Course-, dose-, and stage-dependent toxic effects of prenatal dexamethasone exposure on fetal articular cartilage development

Chen, Ze; Zhao, Zhe; Li, Yunzepeng; Zhang, Xingyu; Li, Bin; Chen, Liaobin; Wang, Hui

doi:10.1016/j.toxlet.2018.01.008

Cited by 27 publications

(22 citation statements)

References 41 publications

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“…Reports from both LaBorde et al and Hansen et al indicated that prenatal dexamethasone exposure from gestation days 9‐14 induced maternal and fetal weight loss, as well as cleft palate in the rats 3,4 . Our previous work also indicated that maternal dexamethasone induced developmental toxicity to both articular cartilage and long bone of the fetal mice in a course‐, dose‐, and stage‐dependent manner 5,6 . Moreover, our previous studies with rats indicated that prenatal dexamethasone exposure also led to an inhibited ossification of the primary ossification center in the fetal femur and the further decrease in peak bone mass of the adult rat offspring 7,8 .…”

Section: Introductionmentioning

confidence: 78%

“…3,4 Our previous work also indicated that maternal dexamethasone induced developmental toxicity to both articular cartilage and long bone of the fetal mice in a course-, dose-, and stage-dependent manner. 5,6 Moreover, our previous studies with rats indicated that prenatal dexamethasone exposure also led to an inhibited ossification of the primary ossification center in the fetal femur and the further decrease in peak bone mass of the adult rat offspring. 7,8 However, whether and how maternal dexamethasone usage during pregnancy affects the development of fetal growth plate, which determines the development and growth of the fetal long bone, is still unknown.…”

Section: Introductionmentioning

confidence: 98%

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GR/Sp3/HDAC1/UGDH signaling participated in the maternal dexamethasone‐induced dysplasia of the rat fetal growth plate

Wen

Shi

et al. 2020

FASEB j.

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Maternal dexamethasone decreases the body length of the newborn. However, whether dexamethasone inhibits the development of the growth plate of the fetal long bone is still unknown. Here, we found that lengths of fetal femur and growth plate were both shorter in the fetuses with maternal dexamethasone (0.2 mg/kg.d from gestation day 9 to 20), with a decreased proteoglycan content of the growth plate in the fetal rat. Notable decreases in both the gene expression and H3K9 acetylation of UDP‐glucose dehydrogenase (Ugdh) gene, which codes a key enzyme in the proteoglycan biosynthesis in the chondrocyte, were also observed. Meanwhile, up‐regulation of glucocorticoid receptor (GR), specific protein 3 (Sp3), and histone deacetylase 1 (Hdac1) gene expression were detected in the fetal growth plate. Similar changes were also observed in the chondrogenic rat bone marrow stromal cells (BMSCs) with excessive exogenous dexamethasone. However, antagonizing GR with RU486 and silencing Hdac1 or Sp3 with specific siRNAs could all stimulate the H3K9 acetylation and gene expression of Ugdh previously inhibited by dexamethasone. Meanwhile, dexamethasone also induced the nuclear translocation of GR, which further directly bound to the Ugdh promoter and interacted with HDAC1 and Sp3, respectively. Collectively, our study revealed that maternal dexamethasone induced the direct binding of GR to the Ugdh promoter of the chondrocyte in the rat fetal growth plate, which recruited HDAC1 and Sp3, induced deacetylation of the H3K9, and subsequently inhibited Ugdh gene expression. Such changes further led to attenuated proteoglycan synthesis in the developing chondrocyte and therefore disrupted the development of growth plate and fetal long bone.

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Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 98%

GR/Sp3/HDAC1/UGDH signaling participated in the maternal dexamethasone‐induced dysplasia of the rat fetal growth plate

Wen

Shi

et al. 2020

FASEB j.

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“…Therefore, to ensure the reliability and rigor of RT-qPCR analysis, it is of considerable significance to screen the stable panel of reference genes in rat developmental periods and verify their reliability. Previous studies showed that the matrix content of cartilage in each of the above periods decreased significantly in the PDE model, and the mRNA and protein expression levels of ACAN were also significantly reduced (Iwaniak et al, 2016;Chen et al, 2018;Xiao et al, 2020). To further verify the reliability of reference genes screened above, we used different reference genes to standardize the mRNA expression of ACAN in offspring rat cartilage in the PDE model.…”

Section: Discussionmentioning

confidence: 99%

“…To further verify the stability and reliability of the screened panel of reference genes, we used the PDE-induced IUGR rat model to confirm the influence of using a single-reference gene or panel of reference genes on the mRNA expression by standardizing cartilage functional gene ACAN at GD20, PW6, and PW12. A large number of early animal and cell experiments had shown that the matrix content of cartilage in each of the above periods decreased significantly in the PDE-induced IUGR model, and the expression levels of ACAN mRNA and protein were also considerably reduced (Iwaniak et al, 2016;Chen et al, 2018;Xiao et al, 2020). The verification results showed that when normalized with the two single reference genes screened above (RPL4 and RPL5), the mRNA expression level of ACAN was significantly reduced in cartilage of male and FIGURE 3 | The candidate reference genes' expression and stability of female rat cartilage in different developmental stages in the PDE-induced IUGR model.…”

Section: Verification Of Stability and Accuracy Of Cartilage Referencmentioning

confidence: 99%

“…Therefore, fetalmaternal glucocorticoid overexposure under prenatal adverse environmental exposure can be a common phenomenon. Moreover, the IUGR model induced by prenatal dexamethasone exposure (PDE) is a classic method (Tomaszewska et al, 2012;Conti et al, 2017;Chen et al, 2018;Liu et al, 2018;Xiao et al, 2018;Li et al, 2019;Wu et al, 2019). Dexamethasone, as a synthetic glucocorticoid, is easy to enter fetus through the placenta (Morales et al, 1986), so the IUGR model induced by PDE can well simulate the overexposure of glucocorticoid in prenatal adverse environments during the development of offspring rats.…”

Section: Introductionmentioning

confidence: 99%

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Selection and Validation of the Optimal Panel of Reference Genes for RT-qPCR Analysis in the Developing Rat Cartilage

Han

et al. 2020

Front. Genet.

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Real-time fluorescence quantitative PCR (RT-qPCR) is widely used to detect gene expression levels, and selection of reference genes is crucial to the accuracy of RT-qPCR results. Minimum Information for Publication of RT-qPCR Experiments (MIQE) proposes that using the panel of reference genes for RT-qPCR is conducive to obtaining accurate experimental results. However, the selection of the panel of reference genes for RT-qPCR in rat developing cartilage has not been well documented. In this study, we selected eight reference genes commonly used in rat cartilage from literature (GAPDH, ACTB, 18S, GUSB, HPRT1, RPL4, RPL5, and SDHA) as candidates. Then, we screened out the optimal panel of reference genes in female and male rat cartilage of fetus (GD20), juvenile (PW6), and puberty (PW12) in physiology with stability analysis software of genes expression. Finally, we verified the reliability of the selected panel of reference genes with the rat model of intrauterine growth retardation (IUGR) induced by prenatal dexamethasone exposure (PDE). The results showed that the optimal panel of reference genes in cartilage at GD20, PW6, and PW12 in physiology was RPL4 + RPL5, which was consistent with the IUGR model, and there was no significant gender difference. Further, the results of standardizing the target genes showed that RPL4 + RPL5 performed smaller intragroup differences than other panels of reference genes or single reference genes. In conclusion, we found that the optimal panel of reference genes in female and male rat developing cartilage was RPL4 + RPL5, and there was no noticeable difference before and after birth.

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Circular RNA Gtdc1 Protects Against Offspring Osteoarthritis Induced by Prenatal Prednisone Exposure by Regulating SRSF1‐Fn1 Signaling

Liu,

Hong,

et al. 2024

Advanced Science

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Chondrodysplasia is closely associated with low birth weight and increased susceptibility to osteoarthritis in adulthood. Prenatal prednisone exposure (PPE) can cause low birth weight; however, its effect on offspring cartilage development remains unexplored. Herein, rats are administered clinical doses of prednisone intragastrically on gestational days (GDs) 0–20 and underwent long‐distance running during postnatal weeks (PWs) 24–28. Knee cartilage is assayed for quality and related index changes on GD20, PW12, and PW28. In vitro experiments are performed to elucidate the mechanism. PPE decreased cartilage proliferation and matrix synthesis, causing offspring chondrodysplasia. Following long‐distance running, the PPE group exhibited more typical osteoarthritis‐like changes. Molecular analysis revealed that PPE caused cartilage circRNomics imbalance in which circGtdc1 decreased most significantly and persisted postnatally. Mechanistically, prednisolone reduced circGtdc1 expression and binding with Srsf1 to promote degradation of Srsf1 via K48‐linked polyubiquitination. This further inhibited the formation of EDA/B+Fn1 and activation of PI3K/AKT and TGFβ pathways, reducing chondrocyte proliferation and matrix synthesis. Finally, intra‐articular injection of offspring with AAV‐circGtdc1 ameliorated PPE‐induced chondrodysplasia, but this effect is reversed by Srsf1 knockout. Altogether, this study confirms that PPE causes chondrodysplasia and susceptibility to osteoarthritis by altering the circGtdc1‐Srsf1‐Fn1 axis; in vivo, overexpression of circGtdc1 can represent an effective intervention target for ameliorating PPE‐induced chondrodysplasia.

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Course-, dose-, and stage-dependent toxic effects of prenatal dexamethasone exposure on fetal articular cartilage development

Cited by 27 publications

References 41 publications

GR/Sp3/HDAC1/UGDH signaling participated in the maternal dexamethasone‐induced dysplasia of the rat fetal growth plate

GR/Sp3/HDAC1/UGDH signaling participated in the maternal dexamethasone‐induced dysplasia of the rat fetal growth plate

Selection and Validation of the Optimal Panel of Reference Genes for RT-qPCR Analysis in the Developing Rat Cartilage

Circular RNA Gtdc1 Protects Against Offspring Osteoarthritis Induced by Prenatal Prednisone Exposure by Regulating SRSF1‐Fn1 Signaling

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