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Establishment and maintenance of pregnancy in the pig is a complex process that relies on conceptus regulation of the maternal proinflammatory response to endometrial attachment. Following elongation, pig conceptuses secrete interferon gamma (IFNG) during attachment to the endometrial luminal epithelium. The objective here was to determine if conceptus production of IFNG is important for early development and establishment of pregnancy. CRISPR/Cas9 gene editing and somatic cell nuclear transfer technologies were used to create an IFNG loss-of-function study in pigs. Wild-type (IFNG+/+) and null (IFNG–/–) fibroblast cells were used to create embryos through somatic cell nuclear transfer. IFNG expression was not detected in IFNG–/– conceptuses on either day 15 or day 17 of pregnancy. Ablation of conceptus IFNG production resulted in the reduction of stromal CD3+ and mast cells, which localized to the site of conceptus attachment on day 15. The uteri of recipients with IFNG–/– conceptuses were inflamed, hyperemic and there was an abundance of erythrocytes in the uterine lumen associated with the degenerating conceptuses. The endometrial stromal extracellular matrix was altered in the IFNG–/– embryo pregnancies and there was an increased endometrial mRNA levels for collagen XVII (COL17A1), matrilin 1 (MATN1), secreted phosphoprotein 1 (SPP1), and cysteine-rich secretory protein 3 (CRISP3), which are involved with repair and remodeling of the extracellular matrix. These results indicate conceptus IFNG production is essential in modulating the endometrial proinflammatory response for conceptus attachment and survival in pigs. Summary sentence Ablation of IFNG in the pig conceptus causes conceptus degeneration and endometrial inflammation.

Secreted phosphoprotein 1 (SPP1, also known as osteopontin) binds integrins to mediate cell–cell and cell–extracellular matrix communication to promote cell adhesion, migration, and differentiation. Considerable evidence links SPP1 to pregnancy in several species. Current evidence suggests that SPP1 is involved in implantation and placentation in mice, but in vivo localization of SPP1 and in vivo mechanistic studies to substantiate these roles are incomplete and contradictory. We localized Spp1 mRNA and protein in the endometrium and placenta of mice throughout gestation, and utilized delayed implantation of mouse blastocysts to link SPP1 expression to the implantation chamber. Spp1 mRNA and protein localized to the endometrial luminal (LE), but not glandular epithelia (GE) in interimplantation regions of the uterus throughout gestation. Spp1 mRNA and protein also localized to uterine naturel killer (uNK) cells of the decidua. Within the implantation chamber, Spp1 mRNA localized only to intermittent LE cells, and to the inner cell mass. SPP1 protein localized to intermittent trophoblast cells, and to the parietal endoderm. These results suggest that SPP1: (1) is secreted by the LE at interimplantation sites for closure of the uterine lumen to form the implantation chamber; (2) is secreted by LE adjacent to the attaching trophoblast cells for attachment and invasion of the blastocyst; and (3) is not a component of histotroph secreted from the GE, but is secreted from uNK cells in the decidua to increase angiogenesis within the decidua to augment hemotrophic support of embryonic/fetal development of the conceptus. Summary sentence Through utilization of delayed implantation, SPP1 mRNA and protein are localized in high levels to the luminal epithelium of interimplantation sites, to focal regions of the implantation chamber and to uterine natural killer cells in the decidua, suggesting roles for implantation in mice.

The vagina is the site of copulation and serves as the birth canal. It also provides protection against external pathogens. In mice, due to the absence of cervical glands, the vaginal epithelium is the main producer of vaginal mucus. The development and differentiation of vaginal epithelium-constituting cells and the molecular characteristics of vaginal mucus have not been thoroughly examined. Here, we characterized vaginal mucous cell development and the expression of mucus-related factors in pregnant mice. The vaginal mucous epithelium layer thickened and became multilayered after Day 12 of pregnancy and secreted increasing amounts of mucus until early postpartum. Using histochemistry and transmission electron microscopy, we found supra-basal mucous cells as probable candidates for precursor cells. In vaginal mucous cells, the expression of TFF1, a stabilizer of mucus, was high, and some members of mucins and antimicrobial peptides (MUC5B and DEFB1) were expressed in a stage-dependent manner. In summary, this study presents the partial characterization of vaginal epithelial mucous cell lineage and expression of genes encoding several peptide substances that may affect vaginal tissue homeostasis and mucosal immunity during pregnancy and parturition. Summary sentence Summary Sentence: Mucous cells in the murine vaginal epithelium differentiate from basal stem cells with acquisition of mucus production and keratinization and display temporally regulated expression of TFF, mucin, and beta-defensins during pregnancy and postpartum.

Gestation period in captive Yangtze finless porpoise (YFP) is a well-coordinated and dynamic process, involving both systemic and local alterations. The gut microbiota and its connection to fecal metabolites are crucial in supporting fetal development and ensuring maternal health during reproductive stages. This study evaluates changes in the gut microbiota and their correlation with fecal metabolites in captive YFPs during different reproductive stages. The results reveal that microbial community structure changed significantly during reproductive stages, while gut microbial diversity remained stable. The genus unclassified Peptostrptococcaceae, Corynebacterium, and norank KD4–96 were significantly greater in non-pregnancy (NP), Terrisporobacter was significantly greater in lactating (LL), and Clostridium was significantly higher in early-pregnancy (EP) compared to the other groups. The host fecal metabolome exhibited significant alterations during the reproductive stages. Indoxyl sulfate, octadecatrienoic acid, and methionyl-methionine were significantly higher in the NP; galactosylglycerol, chondroitin 6-sulfate, and lumichrome were significantly higher in the EP and mid-pregnancy (MP); and valylleucine and butyryl-l-carnitine were significantly higher in the LL. The altered metabolites were mostly concentrated in pathways associated with arachidonic acid metabolism (significantly altered in NP), leucine, valine, and isoleucine biosynthesis (significantly altered in EP and MP), and glycerophospholipid metabolism (significantly altered in LL compared to others stages). Additionally, we found a strong link between variations in the host metabolism and alterations in the fecal bacteria of captive YFP. In conclusion, this study provides detailed insights into host metabolic and fecal bacterial changes in captive YFP during reproduction stages, providing important knowledge for improving the reproductive management in the captive YFP. Summary Sentence The current study aims to evaluate changes in the gut microbiota and their correlation with fecal metabolites in captive YFPs during different reproductive stages by providing important knowledge for improving the reproductive management of captive YFPs. Graphical Abstract

Interactions between female metabolic status, immune response, and reproductive system functioning are complex and not fully understood. We hypothesized that chemerin, considered a hormonal link between the above-mentioned processes, influences endometrial functions, particularly cytokine secretion and signaling. Using porcine endometrial explants collected during early pregnancy and the estrous cycle, we investigated chemerin effects on the secretion of interleukins (IL-1β, IL-6, and IL-8), leukemia inhibitory factor, tumor necrosis factor α, transforming growth factor α, and protein abundances of their respective receptors. Our results demonstrate chemerin modulation of cytokine secretion and receptor expression, with effects dependent on the stage of pregnancy and dose of chemerin. Furthermore, chemerin influences the phosphorylation of stress-activated protein kinase/Jun-amino-terminal kinase and nuclear factor kappa-light-chain-enhancer of activated B cells in the endometrium. Chemerin multifaceted actions, such as involvement in immune response, cell proliferation, and tissue remodeling, seem to be mediated by cytokines, at least in the endometrium. These findings underscore the potential crosstalk between chemerin and hormonal signaling pathways, providing insights into the complex mechanisms underlying early pregnancy establishment and maintenance. Graphical Abstract

The gut microbiota is influenced by environmental factors such as food. Maternal diet during pregnancy modifies the gut microbiota composition and function, leading to the production of specific compounds that are transferred to the fetus and enhance the ontogeny and maturation of the immune system. Prebiotics are fermented by gut bacteria, leading to the release of short-chain fatty acids that can specifically interact with the immune system, inducing a switch toward tolerogenic populations and therefore conferring health benefits. In this study, pregnant BALB/cJRj mice were fed either a control diet or a diet enriched in prebiotics (Galacto-oligosaccharides/Inulin). We hypothesized that galacto-oligosaccharides/inulin supplementation during gestation could modify the maternal microbiota, favoring healthy immune imprinting in the fetus. Galacto-oligosaccharides/inulin supplementation during gestation increases the abundance of Bacteroidetes and decreases that of Firmicutes in the gut microbiota, leading to increased production of fecal acetate, which was found for the first time in amniotic fluid. Prebiotic supplementation increased the abundance of regulatory B and T cells in gestational tissues and in the fetus. Interestingly, these regulatory cells remained later in life. In conclusion, prebiotic supplementation during pregnancy leads to the transmission of specific microbial and immune factors from mother to child, allowing the establishment of tolerogenic immune imprinting in the fetus that may be beneficial for infant health outcomes.

The endometrium undergoes a pregnancy-delivery-repair cycle multiple times during the reproductive lifespan in females. Decidualization is one of the critical events for the success of this essential process. We have previously reported that Notch1 is essential for artificial decidualization in mice. However, in a natural pregnancy, the deletion of Notch1 (PgrCre/+Notch1f/f, or Notch1d/d) only affects female fertility in the first 30 days of a 6-month fertility test, but not the later stages. In the present study, we undertook a closer evaluation at the first pregnancy of these mice to attempt to understand this puzzling phenomenon. We observed a large number of pregnancy losses in Notch1d/d mice in their first pregnancy, which led to the subfertility observed in the first 30 days of the fertility test. We then demonstrated that the initial pregnancy loss is a consequence of impaired decidualization. Furthermore, we identified a group of genes that contribute to Notch1 regulated decidualization in a natural pregnancy. Gene ontogeny analysis showed that these differentially expressed genes in the natural pregnancy are involved in cell–cell and cell–matrix interactions, different from genes that have been previously identified from the artificial decidualization model, which contribute to cell proliferation and apoptosis. In summary, we determined that Notch1 is essential for normal decidualization in the mouse uterus only in the first pregnancy but not in subsequent ones. Summary sentence Notch1 is essential for normal decidualization in the mouse uterus only in the first pregnancy but not in subsequent ones; the initial pregnancy loss is a consequence of impaired decidualization.

Abstract Twenty-one of each pregnant (P) and nonserviced, nonpregnant (NP) sister-pairs of gilts were selected to investigate the effect of pregnancy on protein deposition (Pd; whole body and maternal), insulin sensitivity, and mRNA abundance of genes involved in energy and AA metabolism. Between breeding (study day 0) and day 111, P and NP gilts received 2.16 kg of the experimental diet (3.34 Mcal ME/kg, 17.6% crude protein, 0.78% standardized ileal digestible lysine) that was formulated to meet the estimated ME requirements of pregnant gilts (and meet or exceed AA requirements). Nitrogen balances were conducted on day 63 and 102 ± 0.2 of the study during 4-d periods. Blood samples were collected on day 43, 56, 71, 85, 98, and 108 ± 0.3 of the study to determine plasma concentrations of fasted IGF-1, estradiol (E2), and estrone sulfate (E1S). Frequently sampled intravenous glucose tolerance tests (FSIGTT) were conducted on day 75 ± 0.7 in 6 P and 5 NP gilts and on day 107 ± 0.4 in 17 P and 17 NP gilts and the MINMOD approach was applied to evaluate whole body insulin sensitivity and pancreatic responsiveness. Longissimus muscle (LM) and s.c. adipose tissue (AD) samples were excised from 12 P and 12 NP gilts at day 111 ± 0.4 of the study after euthanasia to determine mRNA abundance of key genes. Whole body Pd was greater (P < 0.001) at day 102 and maternal Pd was lower (P < 0.002) at day 63 and 102 for P compared to NP gilts. Plasma concentrations of E1S and E2 increased (P < 0.05) with study day for P gilts and remained constant for NP gilts, which coincided with reduced plasma concentrations of IGF-1 and increased estrogen receptor alpha (ESR1) mRNA abundance in LM of P gilts. Glucose effectiveness was not different between P and NP gilts, but whole body insulin sensitivity was lower (P = 0.004) in P compared to NP gilts on day 75 and 107, which corresponded with reduced mRNA abundances of SLC2A4, HK2, SREBF1, and FASN, and increased abundances of PDK4 and PPARGC1A in LM and AD. When fed identically, P gilts had greater whole body Pd at day 102, which reflects Pd in the pregnancy-associated tissues (at the expense of maternal Pd), likely driven by estrogen-stimulated insulin resistance in peripheral tissue and subsequent modulation of gene expression relating to glucose metabolism.

In ruminants, conceptus elongation requires the endometrium and its secretions. The amino acid, carbohydrate, and protein composition of the uterine lumen during early pregnancy has been defined in sheep; however, a comprehensive understanding of metabolomic changes in the uterine lumen is lacking, particularly with respect to lipids. Here, the lipidome and primary metabolome of the uterine lumen, endometrium, and/or conceptus was determined on day 14 of the estrous cycle and pregnancy. Lipid droplets and select triglycerides were depleted in the endometrium of pregnant ewes. In contrast, select ceramides, diglycerides, and non-esterified fatty acids as well as several phospholipid classes (phosphatidylcholine, phosphatidylinositol, phosphatidylglycerols, and diacylglycerols) were elevated in the uterine lumen of pregnant ewes. Lipidomic analysis of the conceptus revealed that triglycerides are particularly abundant within the conceptus. Primary metabolite analyses found elevated amino acids, carbohydrates, and energy substrates, among others, in the uterine lumen of pregnant ewes. Collectively, this study supports the hypothesis that lipids are important components of the uterine lumen that govern conceptus elongation and growth during early pregnancy. Summary sentence: There are dynamic changes in the lipid and metabolite composition of the uterine lumen during early pregnancy in sheep.

During gestation, the female reproductive tract must maintain pregnancy while concurrently preparing for parturition. Here, we explore the transitions in gene expression and protein turnover (fractional synthesis rates [FSR]) by which the cervix implements a transition from rigid to compliant. Shifts in gene transcription to achieve immune tolerance and alter epithelial cell programs begin in early pregnancy. Subsequently, in mid-to-late pregnancy transcriptional programs emerge that promote structural reorganization of the extracellular matrix (ECM). Stable isotope labeling revealed a striking slowdown of overall FSRs across the proteome on gestation day 6 that reverses in mid-to-late pregnancy. An exception was soluble fibrillar collagens and proteins of collagen assembly, which exhibit high turnover in nonpregnant cervix compared with other tissues and FSRs that continue throughout pregnancy. This finding provides a mechanism to explain how cross-linked collagen is replaced by newly synthesized, less cross-linked collagens, which allows increased tissue compliance during parturition. The rapid transition requires a reservoir of newly synthesized, less cross-linked collagens, which is assured by the high FSR of soluble collagens in the cervix. These findings suggest a previously unrecognized form of “metabolic flexibility” for ECM in the cervix that underlies rapid transformation in compliance to allow parturition. Summary sentence Flux proteomics identify a steady reservoir of newly synthesized fibrillar collagens in the pregnant cervix, which in conjunction with pregnancy-specific transcriptional programs ensure increased cervical compliance during the process of birth. Graphical Abstract