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  • 刊频： Monthly, 2009-
  • NLM标题： Reprod Sci
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  • 1.

    【2hr】Antenatal Microbial Colonization of Mammalian Gut

    包量

    机译 哺乳动物肠道的产前微生物定殖
    摘要：The widely accepted dogma of intrauterine sterility and initial colonization of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta, and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations and to assess fetal colonization before parturition. To this end, we analyzed sterilely collected intestinal tissues, placenta, and amniotic fluid from rodent fetuses and tissues from autoptic human fetuses. Total bacterial DNA was extracted from collected samples and analyzed by Next Generation Sequencing (NGS) techniques using hypervariable 16S ribosomal RNA (rRNA) regions (V3-V4). Colonizing microbes were visualized in situ, using labeled probes targeting 16S ribosomal DNA by fluorescent in situ hybridization. The NGS analysis showed the presence of pioneer microbes in both rat and human intestines as well as in rodent placentas and amniotic fluids. Microbial communities showed fetus- and dam-dependent clustering, confirming the high interindividual variability of commensal microbiota even in the antenatal period. Fluorescent in situ hybridization analysis confirmed the microbes’ presence in the lumen of the developing gut. These findings suggest a possible antenatal colonization of the developing mammaliangut.
  • 2.

    【2hr】The Association of Maternal Age With Fetal Growth and Newborn Measures: The Mumbai Maternal Nutrition Project (MMNP)

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    机译 产妇年龄与胎儿生长和新生儿措施的关联：孟买产妇营养计划（MMNP）
    摘要：Background:Young maternal age is associated with poorer birth outcomes, but the mechanisms are incompletely understood. Using data from a prospective cohort of pregnant women living in Mumbai slums, India, we tested whether lower maternal age was associated with adverse fetal growth.
  • 3.

    【2hr】G-Protein-Coupled Receptor CXCR7 Is Overexpressed in Human and Murine Endometriosis

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    机译 G蛋白偶联的受体CXCR7在人类和小鼠子宫内膜异位症中过表达。
    摘要：Endometriosis is a chronic inflammatory disease. Dysfunctional regulation of chemokines and chemokine receptors is a crucial aspect of endometriosis pathogenesis. Chemokine G-protein-coupled receptors (GPCRs) are important drug targets that regulate inflammation and immunity. Recently, CXCR7, a C-X-C motif containing GPCR, has been identified as a receptor for chemokine ligand CXCL12, one of the best characterized chemokines for cell trafficking, angiogenesis, and cell proliferation in cancer and inflammation. Here, we investigated the expression and localization of CXCR7 in human endometriosis and a murine model of the disease. Normal endometrial epithelium and stroma showed undetectable or very low expression of CXCR7, without any significant changes across phases of the menstrual cycle in humans. CXCR7 is significantly upregulated in endometriosis, showing higher staining in glands and in associated vessels. The mouse model recapitulated the human findings. In conclusion, overexpression of CXCR7 in different cellular populations of endometriosis microenvironment may play a role in the pathogenesis and represent a novel target for treatment.
  • 4.

    【2hr】Anoctamin Channels in Human Myometrium: A Novel Target for Tocolysis

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    机译 人子宫肌层中的octamin通道：宫缩的新目标
    摘要：Background:Spontaneous preterm labor leading to preterm birth is a significant obstetric problem leading to neonatal morbidity and mortality. Current tocolytics are not completely effective and novel targets may afford a therapeutic benefit.
  • 5.

    【2hr】Sex-Dependent Influence of Developmental Toxicant Exposure on Group B Streptococcus-Mediated Preterm Birth in a MurineModel

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    机译 发育毒性暴露对鼠类B组链球菌介导的早产的性别依赖性影响模型
    摘要：Infectious agents are a significant risk factor for preterm birth (PTB); however, the simple presence of bacteria is not sufficient to induce PTB in most women. Human and animal data suggest that environmental toxicant exposures may act in concert with other risk factors to promote PTB. Supporting this “second hit” hypothesis, we previously demonstrated exposure of fetal mice (F1 animals) to the environmental endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to an increased risk of spontaneous and infection-mediated PTB in adult animals. Surprisingly, adult F1males also confer an enhanced risk of PTB to their control partners. Herein, we used a recently established model of ascending group B Streptococcus (GBS) infection to explore the impact of a maternal versus paternal developmental TCDD exposure on infection-mediated PTB in adulthood. Group B Streptococcus is an important contributor to PTB in women and can have serious adverse effects on their infants. Our studies revealed that although gestation length was reduced in control mating pairs exposed to low-dose GBS, dams were able to clear the infection and bacterial transmission to pups was minimal. In contrast, exposure of pregnant F1females to the same GBS inoculum resulted in 100% maternal and fetal mortality. Maternal health and gestation length were not impacted in control females mated to F1males and exposed to GBS; however, neonatal survival was reduced comparedto controls. Our data revealed a sex-dependent impact of parental TCDD exposure onplacental expression of Toll-like receptor 2 and glycogen production, which may beresponsible for the differential impact on fetal and maternal outcomes in response to GBSinfection.
  • 6.

    【2hr】Environmental Manipulations as an Effective Alternative Treatment to Reduce Endometriosis Progression

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    机译 环境操纵作为减少子宫内膜异位症进展的有效替代疗法
    摘要：Treatments for endometriosis include pharmacological or surgical procedures that produce significant side effects. We aimed to determine how environmental enrichment (EE) could impact the progression of endometriosis using the autotransplantation rat model. Female rats were exposed to EE (endo-EE: toys and nesting materials, 4 rats per cage, larger area enclosure) or no enrichment (endo-NE: 2 rats per cage) starting on postnatal day 21. After 8 weeks, sham surgery or surgical endometriosis was induced by suturing uterine horn tissue next to the intestinal mesentery, then allowed to progress for 60 days during which EE or NE continued. At the time of killing, we measured anxiety behaviors, collected endometriotic vesicles and uterus, and processed for quantitative real-time polymerase chain reaction for corticotropin-releasing hormone (CRH), urocortin-1, CRH receptors type 1 and type 2, and glucocorticoid receptor (GR). Endometriosis did not affect anxiety-like behaviors, yet rats in enriched conditions showed lower basal anxiety behaviors than the nonenriched group. Importantly, the endo-EE group showed a 28% reduction in the number of endometriosis vesicles and the vesicles were significantly smaller compared to the endo-NE group. Endometriosis increased CRH and GR only in the vesicles of endo-NE, and this increase was dampened in the endo-EE. However, urocortin 1 was increased in the vesicles of the endo-EE group, suggesting different pathways of activation of CRH receptors in this group. Our results suggest that the use of multimodal complementary therapies that reduce stress in endometriosis could be an effective and safe treatment alternative, with minimal side effects.
  • 7.

    【2hr】Effect of Normal Pregnancy Followed by Lactation on Long-Term Maternal Health in a Mouse Model

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    机译 正常妊娠后哺乳期对小鼠模型中长期孕妇健康的影响
    摘要：Although it has been widely accepted that pregnancies with complications are associated with increased maternal cardiovascular risk later in life, there is no consensus if noncomplicated pregnancy followed by lactation plays a protective role or is a risk factor. The objective of this study was to investigate the effects of normal pregnancy and lactation on long-term maternal health in a mouse model. CD-1 mice were allocated to breeding (primigravid [PG]) and nonbreeding (nulligravid [NG]) groups. The PG group proceeded through normal pregnancy and delivery. Using a telemetry system, blood pressure (BP) was analyzed in the PG group at 6 months postpartum and in age-matched NG mice. Serum analytes, gene expressions, and protein levels were determined using appropriate analysis methods. Primigravid mice had significantly lower systolic and diastolic BP and fasting glucose levels. Circulating oxytocin (OXT) levels were significantly higher in PG mice. Oxt gene expression was significantly higher in the heart and aorta and lower in visceral adipose tissue (VAT) from PG mice. The oxytocin receptor (Oxtr) gene expression was significantly higher in the heart, aorta, and VAT from PG animals. The level of Oxtr DNA hypermethylation and the expression of mmu-miR-29a were significantly lower in the hearts of PG mice. In PG VAT, glucose transporter-4 expression was significantly higher. Our study demonstrates that a history of normal pregnancy followed by lactation was associated with lower maternal cardiovascular risk factors later in life in female mouse.
  • 8.

    【2hr】The Effect of Prenatal Alcohol Exposure on Fetal Growth and Cardiovascular Parameters in a Baboon Model of Pregnancy

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    机译 狒狒妊娠模型中产前酒精暴露对胎儿生长和心血管参数的影响
    摘要：Prenatal alcohol exposure often results in an array of fetal developmental abnormalities termed fetal alcohol spectrum disorders (FASDs). Despite the high prevalence of FASDs, the pathophysiology of fetal damage by alcohol remains poorly understood. One of the major obstacles in studying fetal development in response to alcohol exposure is the inability to standardize the amount, pattern of alcohol consumption, and peak blood alcohol levels in pregnant mothers. In the present study, we used Doppler ultrasonography to assess fetal growth and cardiovascular parameters in response to alcohol exposure in pregnant baboons. Baboons were subjected to gastric alcohol infusion 3 times during the second trimester equivalent to human pregnancy, with maternal blood alcohol levels reaching 80 mg/dL within 30 to 60 minutes following alcohol infusion. The control group received a drink that was isocaloric to the alcohol-containing one. Doppler ultrasonography was used for longitudinal assessment of fetal biometric parameters and fetal cardiovascular indices. Fetal abdominal and head circumferences, but not femur length, were significantly decreased in alcohol-exposed fetuses near term. Peak systolic velocity of anterior and middle cerebral arteries decreased during episodes of alcohol intoxication, but there was no difference in Doppler indices between groups near term. Acute alcohol intoxication affected fetal cerebral blood flow independent of changes in the fetal cardiac output. Unlike fetal growth parameters, changes in vascular indices did not persist over gestation. In summary, alcohol effects on fetal growth and on fetal vascular function have different time courses.
  • 9.

    【2hr】Matrix Metalloprotease-1 and Elastase Are Novel Uterotonic Agents Acting Through Protease-Activated Receptor 1

    包量

    机译 基质金属蛋白酶-1和弹性蛋白酶是通过蛋白酶激活受体1作用的新型子宫渗透剂。
    摘要：Matrix metalloproteinase-1 (MMP-1) and neutrophil elastase are proteolytic enzymes involved in tissue remodeling, but a role for them as uterotonic agents has not been considered. However, both these proteases activate protease-activated receptor 1 (PAR-1) that mediates thrombin-induced contractions. Matrix metalloproteinase-1 and elastase are products of neutrophils that infiltrate intrauterine tissues at the time of labor, so we tested the hypothesis that these proteases might be novel uterotonic agents acting via PAR-1. Decidual tissue was collected from fetal membranes of term not-in-labor (TNL), term labor (TL), and preterm labor (PTL) women and analyzed for gene and protein expression of MMP-1 and neutrophil elastase. Contractile effects of MMP-1 and elastase were tested with uterine strips of day 19 and 20 gestation rats. Expression of MMP-1 and neutrophil elastase was increased in TL and PTL as compared to TNL. Expression of both the pro- and active enzymes of MMP-1 increased progressively from TNL to TL to PTL. Tumor necrosis factor-α, a neutrophil product, increased MMP-1 in decidual and myometrial cells. Both MMP-1 and elastase stimulated strong contractions of myometrial strips, which were prevented by inhibition of PAR-1 and inhibition of inositol trisphosphate receptor or calcium channel blockade. Indomethacin did not prevent protease-induced contractions. These data suggest that MMP-1 and neutrophil elastase may be important but heretofore unrecognized players in stimulating uterine contractions at the time of labor, and they may explain why indomethacin delays, but does not prevent, PTL because indomethacin inhibits the prostaglandin component but not the protease component of labor.
  • 10.

    【2hr】Ulipristal Acetate and Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Placebo Controlled Trial

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    机译 人体人类平滑肌瘤中的上乙酸和细胞外基质生产：随机安慰剂对照试验的实验室分析。
    摘要：In a prior randomized controlled study, patients treated with ulipristal acetate (UPA) or placebo for 3 months had a decrease in leiomyoma size. A total of 10 patients’ tissue samples (5 placebo and 5 treated with 10 mg/d UPA) that underwent hysterectomy and tissue preservation were identified from this study. Quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting were used to assess fold gene and protein expression of extracellular membrane (ECM) proteins: collagen 1A (COL1A), fibronectin (FN1), and versican (VCAN) of the samples. Confirmatory immunohistochemical analysis was performed. Changes in total matrix collagen were examined using Masson trichrome staining. Multiplex measurement of the matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases was performed. Compared to placebo-treated surgical specimens, 80% of the treated specimens showed decrease in VCAN protein, 60% showed decrease in FN1, but no consistent alteration in COL1A. This effect was also supported by immunohistochemistry where leiomyoma surgical specimens demonstrated decreased amount of FN1 and VCAN on UPA treatment. Increased MMP2 and decreased MMP9 in treated patient leiomyomas indicate both degradation of the matrix and inhibition of the pathway involved in matrix production. Treatment with UPA decreased fibroid volume in placebo-controlled, randomized trials. Treatment with UPA decreased gene expression and protein production in leiomyoma tissue, suggesting both an impact on water content and ECM protein concentration as a mechanism of ulipristal-mediated decrease in leiomyoma size.
  • 11.

    【2hr】Adiposity, but not Obesity, Is Associated With Arterial Stiffness in YoungNulliparous Women

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    机译 肥胖而非肥胖与年轻人的动脉僵硬度有关无核妇女
    摘要：Subclinical vascular dysfunction is increasingly recognized as an independent risk factor for cardiovascular events and adverse pregnancy outcomes. The evidence linking indices of obesity and vascular dysfunction is mixed. As an example, some data suggest that adiposity may be a better predictor of endothelial dysfunction than body mass index (BMI). The aim of the current study is to compare the association of obesity, as evaluated by BMI, and a direct measure of body fat to biophysical parameters of vascular function including flow-mediated vasodilation and pulse wave velocity (PWV) in healthy nulliparous reproductive-age women. This is a secondary analysis of data collected as a prospective study of prepregnancy physiology in healthy, nulliparous women. Body mass index was calculated as weight (kg)/height (m2). Total and android body fat were calculated by dual-energy X-ray absorptiometry. Brachial PWV and flow-mediated vasodilation were assessed ultrasonographically. Seventy-nine women were evaluated. Mean BMI was 24.4 (5.4) kg/m2, and 15% of women were obese (BMI ≥ 30 kg/m2). In contrast, 39% were considered to have excess adiposity, with ≥39% android body fat. Brachial PWV was associated with increased adiposity, but not obesity. We found no differences in flow-mediated dilation associated with either BMI or body fat. Adiposity may be superior to BMI in identifying women with vascular dysfunction atincreased risk of adverse pregnancy outcome and cardiovascular disease. Properidentification may allow implementation of prevention strategies to improve perinataloutcomes and maternal health.
  • 12.

    【2hr】Effect of Pregnancy Interval on Second Pregnancy Blood Pressure Following Prior Preeclampsia

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    机译 妊娠间隔对先兆子痫后第二次妊娠血压的影响
    摘要：Objective:Preeclampsia generally occurs in first pregnancies and tends not to recur when the interpregnancy interval (IPI) is short. We hypothesized that, in women experiencing preeclampsia in their first pregnancy, the difference in mean arterial pressure (MAP) across pregnancy between their index and subsequent pregnancy would be inversely associated with the length of time between pregnancies and that the interval between pregnancies will be directly associated with the likelihood of preeclampsia recurrence.
  • 13.

    【2hr】Prenatal Growth Patterns and Birthweight Are Associated With Differential DNAMethylation and Gene Expression of Cardiometabolic Risk Genes in Human Placentas: ADiscovery-Based Approach

    包量

    机译 产前生长方式和出生体重与DNA差异相关人体胎盘中心脏代谢风险基因的甲基化和基因表达：A基于发现的方法
    摘要：Inherent genetic programming and environmental factors affect fetal growth in utero. Epidemiologic data in growth-altered fetuses, either intrauterine growth restricted (IUGR) or large for gestational age (LGA), demonstrate that these newborns are at increased risk of cardiometabolic disease in adulthood. There is growing evidence that the in utero environment leads to epigenetic modification, contributing to eventual risk of developing heart disease or diabetes. In this study, we used reduced representation bisulfite sequencing to examine genome-wide DNA methylation variation in placental samples from offspring born IUGR, LGA, and appropriate for gestational age (AGA) and to identify differential methylation of genes important for conferring risk of cardiometabolic disease. We found that there were distinct methylation signatures for IUGR, LGA, and AGA groups and identified over 500 differentially methylated genes (DMGs) among these group comparisons. Functional and gene network analyses revealed expected relationships of DMGs to placental physiology and transport, but also identified novel pathways with biologic plausibility and potential clinical importance to cardiometabolic disease. Specific loci for DMGs of interest had methylation patterns that were strongly associated with anthropometric presentations. We further validated altered gene expression of these specific DMGs contributing to vascular and metabolic diseases (SLC36A1, PTPRN2, CASZ1,IL10), thereby establishing transcriptional effects toward assigning functionalsignificance. Our results suggest that the gene expression and methylation state of thehuman placenta are related and sensitive to the intrauterine environment, as it affectsfetal growth patterns. We speculate that these observed changes may affect risk foroffspring in developing adult cardiometabolic disease.
  • 14.

    【2hr】Tropomyosin Receptor Kinase B Agonist, 7,8-Dihydroxyflavone, Improves Mitochondrial Respiration in Placentas From Obese Women

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    机译 Tropomyosin受体激酶B激动剂7,8-二羟基黄酮可改善肥胖女性胎盘的线粒体呼吸作用。
    摘要：Maternal obesity negatively impacts the placenta, being associated with increased inflammation, decreased mitochondrial respiration, decreased expression of brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TRKB). TRKB induction by 7,8-dihydroxyflavone (7,8-DHF) improves energy expenditure in an obesity animal model. We hypothesized that TRKB activation would improve mitochondrial respiration in trophoblasts from placentas of obese women. Placentas were collected from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI > 30) women at term following cesarean section delivery without labor. Cytotrophoblasts were isolated and plated, permitting syncytialization. At 72 hours, syncytiotrophoblasts (STs) were treated for 1 hour with 7,8-DHF (10 nM–10 M), TRKB antagonists (ANA-12 (10 nM–1 M), Cyclotraxin B (1 nM–1M)), or vehicle. Mitochondrial respiration was measured using the XF24 Extracellular Flux Analyzer. TRKB, MAPK, and PGC1α were measured using Western blotting. Maternal obesity was associated with decreased mitochondrial respiration in STs; however, 7,8-DHF increased basal, ATP-coupled, maximal, spare capacity, and nonmitochondrial respiration. A 10 μM dose of 7,8-DHF reduced spare capacity in STs from lean women, with no effect on other respiration parameters. 7,8-DHF had no effect on TRKB phosphorylation; however, there was a concentration-dependent decrease of p38 MAPK phosphorylation and increase of PGC1α in STs from obese, but not in lean women. TRKB antagonism attenuated ATP-coupled respiration, maximal respiration, and spare capacity in STs from lean and obese women. 7,8-DHF improves mitochondrial respiration in STs from obese women, suggesting that the obese phenotype in the placenta can be rescued by TRKB activation.
  • 15.

    【2hr】Control of Progesterone Receptor-A Transrepressive Activity in Myometrial Cells: Implications for the Control of Human Parturition

    包量

    机译 子宫肌层细胞中孕酮受体-A抑制活动的控制：对人类分娩的控制意义。
    摘要：Uterine quiescence during pregnancy is maintained by progesterone primarily via signaling mediated by the type-B progesterone receptor (PR-B) in myometrial cells. Withdrawal of PR-B-mediated progesterone activity is a principal trigger for labor. One mechanism for PR-B withdrawal is by inhibition of its activity by the type-A PR (PR-A) isoform in myometrial cells. We hypothesized that human parturition involves hormonal interactions that induce the capacity for PR-A to inhibit PR-B in myometrial cells and that pro-inflammatory cytokines are major regulators of this process. We tested this hypothesis in an immortalized human myometrial cell line, hTERT-HMA/B, in which levels of PR-A and PR-B can be experimentally controlled. We found that the capacity for PR-A to repress PR-B, assessed by activity of a transiently transfected reporter DNA controlled by the progesterone response element, and expression of FK506 binding protein 5 (FKBP5) an endogenous PR-B responsive gene, was increased by serum supplementation and interleukin-1β. In pregnant uterus, FKBP5 was detected exclusively in myometrial cells and its expression decreased with advancing gestation and in association with the onset of labor at term. These findings suggest that in myometrial cells the repressive activity of PR-A on PR-B increases with advancing gestation and is induced by pro-inflammatory cytokines. This may be a key mechanism linking inflammation with the onset of labor.
  • 16.

    【2hr】Low Vitamin D is Associated With Infections and Proinflammatory Cytokines During Pregnancy

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    机译 低维生素D与怀孕期间的感染和促炎性细胞因子有关
    摘要：Vitamin D is known to regulate innate and adaptive immune processes at the cellular level, but the role of vitamin D status on associated inflammatory processes across pregnancy is unclear. Our primary objective was to evaluate the relationships between serum biomarkers of inflammation (interleukin [IL]-6, IL-10, tumor necrosis factor [TNF]-α), acute-phase proteins (C-reactive protein and hepcidin) and vitamin D status, 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D), measured across pregnancy and in the neonate at birth. A second objective was to identify associations between vitamin D status and clinically diagnosed infections. In this study, 158 racially and ethnically diverse pregnant adolescents were recruited from the Rochester Adolescent Maternity Program (RAMP) in Rochester, NY. Serum 1,25(OH)2D was significantly lower in adolescents and neonates with IL-6 concentrations above the 75th percentile at delivery (P = .04) and at birth (P = .004), respectively. After adjusting for other potential covariates of inflammation, maternal serum 1,25(OH)2D was significantly positively associated with TNF-α during pregnancy (P = .02), but at delivery 1,25(OH)2D and TNF-α were inversely associated with one another (P = .02). Teens with 25(OH)D concentrations <30 ng/mL were more likely to test positive for candida (P = .002) and bacterial vaginosis (P = .02) during pregnancy. African Americans exhibited significantly lower TNF-α concentrations at both mid-gestation (P = .009) and delivery (P = .001) compared to the Caucasian adolescents. These results suggest that lower maternal vitamin D status may increase risk of infection across gestation.
  • 17.

    【2hr】Endometrial Stromal and Epithelial Cells Exhibit Unique Aberrant MolecularDefects in Patients With Endometriosis

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    机译 子宫内膜间质和上皮细胞表现出独特的异常分子子宫内膜异位症患者的缺陷
    摘要：Context:Endometriosis is a chronic inflammatory disease that causes pain and infertility in women of reproductive age.
  • 18.

    【2hr】Trophoblast Glycoprotein (TPGB/5T4) in Human Placenta: Expression, Regulation, and Presence in Extracellular Microvesicles and Exosomes

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    机译 胎盘中滋养层糖蛋白（TPGB / 5T4）：在细胞外微泡和外泌体中的表达，调控和存在
    摘要：Background:Many parallels exist between growth and development of the placenta and that of cancer. One parallel is shared expression of antigens that may have functional importance and may be recognized by the immune system. Here, we characterize expression and regulation of one such antigen, Trophoblast glycoprotein (TPGB; also called 5T4), in the placenta across gestation, in placentas of preeclamptic (PE) pregnancies, and in purified microvesicles and exosomes.
  • 19.

    【2hr】Expression of StAR and Key Genes Regulating Cortisol Biosynthesis in Near Term Ovine Fetal Adrenocortical Cells: Effects of Long-Term Hypoxia

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    机译 StAR和调节短时胎儿胎儿肾上腺皮质细胞皮质醇生物合成关键基因的表达：长期缺氧的影响。
    摘要：We previously demonstrated decreased expression of key genes regulating cortisol biosynthesis in long-term hypoxic (LTH) sheep fetal adrenals compared to controls. We also showed that inhibition of the extracellular signal–regulated kinases (ERKs) with the mitogen-activated protein kinase (MEK)/ERK inhibitor UO126 limited adrenocorticotropic (ACTH)-induced cortisol production in ovine fetal adrenocortical cells (FACs), suggesting a role for ERKs in cortisol synthesis. This study was designed to determine whether the previously observed decrease in LTH cytochrome P45011A1/cytochrome P450c17 (CYP11A1/CYP17) in adrenal glands was maintained in vitro, and whether ACTH alone with or without UO126 treatment had altered the expression of CYP11A1, CYP17, and steroidogenic acute regulatory protein (StAR) in control versus LTH FACs. Ewes were maintained at high altitude (3820 m) from ∼40 days of gestation (dG). At 138 to 141 dG, fetal adrenal glands were collected from LTH (n = 5) and age-matched normoxic controls (n = 6). Fetal adrenocortical cells were challenged with ACTH (10−8 M) with or without UO126 (10 µM) for 18 hours. Media samples were collected for cortisol analysis and messenger RNA (mRNA) for CYP11A1, CYP17, and StAR was quantified by quantitative real-time polymerase chain reaction. Cortisol was higher in the LTH versus control (P < .05). StAR mRNA was decreased in LTH versus control (P < .05). U0126 alone had no effect on mRNA in either group. UO126 prevented the increase in CYP11A1 and CYP17 in control FACs. Basal CYP11A1 and CYP17 were not different in LTH versus control. ACTH increased CYP11A1 and CYP17 only in control FACs (P < .05). U1026 attenuated the ACTH response indicative of a role for ERK in CYP11A1 and CYP17 expression. ACTH may require additional factors in FACs to fully regulate StAR expression.
  • 20.

    【2hr】Adverse Placental Perfusion and Pregnancy Outcomes in a New Nonhuman PrimateModel of Gestational Protein Restriction

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    机译 新型非人类灵长类动物的不良胎盘灌注和妊娠结局妊娠蛋白限制模型
    摘要：Maternal malnutrition during pregnancy impacts fetal growth, with developmental consequences that extend to later life outcomes. In underdeveloped countries, this malnutrition typically takes the form of poor dietary protein content and quality, even if adequate calories are consumed. Here, we report the establishment of a nonhuman primate model of gestational protein restriction (PR) in order to understand how placental function and pregnancy outcomes are affected by protein deficiency. Rhesus macaques were assigned to either a control diet containing 26% protein or switched to a 13% PR diet prior to conception and maintained on this PR diet throughout pregnancy. Standard fetal biometry, Doppler ultrasound of uteroplacental blood flow, ultrasound-guided amniocentesis, and contrast-enhanced ultrasound (CE-US) to assess placental perfusion were performed mid-gestation (gestational day 85 [G85] where term is G168) and in the early third trimester (G135). Our data demonstrate that a 50% reduction in dietary protein throughout gestation results in reduced placental perfusion, fetal growth restriction, and a 50% rate of pregnancy loss. In addition, we demonstrate reduced total protein content and evidence of fetal hypoxia in the amniotic fluid. This report highlights the use of CE-US for in vivo assessment of placental vascular function. The ability to detect placental dysfunction, and thus a compromised pregnancy, early in gestation, mayfacilitate the development of interventional strategies to optimize clinical care andimprove long-term offspring outcomes, which are future areas of study in this newmodel.
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