Dexamethasone induces transgenerational inheritance of fetal-derived glomerulosclerosis phenotype in offspring through GR/DNMT3a mediated alterations of the lncRNA-Meg3/Notch signaling pathway
Abstract Prenatal dexamethasone exposure (PDE) has been reported to be associated with negative pregnancy outcomes and increased susceptibility to chronic diseases in their offspring. This study aimed to explore the transgenerational effects and mechanisms of renal developmental toxicity in offsprin...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-025-02346-1 |
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| Summary: | Abstract Prenatal dexamethasone exposure (PDE) has been reported to be associated with negative pregnancy outcomes and increased susceptibility to chronic diseases in their offspring. This study aimed to explore the transgenerational effects and mechanisms of renal developmental toxicity in offspring induced by PDE. We found that PDE caused fetal renal dysplasia and adult glomerulosclerosis phenotype in F1-F3 female offspring. Sequencing and experimental assays revealed that PDE reduced DNA methylation levels in the promoter region of the imprinted gene lncRNA Meg3 (Meg3), increased the expression of Meg3 and reduced the expression of the downstream Notch signaling pathway in kidneys of F1-F3 female fetuses. Meanwhile, Meg3 expression was increased in oocytes of PDE F1 and F2 offspring. The results of the in vitro experiments confirmed that dexamethasone activates GR and reduces DNMT3a expression in primary metanephric mesenchymal stem cells (MMSCs), which causes Meg3 hypomethylation/hyperexpression and the inhibition of the Notch signaling pathway, resulting in fetal renal dysplasia. Knockdown of GR expression, overexpression of DNMT3a, or silencing of Meg3 could reverse the downstream-associated alterations. In summary, PDE induced fetal-derived glomerulosclerosis phenotype mediated by the GR/DNMT3a/Meg3/Notch signal pathway in fetal rats, which had transgenerational inheritance effects and may be associated with increased Meg3 expression transmitted via oocytes. This study confirmed the transgenerational inheritance of fetal-derived glomerulosclerosis phenotype induced by PDE and provided an experimental basis for investigating the underlying mechanisms. Graphical Abstract |
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| ISSN: | 1478-811X |