The activation of cGAS-STING pathway causes abnormal uterine receptivity in aged mice.

Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E2) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E2, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.

Histamine promotes mouse decidualization through stimulating epithelial amphiregulin release.

Accumulating evidence shows that inflammation is essential for embryo implantation and decidualization. Histamine, a proinflammatory factor that is present in almost all mammalian tissues, is synthesized through decarboxylating histidine by histidine decarboxylase (HDC). Although histamine is known to be essential for decidualization, the underlying mechanism remains undefined. In the present study, histamine had no obvious direct effects on in vitro decidualization in mice. However, the obvious differences in HDC protein levels between day 4 of pregnancy and day 4 of pseudopregnancy, as well as between delayed and activated implantation, suggested that the blastocyst may be involved in regulating HDC expression. Furthermore, blastocyst-derived tumor necrosis factor α (TNFα) significantly increased HDC levels in the luminal epithelium. Histamine increased the levels of amphiregulin (AREG) and disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) proteins, which was abrogated by treatment with famotidine, a specific histamine type 2 receptor (H2R) inhibitor, or by TPAI-1 (a specific inhibitor of ADAM17). Intraluminal injection of urocanic acid (HDC inhibitor) on day 4 of pregnancy significantly reduced the number of implantation sites on day 5 of pregnancy. TNFα-stimulated increases in HDC, AREG and ADAM17 protein levels was abrogated by urocanic acid, a specific inhibitor of HDC. Additionally, AREG treatment significantly promoted in vitro decidualization. Collectively, our data suggests that blastocyst-derived TNFα induces luminal epithelial histamine secretion, and histamine increases mouse decidualization through ADAM17-mediated AREG release.

Tryptophan in the mouse diet is essential for embryo implantation and decidualization.

Introduction: Nutritional deficiency occurs frequently during pregnancy and breastfeeding. Tryptophan (Trp), an essential amino acid which is critical for protein synthesis, serves as the precursor for serotonin, melatonin, and kynurenine (Kyn). The imbalance between serotonin and kynurenine pathways in Trp metabolism is closely related to inflammation and depression. This study assessed the effects of Trp deficiency on mouse early pregnancy. Methods: Embryo implantation and decidualization were analyzed after female mice had been fed diets containing 0.2% Trp (for the control group), 0.062% Trp (for the low Trp group) and 0% Trp (for the Trp-free group) for two months. The uteri of the mice were collected on days 4, 5, and 8 of pregnancy for further analysis. Results: On day 8 of pregnancy, the number of implantation sites were found to be similar between the control and the low Trp groups. However, no implantation sites were detected in the Trp-free group. On day 5 of pregnancy, plane polarity- and decidualization-related molecules showed abnormal expression pattern in the Trp-free group. On day 4 of pregnancy, there was no significant difference in uterine receptivity molecules between the low-Trp group and the control group, but uterine receptivity was abnormal in the Trp-free group. At implantation sites of the Trp-free group, IDO and AHR levels were markedly elevated. This potentially increased levels of Kyn, 2-hydroxy estradiol, and 4-hydroxy estradiol to affect decidualization. Conclusions: Trp-free diet may impair decidualization via the IDO-KYN-AHR pathway.

BHPF exposure impairs mouse and human decidualization.

Although BHPF has been widely used in plastic manufacturing as a substitute for BPA, current evidence suggests that BHPF also causes harmful effects on reproduction. However, effects of BHPF on mammalian early pregnancy are still poorly defined. This study aimed to explore the effects of BHPF on early pregnancy, especially decidualization and embryonic development in mice and human beings. The results showed that 50 and 100 mg/kg BHPF exposure reduced birth weight, and implantation site weight on the day 8 of pregnancy in mice. Because BHPF inhibits both embryo development and artificial decidualization in mice, suggesting that the detrimental effects of BHPF should be from its effects on embryo development and decidualization. Under in vitro decidualization, 10 µM BHPF inhibits decidualization and leads to disordered expression of Lamin B1 and collagen in mice. In addition, 10 µM BHPF also inhibits decidualization, and causes disordered expression of both collagen III and Lamin B1 under human in vitro decidualization. However, collagen III supplementation can rescue BHPF inhibition on decidualization. Further, our study demonstrates that BHPF impairs human decidualization through the HB-EGF/EGFR/STAT3/Collagen III pathway. Taken together these data suggest that exposure to BHPF impairs mouse and human decidualization during early pregnancy.