Sp1 participates in the cadmium-induced imbalance of the placental glucocorticoid barrier by suppressing 11β-HSD2 expression

Fengyun, Fan; Shen, Wan-Ting; Wu, Sisi; Chen, Na; T, Xia; Wang, Fan; Zhang, Qiong

doi:10.1016/j.envpol.2020.113976

Cited by 15 publications

(8 citation statements)

References 54 publications

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“…The top ranked transcription factor was specificity protein 1 (SP1), a zinc finger transcription factor that binds to a variety of GC-rich motifs and regulates the expression and function of miRNAs as well as the expression of genes associated with embryonic development and differentiation ( 36 , 37 ). SP1 has been shown to regulate the placental glucocorticoid barrier by repressing the expression of 11β-hydroxysteroid dehydrogenase type 2, leading to fetal growth restriction (FGR) ( 38 ). One study identified the interaction of miR-331-3p with SP1 and the interaction of miR-331-3p and miR-1908-5p with glycosyltransferases as a novel mechanism for ABO blood group regulation ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Hub Genes and MicroRNAs in Human Placental Tissues from In Vitro Fertilization-Embryo Transfer

et al. 2021

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ObjectiveSupraphysiological hormone exposure, in vitro culture and embryo transfer throughout the in vitro fertilization-embryo transfer (IVF-ET) procedures may affect placental development. The present study aimed to identify differences in genomic expression profiles between IVF-ET and naturally conceived placentals and to use this as a basis for understanding the underlying effects of IVF-ET on placental function.MethodsFull-term human placental tissues were subjected to next-generation sequencing to determine differentially expressed miRNAs (DEmiRs) and genes (DEGs) between uncomplicated IVF-ET assisted and naturally conceived pregnancies. Gene ontology (GO) enrichment analysis and transcription factor enrichment analysis were used for DEmiRs. MiRNA-mRNA interaction and protein-protein interaction (PPI) networks were constructed. In addition, hub genes were obtained by using the STRING database and Cytoscape. DEGs were analyzed using GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Differentially expressed miRNAs were validated through qRT-PCR.ResultsCompared against natural pregnancies, 12 DEmiRs and 258 DEGs were identified in IVF-ET placental tissues. In a validation cohort, it was confirmed that hsa-miR-204-5p, hsa-miR-1269a, and hsa-miR-941 were downregulation, while hsa-miR-4286, hsa-miR-31-5p and hsa-miR-125b-5p were upregulation in IVF-ET placentas. Functional analysis suggested that these differentially expressed genes were significantly enriched in angiogenesis, pregnancy, PI3K-Akt and Ras signaling pathways. The miRNA-mRNA regulatory network revealed the contribution of 10 miRNAs and 109 mRNAs while EGFR was the most highly connected gene among ten hub genes in the PPI network.ConclusionEven in uncomplicated IVF-ET pregnancies, differences exist in the placental transcriptome relative to natural pregnancies. Many of the differentially expressed genes in IVF-ET are involved in essential placental functions, and moreover, they provide a ready resource of molecular markers to assess the association between placental function and safety in IVF-ET offspring.

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Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Hub Genes and MicroRNAs in Human Placental Tissues from In Vitro Fertilization-Embryo Transfer

et al. 2021

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“…However, biological analysis of the promoter sequence of the 11β-HSD2 gene indicated that the 11β-HSD2 promoter did not contain a cAMP-response element; therefore, the effect of cAMP on the expression of 11β-HSD2 was potentially indirectly mediated via other transcription factors ( 28 ). Sp1 is a sequence-specific DNA-binding protein that regulates the transcription of cellular and viral genes containing GC-rich promoters ( 29 ). A previous study suggested that the expression of 11β-HSD2 is highly tissue-specific in vivo ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

cAMP regulates 11β‑hydroxysteroid dehydrogenase‑2 and Sp1 expression in MLO‑Y4/MC3T3‑E1 cells

et al. 2020

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11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) is one of the key enzymes in glucocorticoid metabolism, which can inactivate local corticosterone and regulate the level of active glucocorticoid in tissues. The expression of 11β-HSD2 and its regulatory pathway serve an important role in the apoptosis of steroid induced osteonecrosis of the femoral head (SANFH). The present study aimed to identify the regulatory effects of cAMP on the expression of Sp1 transcription factor (Sp1) and 11β-HSD2 in osteocytes at the cellular level. Murine long bone osteocyte Y4 (MLO-Y4) clone cells and mouse embryo osteoblast-like (MC3T3-E1) cells were cultured in vitro with adenylate cyclase activator or inhibitor (forskolin and SQ22536, respectively) to investigate the effects of alterations to intracellular cAMP levels. mRNA and protein expression levels of Sp1 and 11β-HSD2 were detected by reverse transcription-quantitative PCR and western blotting, respectively. Compared with the negative control group, the mRNA and protein expression levels of Sp1 were significantly increased in the activation group, whereas Sp1 expression levels were significantly decreased in the inhibition group. Similarly, compared with the negative control group, the mRNA and protein expression levels of 11β-HSD2 were significantly increased in the activator group, but significantly decreased in the inhibitor group. The aforementioned results indicated that intracellular cAMP levels significantly regulated the expression of Sp1 and 11β-HSD2 in mouse osteocytes and osteoblasts. Therefore, the present study suggested a potential therapeutic strategy for the prevention of osteonecrosis of the femoral head.

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“…SD rats were reared as described in previous studies. [9] A positive vaginal smear can be used as a confirmation of pregnancy, and the day of a positive smear is determined as gestational day (GD) 0. Pregnant rats were randomly selected and segregated into 6 groups (n = 6/group).…”

Section: Animals and Treatmentmentioning

confidence: 99%

“…Statistics on the incidence of FGR as described in the previous study. [9] Placental tissue were transferred to liquid nitrogen immediately, followed by storage at −80°C until subsequent experiments.…”

Section: Animals and Treatmentmentioning

confidence: 99%

“…[8] A recent study has revealed that Cd mediates the downregulation of 11β-HSD2 by regulating specificity protein 1 (Sp1). [9] Sp1, as a zinc-finger protein, can bind to GC-rich sections of 11β-HSD2 promoter. [10] Cd can damage the DNA domain by replacing zinc in the Sp1 binding domain [11] and result in decreases in the binding of Sp1 to 11β-HSD2 promoter and also reductions in 11β-HSD2 expression.…”

Section: Introductionmentioning

confidence: 99%

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Selenium attenuates the cadmium‐induced placenta glucocorticoid barrier damage by up‐regulating the expression of specificity protein 1

Chen

et al. 2022

J Biochem & Molecular Tox

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Cadmium (Cd) is an environmental pollutant and pregnant women are especially susceptible to the effects of exposure to Cd. Our previous study found Cd can be accumulated in the placenta and causes fetal growth restriction (FGR) through damage the placental glucocorticoid barrier. Selenium (Se), as an essential micronutrient, can allivate Cd-induced toxicity. In this study, we aim to explore the protective mechanism of Se against Cd-induced the placental glucocorticoid barrier damage and FGR. Pregnant Sprague Dawley (SD) rats were exposed to CdCl 2 (1 mg/kg/day) and Na 2 SeO 3 (0.1-0.2-0.3 mg/kg/day) by gavage from gestational day (GD) 0 to GD 19. The results showed that reduced fetal weight, increased corticosterone concentrations in the maternal and fetal serum, and impaired placental labyrinth layer blood vessel development, appeared in pregnant rats after Cd exposure and improved after treated with Se. In cell experiments, we confirmed that Se reduces Cd-induced apoptosis. Moreover, Se can abolish Cd-induced 11β-HSD2 and specificity protein 1 (Sp1) decreasing in vivo and vitro. In human JEG-3 cells, the knockdown of Sp1 expression by small interfering RNA can suppressed the protective effect of Se on Cd-induced 11β-HSD2 decreasing. In general, our results demonstrated that Se is resistant to Cd-induced FGR through upregulating the placenta barrier via activation of the transcription factor Sp1.

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Sp1 participates in the cadmium-induced imbalance of the placental glucocorticoid barrier by suppressing 11β-HSD2 expression

Cited by 15 publications

References 54 publications

Integrated Analysis of Hub Genes and MicroRNAs in Human Placental Tissues from In Vitro Fertilization-Embryo Transfer

Integrated Analysis of Hub Genes and MicroRNAs in Human Placental Tissues from In Vitro Fertilization-Embryo Transfer

cAMP regulates 11β‑hydroxysteroid dehydrogenase‑2 and Sp1 expression in MLO‑Y4/MC3T3‑E1 cells

Selenium attenuates the cadmium‐induced placenta glucocorticoid barrier damage by up‐regulating the expression of specificity protein 1

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