neonatal respiratory distress syndrome, and decrease perinatal mortality[1,2]. It has been widely used as a medication for several types of severe disorders of pregnancy, including premature delivery[3,4]. Peak bone mass is the maximum bone mass in humans or animals under physiological conditions It is a key determinant of skeletal health throughout life. Any factors that inhibit BMSCs differentiating osteoblasts may lead to the low peak bone mass and high susceptibility to osteoporosis in adulthood. The local RAS in different organs or tissues plays an important role in diverse physiological functions including cell proliferation, differentiation, and apoptosis 18–20
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