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Metritis is a disease of particular concern after calving because of its profound negative effects on the reproductive performance of dairy cows. Cows at risk for metritis have shorter feeding times in the days before calving but prepartum dry matter intake (DMI) and water intake may also be useful in identifying cows at risk for this disease. Feeding, drinking, and intake measures may also be affected by social interactions among group-housed cows. The objective of this study, therefore, was to measure intake, feeding, drinking, and social behavior to determine which measures could identify cows at risk for metritis after calving. Feeding and drinking behavior and intake measures were collected from 101 Holstein dairy cows from 2wk before until 3wk after calving using an electronic monitoring system. Social behavior at the feed bunk was assessed from video recordings. Metritis severity was diagnosed based on daily rectal body temperature as well as condition of vaginal discharge that was assessed every 3 d after calving until d +21. In this study, 12% of cows were classified as severely metritic and 27% as mildly metritic. Prepartum feeding time and DMI were best able to identify cows at risk for metritis. Cows that developed severe metritis spent less time feeding and consumed less feed compared with healthy cows beginning 2wk before the observation of clinical signs of infection. For every 10-min decrease in average daily feeding time during the week before calving, the odds of severe metritis increased by 1.72, and for every 1-kg decrease in DMI during this period, cows were nearly 3 times more likely to be diagnosed with this disorder. During the week before calving, cows that were later diagnosed with severe metritis had lower DMI and feeding times during the hours following fresh feed delivery. During this period these cows also engaged in fewer aggressive interactions at the feed bins compared with cows that remained healthy. This research is the first to show that social behavior may play an important role in transition cow health. Research is now required to determine how management should be changed to reduce or prevent illness in transition dairy cows.

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.

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.

Data generated from 796 Holstein cows enrolled in a clinical trial to investigate the health effect of a monensin controlled release capsule were analyzed to investigate the association between circulating serum β-hydroxybutyrate (BHBA) concentration in the peri-parturient period and subsequent reproductive performance. Overall, accounting for both repeated measures within cow and clustering at the herd level, non-pregnant cows after first insemination tended to have increased circulating BHBA concentrations from 3 wk before calving to 9 wk after calving relative to pregnant cows. Including the interaction between the week of sample collection and pregnancy outcome, non-pregnant cows had higher circulating BHBA concentrations in the second week after calving than cows diagnosed pregnant after first artificial insemination. Within individual weeks, cows with circulating BHBA concentrations ≥1,000μmol/L in the first week postpartum were less likely to be diagnosed pregnant after first insemination. In the second week postpartum, the cows with circulating BHBA concentrations ≥1,400μmol/L were significantly less likely to be pregnant after first artificial insemination. A dose response relationship was found when a comparison of the probability of pregnancy after first insemination and duration of elevated circulating ketone bodies was investigated. The probability of pregnancy was reduced by 20% in cows diagnosed subclinically ketotic in either the first or second week postpartum. Nevertheless, cows above the subclinical ketosis threshold in both the first and second week postpartum were 50% less likely to be pregnant after first insemination. Similarly, the median time to pregnancy increased in cows experiencing elevated BHBA concentrations in either (124 d) or both (130 d) the first and second week postpartum relative to cows never experiencing elevated BHBA concentrations (108 d). To further investigate this, the effect of elevated circulating BHBA was permitted to vary with time. The effect decreased with time, such that the daily probability of pregnancy increased similar to nonsubclinically ketotic cows by approximately 160 d in milk. From this analysis, both the relative circulating concentration of BHBA and the duration of elevated circulating BHBA were negatively associated with the probability of pregnancy at first service.

DNA methylation is an essential epigenetic process in mammals, intimately involved in gene regulation. Here we address the extent to which genetics, sex, and pregnancy influence genomic DNA methylation by intercrossing 2 inbred mouse strains, C57BL/6N and C3H/HeN, and analyzing DNA methylation in parents and offspring using whole-genome bisulfite sequencing. Differential methylation across genotype is detected at thousands of loci and is preserved on parental alleles in offspring. In comparison of autosomal DNA methylation patterns across sex, hundreds of differentially methylated regions are detected. Comparison of animals with different histories of pregnancy within our study reveals a CpG methylation pattern that is restricted to female animals that had borne offspring. Collectively, our results demonstrate the stability of CpG methylation across generations, clarify the interplay of epigenetics with genetics and sex, and suggest that CpG methylation may serve as an epigenetic record of life events in somatic tissues at loci whose expression is linked to the relevant biology. DNA methylation is an epigenetic mark involved in gene regulation. Here the authors investigate the extent to which genetics, sex and pregnancy influence genomic DNA methylation in mice, providing evidence of the stability of CpG methylation across generation and suggest that CpG methylation may serve as an epigenetic record of life events in somatic tissues at loci whose expression is linked to the relevant biology.

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.

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.

Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn 1 , 2 , 3 , 4 , 5 , 6 , 7 . Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8 ). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age-associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease. Increased maternal age is known to increase the risk of congenital heart disease in offspring; here, this link is investigated by transplanting ovaries between young and old mice, revealing that the maternal-age-associated risk is independent of the age of the ovaries but depends on the age of the mother, and that this risk can be mitigated by maternal genetic background or exercise. Heart disease risk and maternal age Patrick Jay and colleagues investigate the known increased risk of congenital heart disease with increased maternal age. By transplanting ovaries between young and old mice they establish that the maternal age-associated risk of congenital heart disease in pups harbouring a mutation of the cardiac transcription factor gene Nkx2-5 is independent of the age of the ovaries and depends on the age of the mother. They further show that maternal exercise can mitigate this age-associated risk, although the mechanisms at work are not yet known.

The impacts of supplementing the diet of gestating gilts twice daily with 4 g of the plant extract silymarin on circulating hormonal concentrations, oxidative status, mammary development, and mammary gene expression at the end of gestation were determined. Gilts were fed conventional diets during gestation and on d 90 they were assigned as controls (CTL; n = 16) or treated (TRT; n = 17) animals. Treatment consisted of providing 4 g of silymarin twice daily until d 110, at which time all gilts were slaughtered to collect mammary tissue for compositional analyses and measures of gene expression and oxidative status, and liver and corpora lutea for measures of oxidative stress variables. Blood samples for hormonal assays and evaluation of oxidative stress biomarkers were obtained on d 89, 94, and 109 of gestation. Silymarin increased (P = 0.05) circulating concentrations of prolactin over all samples in the repeated in time analysis. In separate analyses for each sampling time, prolactin concentrations in TRT gilts tended (P < 0.10) to be greater than in CTL gilts on d 94 of gestation. Repeated in time analysis also revealed that silymarin reduced (P ≤ 0.05) plasmatic accumulation of biomarkers of oxidative damage to protein (protein carbonyls) between d 89 and 109. There was no effect (P > 0.10) of treatment on progesterone, estradiol, leptin, or 8-hydroxy-2'-deoxyguanosine concentrations. Percent fat in mammary parenchyma was greater (P ≤ 0.05), percent protein was lesser (P ≤ 0.05), and concentrations of both RNA (P ≤ 0.01) and DNA (P < 0.05) were lesser in TRT than CTL gilts. Mammary parenchyma from TRT gilts had lower (P ≤ 0.05) mRNA abundance for STAT5A and leptin and tended to have lower (P ≤ 0.10) abundance for STAT5B than CTL gilts. Silymarin reduced (P ≤ 0.001) protein carbonyls concentrations in liver of TRT gilts. No effect of treatment was observed on antioxidant gene expression and enzymatic activities in liver samples while total superoxide dismutase activity tended to be higher (P ≤ 0.10) in the corpora lutea of TRT animals when compared with CTL. This is the first demonstration that, in female pigs, silymarin can increase prolactin concentrations and protect against oxidative stress, yet the increase in prolactin was not enough to have beneficial effects on mammary gland development in late gestation.

A single ovulation, reciprocal embryo transfer study was used to investigate effects of oocyte competence and maternal environment on pregnancy establishment and maintenance in beef cows. Estrous cycles were synchronized in suckled beef cows and embryo donors were inseminated on d 0 (n = 810). Cows were classifi ed on d 0 as having a small (<12.5 mm) or large (≥12.5 mm) ovulatory follicle and randomly chosen as donors or recipients to remove confounding effects of ovulatory follicle size on fertility. Embryos (n = 393) or oocytes (n = 44) were recovered on d 7, and all viable embryos were transferred into recipients (n = 354). All statistical analyses were conducted using the GLM procedure of SAS. Path analysis (with significance set at P < 0.10) was used to examine potential cause–effect relationships among the measured variables. Greater donor cow BW, circulating estradiol concentration at insemination, postpartum interval, and ovulatory follicle size directly increased (P < 0.10) fertilization success. Greater donor cow age was the only factor that directly decreased (P < 0.10) fertilization success. Viability of d-7 embryos was directly inhibited (P < 0.10) by rapid follicular growth rate from d –2 to 0 and heavier BW. Direct beneficial effects to embryo viability were increased serum progesterone concentration on d –2 and ovulatory follicle size. Pregnancy maintenance from d 7 to 27 was enhanced (P < 0.10) by increased serum estradiol concentration on d 0 and progesterone concentration on d 7 in the recipient cow. Increased follicular diameter in the recipient cow on d 0 was detrimental to pregnancy maintenance from d 7 to 27. This manuscript defines the complex interplay and relative contributions of endocrine and physical factors both prior and subsequent to fertilization that influence both oocyte competence and maternal environment and their roles in establishment and maintenance of pregnancy.