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Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats.

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 ? 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.

SUBMITTER: Xiao H

PROVIDER: S-EPMC5974192 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats.

Xiao Hao H Wen Yinxian Y Pan Zhengqi Z Shangguan Yangfan Y Qin Jun J Tan Yang Y Jiang Hongqiang H Li Bin B Zhang Qi Q Chen Liaobin L Wang Hui H

Cell death & disease 20180529 6

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. Th ...[more]

PMID: 29844424

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Project description:Intrauterine growth restricted offspring suffer from abnormal glucose homeostasis and ? cell dysfunction. In this study, we observed the dynamic changes of glucose metabolic phenotype, pancreatic morphology, and insulin synthesis in prenatal ethanol exposure (PEE) male offspring rats, and to explore the potential intrauterine programming mechanism of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis. Ethanol (4 g/kg·d) was administered through oral gavage during gestational day (GD) 9-20. Serum glucose and insulin levels, pancreatic ? cell mass, and expression of glucocorticoid receptor (GR), IGF1 and insulin were determined on GD20, postnatal week (PW) 6, PW12 with/without chronic stress (CS), and PW24, respectively. Both intraperitoneal glucose and insulin tolerance tests were conducted at PW12 and PW24. Results showed that the serum glucose and insulin levels as well as pancreatic ? cell mass were reduced on GD20 in PEE males compared with the controls, while pancreatic GR expression was enhanced but IGF1 and INS1/2 expression were suppressed. After birth, compared with the controls, ? cell mass in the PEE males was initially decreased at PW6 and gradually recovered from PW12 to PW24, which was accompanied by increased serum glucose/insulin levels and insulin resistance index (IRI) at PW6 and decreased serum glucose contents at PW12, as well as unchanged serum glucose/insulin concentrations at PW24. In addition, both improved glucose tolerance and impaired insulin sensitivity of the PEE males at PW12 were inversed at PW24. Moreover, at PW6 and PW12, pancreatic GR expression in the PEE group was decreased, while IGF1 expression was reversely increased, resulting in a compensatory increase of insulin expression. Moreover, CS induced pancreatic GR activation and inhibited IGF1 expression, resulting in impaired insulin biosynthesis. Conclusively, the above changes were associated with age and the intrauterine programming alteration of GC-IGF1 axis may be involved in prenatal and postnatal pancreatic dysplasia and impaired insulin biosynthesis in PEE male offspring.

Dataset Information

Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats.

Publications

Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats.

Similar Datasets

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