Elevated insulin levels compromise endometrial decidualization in mice with decrease in uterine apoptosis in early-stage pregnancy

Zhang, Chen; Yang, Chengshun; Li, Na; Liu, Xueqing; He, Junlin; Ding, Yubin; Tong, Chao; Peng, Chuan; Yin, Hubin; Wang, Yingxiong; Gao, Rufei

doi:10.1007/s00204-019-02601-8

Cited by 23 publications

(14 citation statements)

References 47 publications

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“…Preimplantation exposure to high concentrations of insulinlike growth factor I results in lower implantation rates in mice (9). Elevated insulin levels could compromise mice decidualization in early-stage pregnancy (10). Previous studies suggested that IR was an independent risk factor for spontaneous abortion and recurrent pregnancy loss (11,12).…”

Section: Introductionmentioning

confidence: 99%

Effect of Hyperinsulinemia and Insulin Resistance on Endocrine, Metabolic, and Reproductive Outcomes in Non-PCOS Women Undergoing Assisted Reproduction: A Retrospective Cohort Study

et al. 2022

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Objective: To evaluate the effect of hyperinsulinemia (HI) and insulin resistance (IR) on endocrine, metabolic, and reproductive outcomes in women without polycystic ovary syndrome (PCOS) undergoing assisted reproduction.Materials and Methods: The study included 1,104 non-PCOS women undergoing in vitro fertilization/intracytoplasmic sperm injection-fresh embryo transfer. HI was evaluated by serum fasting insulin (FIN), and IR was evaluated by homeostatic model assessment of insulin resistance index (HOMA-IR). In addition, biometric, sex hormone, and metabolic parameters were measured. Independent t-test, linear, and logistic regression examined associations between HI, IR, and endocrine, metabolic, ovarian stimulation characteristics, and reproductive outcomes.Results: Women with HI and IR had lower levels of progesterone, luteinizing hormone, follicle-stimulating hormone, estradiol, high-density lipoproteins, and increased levels of triglycerides low-density lipoproteins. For ovarian stimulation characteristics, those with HI and IR had a longer duration of stimulation, a higher total gonadotropin dose, and a lower peak estradiol level. Linear regression confirmed these associations. For reproductive outcomes, HI and IR were not associated with clinical pregnancy, live birth, and miscarriage.Conclusions: HI and IR did not impair reproductive outcomes in non-PCOS women undergoing assisted reproduction.

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Section: Introductionmentioning

confidence: 99%

Effect of Hyperinsulinemia and Insulin Resistance on Endocrine, Metabolic, and Reproductive Outcomes in Non-PCOS Women Undergoing Assisted Reproduction: A Retrospective Cohort Study

et al. 2022

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“…The mouse model of artificially induced decidualization was generated according to standard criteria (Zhang et al, 2019). CD1 female mice in oestrus were mated with vasectomized males to establish pseudopregnancy models.…”

Section: Methodsmentioning

confidence: 99%

Exposure to ethylparaben and propylparaben interfere with embryo implantation by compromising endometrial decidualization in early pregnant mice

Wang

Yang

et al. 2021

J of Applied Toxicology

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Ethylparaben (EtP) and propylparaben (PrP) are common preservatives and well‐known endocrine‐disrupting chemicals. Studies have demonstrated that they can reduce female fertility, but the underlying mechanism, especially that on embryo implantation, is still poorly understood. Endometrial decidualization is a critical event for embryo implantation. In this study, we aimed to explore the effects of EtP/PrP on endometrial decidualization. Pregnant mice were dosed daily by oral gavage with EtP at 0, 400, 800 and 1600 mg/kg or with PrP at 0, 625, 1250 and 2500 mg/kg from Day 1 of pregnancy until sacrifice. The results showed that the rate of pregnant mice with impaired embryo implantation, whose number of implantation sites was less than 7, was significantly increased after exposure to 1600 mg/kg EtP or 2500 mg/kg PrP. Further study found that the expression of endometrial decidualization markers HOXA10, MMP9 and PR was significantly downregulated in 1600 mg/kg EtP group and 2500 mg/kg PrP group. Notably, serum oestrogen and progesterone levels were significantly increased, whereas the expression of uterine oestrogen receptor and progesterone receptor was decreased following 1600 mg/kg EtP or 2500 mg/kg PrP exposure. In the breeding test, fewer offspring were found after females were exposed to 1600 mg/kg EtP or 2500 mg/kg PrP in early pregnancy. This demonstrated that exposure to EtP/PrP interfered with embryo implantation by compromising endometrial decidualization in early‐stage pregnant mice. Disorders of reproductive hormones and hormone receptor signals could be responsible for impaired decidualization. This study broadened the understanding on the biological safety of EtP and PrP.

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“…The uterus is a complex organ comprising multiple types of cells, such as natural killer cells, endometrial epithelial cells, and stromal cells. During decidualization, stromal cells started transforming into decidual cells (C. Zhang et al, 2019). To further validate the effects of folate deficiency on the differentiation of endometrial stromal cells into decidual cells, the mESCs were isolated from folate deficient and normal mice, respectively (Figure S1), and were decidualized artificially by hormone in vitro.…”

Section: Endometrial Decidualization Was Impaired By Folate Deficiency In Early Pregnant Mice and In Primary Mescsmentioning

confidence: 99%

AMPK/mTOR downregulated autophagy enhances aberrant endometrial decidualization in folate‐deficient pregnant mice

Zhang

Gao

Zhang

et al. 2021

Journal Cellular Physiology

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Existing evidence suggests that adverse pregnancy outcomes are closely related to dietary factors. Folate plays an important role in neural tube formation and fetal growth, folate deficiency is a major risk factor of birth defects. Our early studies showed that folate deficiency could impair enddecidualization, however, the mechanism is still unclear. Dysfunctional autophagy is associated with many diseases.Here, we aimed to evaluate the adverse effect of folate deficiency on endometrial decidualization, with a particular focus on endometrial cell autophagy. Mice were fed with no folate diet in vivo and the mouse endometrial stromal cell was cultured in a folate-free medium in vitro. The decrease of the number of endometrial autophagosomes and the protein expressions of autophagy in the folate-deficient group indicated that autophagosome formation, autophagosome-lysosome fusion, and lysosomal degradation were inhibited. Autophagic flux examination using mCherry-GFP-LC3 transfection showed that the fusion of autophagosomes with lysosomes was inhibited by folate deficiency. Autophagy inducer rapamycin could reverse the impairment of folate deficiency on endometrial decidualization. Moreover, folate deficiency could reduce autophagy by disrupting AMPK/mTOR signaling, resulting in aberrant endometrial decidualization and adverse pregnancy outcomes. Further coimmunoprecipitation examination showed that decidual marker protein Hoxa10 could interact with autophagic marker protein Cathepsin L, and the interaction was notably reduced by folate deficiency. In conclusion, AMPK/mTOR downregulated autophagy was essential for aberrant endometrial decidualization in early pregnant mice, which could result in adverse pregnancy outcomes. This provided some new clues for understanding the causal mechanisms of birth defects induced by folate deficiency.

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Elevated insulin levels compromise endometrial decidualization in mice with decrease in uterine apoptosis in early-stage pregnancy

Cited by 23 publications

References 47 publications

Effect of Hyperinsulinemia and Insulin Resistance on Endocrine, Metabolic, and Reproductive Outcomes in Non-PCOS Women Undergoing Assisted Reproduction: A Retrospective Cohort Study

Effect of Hyperinsulinemia and Insulin Resistance on Endocrine, Metabolic, and Reproductive Outcomes in Non-PCOS Women Undergoing Assisted Reproduction: A Retrospective Cohort Study

Exposure to ethylparaben and propylparaben interfere with embryo implantation by compromising endometrial decidualization in early pregnant mice

AMPK/mTOR downregulated autophagy enhances aberrant endometrial decidualization in folate‐deficient pregnant mice

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