Low miR-92a-3p in oocytes mediates the multigenerational and transgenerational inheritance of poor cartilage quality in rat induced by prenatal dexamethasone exposure.

An adverse environment during pregnancy leads to intrauterine programming changes in multiple generations, resulting in the multigenerational inheritance of abnormal phenotype. Here, we reported the multigenerational inheritance of poor articular cartilage quality induced by prenatal dexamethasone exposure (PDE) with 0.2 mg/kg·d dexamethasone from gestational day (GD) 9 to GD20 in Wistar rats and investigated its intrauterine epigenetic programming mechanism. For the F1 female offspring at GD20, we found that the matrix synthesis of cartilage was suppressed, the histone 3 lysine 9 acetylation (H3K9ac) level and mRNA expression of the TGFβ signaling pathway were decreased, and the expression of histone deacetylase (HDAC) 2 was increased in the cartilage. Meaningfully, the similar changes were also found in the F1-F3 female adult offspring. Furthermore, PDE decreased the expression of miR-92a-3p in the oocytes of the F1-F2 offspring and in the cartilage of the F1-F3 generations. In vitro, the effect of dexamethasone on chondrocytes revealed that it inhibited the expression of miR-92a-3p through activating and binding glucocorticoid receptor, and reduced the H3K9ac level in the promoter of the TGFβ signaling pathway through the increased HDAC2. In conclusion, PDE induces the multigenerational inheritance of poor articular cartilage quality in female adult offspring; the potential mechanism involves the intergenerational effect of low miR-92a-3p expression in oocytes and low functional programming of TGFβ signaling pathway induced by decreased H3K9ac level via upregulating HDAC2. This study provides a new perspective to explain the multi-generation inheritance of PDE-induced organ dysplasia in adult offspring.