Decidual Cell Response Research Articles

S03.1: Decidual NK cell response to placental infection in human pregnancy

S03.1: Decidual NK cell response to placental infection in human pregnancy

Post natal cardiovascular assessments in non-clinical pediatric studies using the jacketed external telemetry in beagles for juvenile toxicology studies

The effects of monobutyl phthalate (MBuP) on reproductive function were determined in pregnant and pseudopregnant rats. Rats were given MBuP by gastric intubation at 250, 500, 750, or 1000 mg/kg on days 0 to 8 of pregnancy and pregnancy outcome was determined on day 20 of pregnancy. The effects of MBuP on the uterine function, as a cause of early embryonic loss, were also determined in pseudopregnant rats, with an induced decidual cell response. The same doses of MBuP were given to pseudopregnant rats on days 0 to 8 of pseudopregnancy and the uterine weight on day 9 served as an index of uterine decidualization. MBuP at 1000 mg/kg caused significant increases in the incidences of preimplantation loss in females successfully mated and of postimplantation loss in females having implantations. Uterine decidualization in pseudopregnant rats was significantly decreased at 1000 mg/kg. These findings suggest that early embryonic loss due to MBuP is mediated, at least in part, via suppression of uterine decidualization, an impairment of uterine function.

The human decidual NK cell response to pathogens

The human decidual NK cell response to pathogens

Decidual Stromal Cell Response to Paracrine Signals from the Trophoblast: Amplification of Immune and Angiogenic Modulators1

During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting the immunoacceptance of the fetal allograph. To our knowledge, global crosstalk between the trophoblast and the decidua has not been elucidated to date, and the present study used a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and further treated with conditioned media from human trophoblasts (TCM) or, as a control, with control conditioned media (CCM) from nondecidualized stromal cells for 0, 3, and 12 h. Total RNA was isolated and processed for analysis on whole-genome, high-density oligonucleotide arrays containing 54,600 genes. We found that 1374 genes were significantly upregulated and that 3443 genes were significantly downregulated after 12 h of coincubation of stromal cells with TCM, compared to CCM. Among the most upregulated genes were the chemokines CXCL1 (GRO1) and IL8,CXCR4, and other genes involved in the immune response (CCL8 [SCYA8], pentraxin 3 (PTX3), IL6, and interferon-regulated and -related genes) as well as TNFAIP6 (tumor necrosis factor alpha-induced protein 6) and metalloproteinases (MMP1, MMP10, and MMP14). Among the downregulated genes were growth factors, e.g., IGF1, FGF1, TGFB1, and angiopoietin-1, and genes involved in Wnt signaling (WNT4 and FZD). Real-time RT-PCR and ELISAs, as well as immunohistochemical analysis of human placental bed specimens, confirmed these data for representative genes of both up- and downregulated groups. The data demonstrate a significant induction of proinflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune environment of the decidua to facilitate the process of implantation and ensure an enriched cytokine/chemokine environment while limiting the mitotic activity of the stromal cells during the invasive phase of implantation.

Methoxychlor Disrupts Uterine Hoxa10 Gene Expression

Methoxychlor (MXC) is a pesticide that has adverse effects on reproductive capability in mice. MXC and its metabolites bind the estrogen receptor and function as endocrine disruptors. MXC diminishes the uterine decidual cell response, necessary for the support of pregnancy. Hoxa10 is an estrogen-regulated gene that is an essential mediator of the decidual response and necessary for pregnancy. Here we demonstrate that a mechanism by which MXC disrupts uterine function is by suppressing Hoxa10 expression. MXC treatment of mice produced a mild uterotropic response as measured by increased uterine weight and epithelial height. MXC treatment of uterine Ishikawa cells in vitro induced Hoxa10 expression. Estrogen receptor (ER) binding to the HOXA10 estrogen response element (ERE) was promoted by treatment with estradiol (E2); however, MXC disrupted E2/ER/ERE complex formation and gel shift. MXC alone allowed weak ER/ERE binding. In vivo MXC blocked the effect of E2 on Hoxa10 expression. Neonatal MXC treatment resulted in an immediate suppression and cellular restriction of Hoxa10 expression as well as a permanent generalized decrease in expression that persisted in the adult. MXC inhibited the expression of Hoxa10, a gene necessary for uterine development and function. One common mechanism by which endocrine disrupting chemicals produce lasting reproductive tract defects is through permanent alteration of developmental gene expression.

Suppression of decidual cell response induced by dibutyltin dichloride in pseudopregnant rats: as a cause of early embryonic loss

In our previous study, dibutyltin dichloride (DBTCl) caused preimplantation embryonic loss and postimplantation embryonic loss in rats following administration at 7.6 mg/kg and above on Days 0–3 and at 3.8 mg/kg and above on Days 4–7 of pregnancy, respectively. This study was designed to assess the effects of DBTCl on uterine function as a cause of early embryonic loss using pseudopregnant rats. DBTCl was given orally to pseudopregnant rats at 3.8, 7.6 or 15.2 mg/kg on pseudopregnant day (PPD) 0–3 or on PPD 4–7. The decidual cell response was induced by bilateral uterine scratch on PPD 4. The uterine weight on PPD 9 served as an index of uterine decidualization. Uterine weight and serum progesterone levels on PPD 9 were significantly decreased after administration of DBTCl at 7.6 mg/kg and above on PPD 0–3 and PPD 4–7. DBTCl had no effect on the serum estradiol levels and number of corpora lutea. Administration of progesterone reversed the suppression of uterine decidualization in rats given DBTCl on PPD 0–3. It can be concluded that DBTCl suppresses the uterine decidual cell response and decreases progesterone levels, and these effects are responsible for early embryonic loss due to DBTCl exposure.

Suppression of uterine decidualization correlated with reduction in serum progesterone levels as a cause of preimplantation embryonic loss induced by diphenyltin in rats

In our previous study, diphenyltin dichloride (DPTCl) at 16.5 mg/kg and higher on days 0–3 of pregnancy was found to induce preimplantation embryonic loss in rats. In the present study, the effects of DPTCl on uterine decidualization in pseudopregnant rats, effects of ovarian hormones on uterine decidualization in ovariectomized rats, and effects of progesterone on the DPTCl-induced preimplantation embryonic loss in pregnant rats were determined. Female rats were given DPTCl by gastric intubation at 4.1, 8.3, 16.5, or 24.8 mg/kg on days 0–3 of pseudopregnancy and the decidual cell response was induced on day 4 of pseudopregnancy. The uterine weight on day 9 of pseudopregnancy served as an index of uterine decidualization. A significant decrease in uterine weight, which indicates suppression of uterine decidualization, was detected at 16.5 and 24.8 mg/kg. Ovarian weight and number of corpora lutea in the DPTCl-treated groups were comparable to the controls. A significant decrease in the serum progesterone levels was found at 16.5 and 24.8 mg/kg in pseudopregnant rats. The hormonal regimen consisting of progesterone and estrone-supported decidual development in ovariectomized rats given DPTCl. Pregnancy rate and number of implantations were significantly lower in the intact mated groups given DPTCl at 16.5 and 24.8 mg/kg on days 0–3 of pregnancy than in the control group and significantly higher in the groups given DPTCl plus progesterone than in the groups given DPTCl alone. These results show that reduction in serum progesterone levels is correlated with suppression of uterine decidualization and progesterone protects against preimplantation embryonic loss induced by DPTCl.

Subtilisin proprotein convertase-6 expression in the mouse uterus during implantation and artificially induced decidualization

During implantation, a balance of factors regulates the invasive properties of the embryo and the anti-invasive properties of uterine decidua. Although antiproteinases such as the metalloproteinase inhibitor TIMP-3 are thought to play critical roles in preventing the overaggressive invasion of trophoblasts, the mechanism of antiproteinase regulation is unknown. Recently, the prohormone convertase SPC-6 has been found to be co-expressed in embryo-proximal decidua in association with TIMP-3. As members of this serine proteinase family are known to activate latent TGFbeta family members which regulate decidual TIMP-3 levels, we sought to characterize the expression of SPC-6 during pregnancy and artificial decidualization. In this study, we demonstrate that the zone of SPC-6 gene expression exhibits a great degree of temporal and spatial overlap with TIMP-3 gene expression in uterine decidua from E5.5 through to E8.5. Like TIMP-3, we demonstrate that SPC-6 expression is induced during the decidual cell response using an in vivo model of artificial decidualization. Both the secreted and membrane bound forms of SPC-6 are expressed throughout the period of decidualization, suggesting that SPC-6 may play multiple roles during this developmental period. This is confirmed by our observation of the movement of SPC-6 expression to the presumptive placental region, as TIMP-3 expression regresses at the implantation site.

Roles of progesterone on suppression of uterine decidualization and implantation failure induced by triphenyltin chloride in rats

ABSTRACT In our previous studies, an administration of triphenyltin chloride (TPTCl) at 4.7 or 6.3 mg/kg on days 0–3 of pregnancy caused implantation failure, and the same doses of TPTCl on days 0–3 of pseudopregnancy caused a suppression of uterine decidualization correlated with a reduction in serum progesterone levels in rats. This study was conducted to determine the roles of progesterone on the TPTCl‐induced suppression of uterine decidualization and implantation failure in rats. Although lower uterine weight was found in hormone‐maintained ovariectomized rats given TPTCl at 4.7 or 6.3 mg/kg on days 0–3 and induced decidual cell response on day 4, no statistical significance in the uterine weight was detected between the control group and the TPTCl‐treated groups. The pregnancy rate and number of implantations in the groups given TPTCl at 4.7 or 6.3 mg/kg on days 0–3 of pregnancy and progesterone on days 0–8 of pregnancy were significantly higher than those in the groups given TPTCl alone. No significant differences in these parameters were found between the control group and the groups given TPTCl and progesterone. It can be concluded that the TPTCl‐induced suppression of uterine decidualization is mediated, at least partially, via the ovarian hormones, and that progesterone protects against the TPTCl‐induced implantation failure.

Effects of monobutyl phthalate on reproductive function in pregnant and pseudopregnant rats

The effects of monobutyl phthalate (MBuP) on reproductive function were determined in pregnant and pseudopregnant rats. Rats were given MBuP by gastric intubation at 250, 500, 750, or 1000 mg/kg on days 0 to 8 of pregnancy and pregnancy outcome was determined on day 20 of pregnancy. The effects of MBuP on the uterine function, as a cause of early embryonic loss, were also determined in pseudopregnant rats, with an induced decidual cell response. The same doses of MBuP were given to pseudopregnant rats on days 0 to 8 of pseudopregnancy and the uterine weight on day 9 served as an index of uterine decidualization. MBuP at 1000 mg/kg caused significant increases in the incidences of preimplantation loss in females successfully mated and of postimplantation loss in females having implantations. Uterine decidualization in pseudopregnant rats was significantly decreased at 1000 mg/kg. These findings suggest that early embryonic loss due to MBuP is mediated, at least in part, via suppression of uterine decidualization, an impairment of uterine function.

Suppression of decidual cell response induced by tributyltin chloride in pseudopregnant rats: a cause of early embryonic loss.

In our previous studies, tributyltin chloride (TBTCl) at doses of 16.3 mg/kg and above caused implantation failure (preimplantation embryonic loss) and postimplantation embryonic loss in rats following administration on gestational day (GD) 0 through GD 3 and GD 4 through GD 7, respectively. This study was designed to assess the effects of TBTCl on uterine function as a cause of early embryonic loss in pseudopregnant rats. TBTCl was given orally to pseudopregnant rats at doses of 4.1, 8.1, 16.3 and 32.5 mg/kg on pseudopregnant day (PPD) 0 to PPD 3 or 8.1, 16.3, 32.5 and 65.1 mg/kg on PPD 4 to PPD 7. The decidual cell response was induced by bilateral scratch trauma on PPD 4. The uterine weight on PPD 9 served as an index of uterine decidualization. Uterine weight and serum progesterone levels on PPD 9 were significantly decreased after administration of TBTCl at doses of 16.3 mg/kg and above on PPD 0 to PPD 3 or PPD 4 to PPD 7. Administration of TBTCl at doses of 8.1 mg/kg and above on PPD 0 to 3 also significantly decreased serum progesterone levels on PPD 4. TBTCl had no effect on ovarian weight and number of corpora lutea. It can be concluded that TBTCl suppresses the uterine decidual cell response and decreases progesterone levels, and these effects are responsible for early embryonic loss due to TBTCl exposure.

Reproductive and developmental toxicity of triphenyltin chloride in rats.

ABSTRACT Reproductive and developmental toxicity of triphenyltin chloride (TPTCI) was evaluated in rats. Although no significant increase in the incidence of fetuses with malformations was observed following administration of TPTCI during organogenesis, a significant increase in the incidence of postimplantation embryonic loss was found. TPTCI during early pregnancy, especially on days 0–3 of pregnancy, caused implantation failure, i. e., preimplantation embryonic loss. The effects of TPTCI on the uterine function, as a cause of implantation failure, were determined using pseudopregnant rats. TPTCI was given on days 0–3 of pseudopregnancy and the decidual cell response was induced on day 4 of pseudopregnancy. Rats was sacrificed on day 9 of pseudopregnancy and the uterine weight served as an index of the uterine decidualization. A significantly lower weight of the uterus, which indicates the suppression of uterine decidualization, was found at the doses which induced implantation failure. These doses of TPTCI also caused a significant decrease in the progesterone levels, which indicates reduced ovarian function. These findings suggest that TPTCI exerts adverse effects on uterine decidualization correlated with the reduction in serum progesterone levels and these effects are responsible, at least in part, for the implantation failure induced by TPTCI.

Effects of dibutyl phthalate on reproductive function in pregnant and pseudopregnant rats

In our previous studies, dibutyl phthalate (DBP) was found to be embryolethal and teratogenic in rats. In this study, the effects of DBP on reproductive function were investigated on pregnant and pseudopregnant rats. Rats were given DBP by gastric intubation at 0, 250, 500, 750, 1000, 1250 or 1500 mg/kg on Days 0 to 8 of pregnancy and the pregnancy outcome was determined on Day 20 of pregnancy. The same doses of DBP were given to pseudopregnant rats, with an induced decidual cell response, on Days 0 to 8 of pseudopregnancy, and the uterine weight on Day 9 served as an index of the uterine decidualization. DBP caused significant increases in the incidences of preimplantation loss in females successfully mated at 1250 and 1500 mg/kg and of postimplantation loss in females having implantations at 750 mg/kg and above. The uterine decidualization in pseudopregnant rats was significantly decreased at 750 mg/kg and above. These findings suggest that early embryonic loss due to DBP may be mediated, at least in part, via the suppression of uterine decidualization, an impairment of uterine function.

Suppression of uterine decidualization as a cause of implantation failure induced by triphenyltin chloride in rats.

In our previous study, triphenyltin chloride (TPTC1) was found to induce implantation failure, as preimplantation embryonic loss, in rats. In this study, the effects of TPTC1 on the uterine function, as a cause of implantation failure, were determined using pseudopregnant rats. Female rats were given TPTC1 by gastric intubation at 3.1, 4.7, and 6.3 mg/kg on pseudopregnant day (PPD) 0 to PPD 3 and the decidual cell response was induced on PPD 4. The uterine weight on PPD 9 served as an index of uterine decidualization. A significant decrease in the uterine weight, which indicates suppression of the uterine decidualization, was detected at 4.7 and 6.3 mg/kg. In our previous study, these doses induced a significant increase in implantation failure in female rats given TPTC1 on gestational day (GD) 0 to 3. The ovarian weight and number of corpora lutea in the TPTC1-treated groups were comparable to that of the controls. A significant decrease in serum progesterone levels after administration of TPTC1 was found at 4.7 and 6.3 mg/kg. These findings suggest that implantation failure due to TPTC1 may be mediated via the suppression of uterine decidualization and correlated with the reduction in serum progesterone levels.

Reproductive effects of butyl benzyl phthalate in pregnant and pseudopregnant rats

In our previous studies, butyl benzyl phthalate (BBP) was found to be embryolethal and teratogenic in rats. In this study, the reproductive effects of BBP were investigated in pregnant and pseudopregnant rats. Rats were given BBP by gastric intubation at 0, 250, 500, 750, or 1000 mg/kg on Days 0 to 8 of pregnancy and the pregnancy outcome was determined on Day 20 of pregnancy. The same doses of BBP were given to pseudopregnant rats, with an induced decidual cell response on Days 0 to 8 of pseudopregnancy, and the uterine weight on Day 9 served as an index of the uterine decidualization. BBP caused significant increases in the incidences of preimplantation loss in females successfully mated at 1000 mg/kg and of postimplantation loss in females having implantations at 750 mg/kg and above. Uterine decidual growth in pseudopregnant rats was significantly decreased at 750 mg/kg and above. These findings suggest that early embryonic loss due to BBP may be mediated, at least in part, via the suppression of uterine decidualization, an impairment of uterine function.

The distribution of laminins and fibronectins is modulated during extravillous trophoblastic cell differentiation and decidual cell response to invasion in the human placenta.

We studied the distribution of laminin (Ln) alpha1-alpha3, beta1-beta3, and gamma1 chains, and of the extradomain-A (EDA) and EDB and the oncofetal epitope of fibronectin (Onc-Fn) in extravillous trophoblastic cells and decidua in the human placenta by immunohistochemistry. We found that the transition from villous to extravillous trophoblast was accompanied by emergence of immunoreactivity for EDA-, EDB-, and Onc-Fn among the cells. Furthermore, whereas the villous trophoblastic basement membrane (BM) contains Ln alpha1, alpha2, beta1, beta2, and gamma1 chains, immunoreactivity for Ln alpha1, beta1, and gamma1, but not for Ln alpha2 and beta2 chains, was detected in association with extravillous trophoblastic cells. Interestingly, although immunoreactivity for the Ln alpha1, alpha2, beta1, beta2, and gamma1 chains was detected in all decidual cell BMs, EDB-Fn and Onc-Fn were detected only in decidua that had been invaded by the trophoblast. In summary, our results describe distinct changes in the distribution of Ln and Fn isoforms during the differentiation of villous trophoblast into extravillous trophoblastic cells. Furthermore, EDB- and Onc-Fn are preferentially found in decidua that has been invaded by the trophoblast, indicating that the deposition of these Fn isoforms reflects a decidual cell response to invasion.

Ketoconazole Impairs Early Pregnancy and the Decidual Cell Response via Alterations in Ovarian Function

Ketoconazole (KCZ) is an imidazole antifungal agent that also affects P450 enzymes of the mammalian steroidogenic system. Several steps in the ovarian steroidogenesis pathway are known to be inhibited by KCZ, but previous work has failed to address the ramifications of such inhibition with respect to early pregnancy. In initial studies, Holtzman rats (8–10/group) were administered 10–100 mg/kg KCZ during days 1–8 of pregnancy. On day 9, evaluations revealed a reduction at both 75 and 100 mg KCZ/kg in the number of implantation sites and serum progesterone levels as well as an increase in ovarian weight The decidual cell response (DCR) was blocked by KCZ in parallel with decreased serum progesterone and increased ovarian weight, indicating direct interference with uterine function. KCZ had no effect when given to long-term-ovariectomized rats that were hormone supplemented to permit the DCR, indicating that the ovary was at least one site of KCZ action on early pregnancy. Measurement of ovarian progesterone production in vitro from ovaries removed from rats treated in vivo with KCZ indicated a decline in progesterone production, suggesting a direct effect of KCZ on ovarian steroidogenesis. These data demonstrate that KCZ can compromise early pregnancy and appears to do so by inhibiting progesterone synthesis in the ovary.

Decidual signals in the establishment of pregnancy: The prolactin family: A review

Decidual cells are responsible for creating a uterine environment supportive of the development of extraembryonic and embryonic tissues. A hormone family structurally related to pituitary PRL is a component of the efferent decidual cell response. Thus far, members of the PRL gene family have been identified in primates and in the rat. Patterns of expression during gestation suggest a role for members of the decidual PRL family in the establishment and maintenance of the gestational state. Precise physiological roles for each member of the decidual PRL family remain to be elucidated.

The Immunolocalization of Basic Fibroblast Growth Factor in the Mouse Uterus During the Initial Stages of Embryo Implantation

Mammalian embryo implantation involves a series of complex interactions between maternal and embryonic cells. Uterine polypeptide growth factors may play critical roles in these cell interactions. Basic fibroblast growth factor (basic FGF) is a member of a family of growth factors. This growth factor may be potentially important for the process of embryo implantation because it (a) is stored within the extracellular matrix and is thus easily available during embryo invasion, (b) is a potent modulator of cell proliferation and differentiation and (c) stimulates angiogenesis. The immunolocalization of basic FGF in the uterus during the peri-implantation period of pregnancy is presented in this study. Uterine tissue samples were obtained on days 6-9 of pregnancy with day 1 of pregnancy being the day of a vaginal copulatory plug. Uterine samples were fixed in Bouin's fluid for no longer than 18 h. Following fixation and paraffin embedding, sections were exposed to primary antisera made in rabbits against either (a) human recombinant basic FGF or (b) 1-24 synthetic fragment of bovine basic FGF. The primary antibody was followed by biotinylated goat anti-rabbit IgG and a biotin-avidin-peroxidase complex. There were no differences in the immunolocalization of basic FGF using either source of primary antibody. Our results demonstrated both temporal and spatial changes in the localization of immunoreactive basic FGF within the implantation chamber during days 6-9 of pregnancy. Inter-implantation sites resembled the non-pregnant uterus with basic FGF present in extracellular matrices including basal laminae. On day 6 of pregnancy, decidual cells within the primary decidual zone lacked both intracellular and pericellular basic FGF while non-decidualized uterine stroma resembled inter-implantation sites. By days 7-8 of pregnancy, the secondary decidual zone had formed and was characterized by the distinct pericellular localization of basic FGF around individual decidual cells. By day 9 of pregnancy, the mesometrial region was forming and contained cords of decidual cells and a labyrinth of maternal blood vessels. The decidual cells contained diffuse intracellular basic FGF. Trophoblast cells were devoid of basic FGF at all times examined. These results indicate that basic FGF is present within the implantation chamber on days 6-9 of pregnancy and may be involved in the decidual cell response, trophoblast cell invasion and angiogenesis.

Evaluation of the effects of methanol during early pregnancy in the rat

Recent attention to methanol (MeOH) as a potential alternative fuel prompted an evaluation of the chemical's effects during early pregnancy. Rats were dosed by gavage during Days 1–8 of pregnancy at 0, 1.6, 2.4, or 3.2 g MeOH/kg/day. Groups of animals were killed on Days 9, 11, or 20 of pregnancy, and maternal, embryonic, or fetal parameters were assessed, depending on the stage of pregnancy. The decidual cell response (DCR) technique was also applied to rats treated with MeOH during pseudopregnancy. Reductions in pregnant uterine and implantation site weights seen on Day 9 are the result of MeOH impedance of normal decidualization, as demonstrated by effects on the DCR. An increase in the extravasation of blood at implantation sites seen on Day 9 did not result in an increase in resorptions by Day 20. The 3.2 g/kg/day dose of MeOH produced a reduction in body weight gain by Day 9, which may be considered an indication of non-specific maternal toxicity. No effect on Day 11 or Day 20 embryo-fetal survival, or development was observed.