Down-regulation of uterine LIF expression induced by the hormonal level disorder causes embryo implantation loss after mice exposed to carbon disulfide at peri-implantation

Wang, Zhen; Sun, Yuan; Wu, Yanling; Zhang, Tongchao; Hu, Chengxia; Zhang, Bingzhen; Wang, Zhiping

doi:10.1016/j.bbrc.2015.09.141

Cited by 12 publications

(4 citation statements)

References 27 publications

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“…First, in this study, we wanted to evaluate the toxic effects and possible mechanism of CS 2 -induced embryo implantation disorders while not to assess the human health risks. Our previous work has proved that there was no significant maternal toxicity at the exposure dosage (0.4 LD 50 , 631.4 mg/kg), 28 while this dosage could induce embryo loss. Second, inhalation is the main route for human exposure to CS 2 .…”

Section: ■ Discussionmentioning

confidence: 92%

Carbon Disulfide Induces Embryo Implantation Disorder by Disturbing the Polarization of Macrophages in Mice Uteri

Zhang

et al. 2019

Chem. Res. Toxicol.

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Carbon disulfide (CS 2 ) induces embryo implantation disorders. Macrophages participate in the process of pregnancy. Therefore, we want to explore the effects of CS 2 exposure on polarization and immune function of macrophages in pregnant mice uteri. The exposure times were gestation days 3 (GD3), 4 (GD4), and 5 (GD5), and the observation end points were arranged in a time series after CS 2 exposure. The uterine tissues were collected to detect the expression levels of macrophages cytokines (IL-6, IL-12, TGF-β1, and Vegf-a) and downstream regulatory cytokines of Th1-type (IL-2 and IFN-γ) and Th2-type (IL-10 and IL-4) by flow cytometry, ELISA, and q-PCR. The results showed that, compared with the controls, the ratios of M1/M2 macrophages in the endometrium significantly increased by 96%, 110%, and 177% at the GD4, GD6, and GD7 observation end points after GD3 exposure and increased about 3.88-fold and 2.37-fold at the GD6 and GD7 observation end points after GD4 exposure, respectively. In contrast, the ratio of M1 and M2 macrophages significantly reduced by 53% at the GD5 observation end point after GD3 exposure. Meanwhile, the expression levels of IL-6 were significantly increased about 2.00-fold for mRNA and 1.60-fold for protein at GD4 observation end points after GD3 exposure, and the mRNA levels of IL-12 increased about 3.61-fold at the GD6 observation end points after GD4 exposure. The mRNA levels of TGF-β1 were significantly decreased by 41%, 25%, and 20% at the GD7 observation end points after exposure at GD3, GD4, and GD5, and the expression levels of Vegf-a mRNA and protein were decreased. Furthermore, the ratio of IL-2/IL4, IL-2/IL-10, IFN-γ/IL-4, and IFN-γ/IL-10 in the uterine tissue was significantly increased at the exposure groups. These findings suggest that the imbalanced polarization of macrophages is the key regulator in the progress of CS 2induced embryo loss.

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Section: ■ Discussionmentioning

confidence: 92%

Carbon Disulfide Induces Embryo Implantation Disorder by Disturbing the Polarization of Macrophages in Mice Uteri

Zhang

et al. 2019

Chem. Res. Toxicol.

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“…MiR-21 was also implicated in the etiology of defective ER, as it was positively regulated by LIF [32]. LIF is a multifunctional glycoprotein produced by endometrial cells [33][34][35], and one of its roles is promoting follicular growth and embryo implantation [36]. In addition, miRNA-145 was also documented to impair embryonic adhesion by directly reducing the expression of IGF-1R, which affected embryo implantation by interaction with IGF-1 [37,38] in endometrial epithelial cells [12].…”

Section: Discussionmentioning

confidence: 99%

Association of miRNA-145 with the occurrence and prognosis of hydrosalpinx-induced defective endometrial receptivity

Wang

et al. 2020

Bosn J of Basic Med Sci

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MiR-145 is reported to facilitate inflammation and is also associated with unsuccessful embryonic implantation. Whether miR-145 mediates inflammatory response underlying hydrosalpinx-induced defective endometrial receptivity (ER) remains unclear, and this study attempted to clarify this point. Endometrium samples were collected from hydrosalpinx patients (case, n = 243) and patients with tubal patency/obstruction (control, n = 187). The peripheral blood samples of cases and controls were collected to determine the genotypes of miR-145 SNPs. The value of miR-145 expression in the diagnosis and prognostic estimation of hydrosalpinx was assessed using ROC curve and regression analysis, respectively. Lipopolysaccharide (LPS) cell model was established with endometrial cells, and cells were transfected with miR-145 mimic, inhibitor, or negative control. MiR-145 and cytokine levels were quantified by quantitative reverse transcription PCR or western blot. MiR-145 expression was significantly higher in hydrosalpinx compared to control group, and high miR-145 expression was significantly associated with moderate/severe tube lesion, high pulsatility index (>1.06), and high resistance index (>0.61) in hydrosalpinx patients. ROC curve analysis indicated that monitoring miR-145 expression may be useful for the diagnosis of hydrosalpinx (AUC = 0.704). A alleles of rs41291957 (G>A) and rs353292 (G>A) were significantly associated with an increased risk of hydrosalpinx compared to G allele (p < 0.05), yet the mutant allele of rs353291 (A>G) and rs4705343 (T>C) significantly reduced susceptibility to hydrosalpinx compared to the wild type allele. Treatments with miR-145 mimic and LPS in endometrial cells significantly increased the levels of TGF-β1, TNF-α, IL-6, and IL-8 compared to negative control, while treatment with miR-145 inhibitor decreased the cytokine levels. In conclusion, abnormally expressed miR-145 may be involved in hydrosalpinx-induced ER defects by regulating inflammatory response.

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“…One of the secretions produced by the endometrial epithelium is the endometrial capacity marker LIF, which binds to the LIF receptor (LIFR) on the endometrial surface, recruits gp130 to form a high-affinity functional receptor complex, and contributes to the activation of the JAK-STAT pathway [6]. STAT3 phosphorylation is essential for the activity of LIF in regulating epithelial cell-cell junctions, polarity and functions during the receptive phase [7]. Moreover, LIF and LIFR are also located in endometrial stromal cells and play an important role in decidualization [9].…”

Section: Discussionmentioning

confidence: 99%

“…Most of the signaling pathways involve ovarian steroid hormones [7]. LIF, a pleiotropic cytokine secreted by glands, directly targets the epithelium and triggers the increased expression of several proteins (HB-EGF, cochlin, IGFBP-3, and IRG1) that promote uterine receptivity [8].…”

Section: Introductionmentioning

confidence: 99%

Activating transcription factor 3 promotes embryo attachment via up-regulation of leukemia inhibitory factor in vitro

Cheng

Liu

Shan

et al. 2017

Reprod Biol Endocrinol

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BackgroundA receptive endometrium is essential for maternal-embryonic molecular communication during implantation. However, the specific molecular regulatory mechanisms of the endometrial capacity remain poorly understood. Here, we examined activating transcription factor 3 (ATF3) expression in human endometria and the functional effect of ATF3 on embryo attachment in vitro.MethodsImmunohistochemistry (IHC) was used to assess the ATF3 expression patterns in human endometria. Quantitative real-time PCR (qRT-PCR), western blotting and immunofluorescence (IF) studies were applied to explore ATF3 expression in Ishikawa cells upon estrogen (E2) and medroxyprogesterone acetate (MPA) treatment. qRT-PCR and western blotting were performed to inspect LIF (leukemia inhibitory factor) expression after enhancement or inhibition of ATF3, and a luciferase reporter assay and ChIP-PCR were used to confirm the regulatory mechanism of ATF3 to LIF. Endometrial epithelial capacity was assessed by an in vitro model of attachment of BeWo spheroids to Ishikawa cells. Western blotting was performed to compare the expression of ATF3 in endometrial samples of recurrent implantation failure (RIF) patients with that in samples from fertile women (FER) who had undergone no less than one successful embryo transplantation.ResultsATF3 was located in human endometrial epithelial cells and stromal cells and was significantly induced by E2 and MPA in Ishikawa cells. Adenovirus-mediated overexpression of ATF3 in Ishikawa cells activated LIF promoter activity and enhanced its expression. Accordingly, the stimulation of BeWo spheroid adhesion promoted by ATF3 was inhibited by pretreatment with a specific antibody against LIF via the antibody-blocking assay. Moreover, ATF3 was aberrantly decreased in the endometria of RIF patients.ConclusionsOur findings suggest that ATF3 plays a significant role in regulating human endometrial receptivity and embryo attachment in vitro via up-regulation of leukemia inhibitory factor.Trial registrationConstruction and management of the Nanjing multi-center biobank. No. 2013-081-01. Registered 10 Dec. 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-017-0260-7) contains supplementary material, which is available to authorized users.

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Down-regulation of uterine LIF expression induced by the hormonal level disorder causes embryo implantation loss after mice exposed to carbon disulfide at peri-implantation

Cited by 12 publications

References 27 publications

Carbon Disulfide Induces Embryo Implantation Disorder by Disturbing the Polarization of Macrophages in Mice Uteri

Carbon Disulfide Induces Embryo Implantation Disorder by Disturbing the Polarization of Macrophages in Mice Uteri

Association of miRNA-145 with the occurrence and prognosis of hydrosalpinx-induced defective endometrial receptivity

Activating transcription factor 3 promotes embryo attachment via up-regulation of leukemia inhibitory factor in vitro

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