Early life risk and resiliency factors and their influences on developmental outcomes and disease pathways: a rapid evidence review of systematic reviews and meta-analyses.

The Developmental Origins of Health and Disease (DOHaD) framework aims to understand how environmental exposures in early life shape lifecycle health. Our understanding and the ability to prevent poor health outcomes and enrich for resiliency remain limited, in part, because exposure-outcome relationships are complex and poorly defined. We, therefore, aimed to determine the major DOHaD risk and resilience factors. A systematic approach with a 3-level screening process was used to conduct our Rapid Evidence Review following the established guidelines. Scientific databases using DOHaD-related keywords were searched to capture articles between January 1, 2009 and April 19, 2019. A final total of 56 systematic reviews/meta-analyses were obtained. Studies were categorized into domains based on primary exposures and outcomes investigated. Primary summary statistics and extracted data from the studies are presented in Graphical Overview for Evidence Reviews diagrams. There was substantial heterogeneity within and between studies. While global trends showed an increase in DOHaD publications over the last decade, the majority of data reported were from high-income countries. Articles were categorized under six exposure domains: Early Life Nutrition, Maternal/Paternal Health, Maternal/Paternal Psychological Exposure, Toxicants/Environment, Social Determinants, and Others. Studies examining social determinants of health and paternal influences were underrepresented. Only 23% of the articles explored resiliency factors. We synthesized major evidence on relationships between early life exposures and developmental and health outcomes, identifying risk and resiliency factors that influence later life health. Our findings provide insight into important trends and gaps in knowledge within many exposures and outcome domains.

Effect of Oral Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on the Vaginal Microbiota, Cytokines and Chemokines in Pregnant Women.

Spontaneous preterm birth is associated with vaginal microbial dysbiosis. As certain strains of lactobacilli help restore homeostasis in non-pregnant women, the goal was to determine the effect of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 administered orally, twice daily for 12 weeks on the vaginal microbiota, cytokines and chemokines of low-risk pregnant women. A double-blind, placebo-controlled, randomized trial comparing probiotic lactobacilli to placebo daily was performed in 86 asymptomatic pregnant women who had an Intermediate or Bacterial Vaginosis Nugent score at 13 weeks. After drop outs, 32 women receiving probiotics and 34 receiving placebo completed the study. The Nugent score returned to normal in 30% of the women in both groups at 28 weeks and was maintained until 35 weeks. The majority of subjects had normal pregnancy outcomes. Ninety-three bacterial species were detected at 13 weeks, with Lactobacillus iners, Lactobacillus crispatus, Gardnerella vaginalis and Atopobium vaginae being the most abundant across pregnancy. There was no difference in the Shannon diversity index between the probiotic and placebo groups at 13, 28 or 35 weeks. Almost all subjects consumed fermented foods and many of the organisms in the vagina are also known to be present in fermented foods. Interleukin-4 in the placebo group and Interleukin-10 in both probiotic and placebo groups increased slightly at 28 weeks but were not different at 35 weeks when compared to 13 weeks. In conclusion, this study showed no adverse issues resulting from 12 week use of probiotic Lactobacillus strains GR-1 and RC-14 during pregnancy in women at low risk for premature birth. The vaginal microbiota demonstrated flux irrespective of this oral probiotic administration.

Effect of Lactobacillus rhamnosus GR-1 Supernatant on Cytokine and Chemokine Output From Human Amnion Cells Treated With Lipoteichoic Acid and Lipopolysaccharide.

Preterm birth occurs in 9% to 13% of all human pregnancies and accounts for 80% of all neonatal morbidities and mortalities. Approximately 40% of all preterm births are idiopathic and about half are associated with infection and/or an activated inflammatory process. Further to studies showing anti-inflammatory effects of supernatant from the probiotic Lactobacillus rhamnosus GR-1 (GR-1), we tested its ability to modulate cytokine and chemokine production from amnion cells in response to stimulation by bacterial wall components, lipopolysaccharide (LPS), and lipoteichoic acid (LTA). Placentae were collected from women undergoing elective cesarean section at term. Amnion cells were cultured for 48 hours to confluence, serum starved for 12 hours, and then treated with GR-1 supernatant (1:20 dilution), followed after 12 hours by LPS (100 ng/mL) or LTA (10 ng/mL) for an additional 12 hours. Both LTA and LPS caused significant increases in the concentration of the pro-inflammatory cytokine, tumor necrosis factor α (TNF-α; 103.9 ± 67.5 pg/mL and 368.3 ± 65.7 pg/mL, respectively) in medium from cultured amnion cells compared to control (<4 pg/mL). There was no significant effect of GR-1 supernatant alone on TNF-α output, but there was significant reduction after LPS treatment. The basal output of the immunomodulatory cytokine, interleukin 6, was 613 ± 170 pg/mL and increased significantly after addition of GR-1 supernatant, LTA, LPS, and combinations of LTA/LPS with GR-1 supernatant. In conclusion, probiotic L rhamnosus GR-1 attenuates the effect of both LPS and LTA in stimulating the output of the pro-inflammatory cytokine TNF-α from mixed cultures of human amnion cells in keeping with previous findings in human trophoblast cells.

Fetal and neonatal outcomes after term and preterm delivery following betamethasone administration.

OBJECTIVE: To determine the effects of betamethasone on fetal growth and neonatal outcomes. METHODS: A retrospective cohort study was performed of deliveries that occurred at Charité University Hospital Berlin, Germany, between January 1996 and December 2008. The betamethasone group included women with preterm labor and symptomatic contractions, cervical insufficiency, preterm premature rupture of membranes, or vaginal bleeding. Women in the control group were matched for gestational age at time of delivery and had not received betamethasone. Fetal growth changes and neonatal anthropometry were compared. RESULTS: Among 1799 newborns in the betamethasone group and 42 240 in the control group, betamethasone was associated with significantly lower birth weight (154 g lower on average) after adjusting for confounders (e.g. hypertension, smoking, and maternal weight), sex, and gestational age at delivery (P<0.05). The higher the dose, the greater the difference in mean birth weight versus controls in births before 34(+0)weeks (≤16 mg -444 g; 24 mg -523 g; >24 mg -811 g), without a detectable improvement in neonatal morbidity or mortality. There was a dose-dependent decline in expected fetal weight gain as estimated by serial ultrasonography examinations 6-8 weeks after betamethasone administration (P<0.05). CONCLUSION: Betamethasone exposure reduces fetal weight gain in a dose-dependent manner without improving neonatal morbidity or mortality.

Is there a role for probiotics in the prevention of preterm birth?

Preterm birth (PTB) continues to be a global health challenge. An over-production of inflammatory cytokines and chemokines, as well as an altered maternal vaginal microbiome has been implicated in the pathogenesis of inflammation/infection-associated PTB. Lactobacillus represents the dominant species in the vagina of most healthy pregnant women. The depletion of Lactobacillus in women with bacterial vaginosis (BV) has been associated with an increased risk of PTB. It remains unknown at what point an aberrant vaginal microbiome composition specifically induces the cascade leading to PTB. The ability of oral or vaginal lactobacilli probiotics to reduce BV occurrence and/or dampen inflammation is being considered as a means to prevent PTB. Certain anti-inflammatory properties of lactobacilli suggest potential mechanisms. To date, clinical studies have not been powered with sufficiently high rates of PTB, but overall, there is merit in examining this promising area of clinical science.

Early dexamethasone treatment induces placental apoptosis in sheep.

Glucocorticoid treatment given in late pregnancy in sheep resulted in altered placental development and function. An imbalance of placental survival and apoptotic factors resulting in an increased rate of apoptosis may be involved. We have now investigated the effects of dexamethasone (DEX) in early pregnancy on binucleate cells (BNCs), placental apoptosis, and fetal sex as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 105) were randomized to control (n = 56, 2 mL saline/ewe) or DEX treatment (n = 49, intramuscular injections of 0.14 mg/kg ewe weight per 12 hours over 48 hours) at 40 to 41 days of gestation (dG). Placentomes were collected at 50, 100, 125, and 140 dG. At 100 dG, DEX in females reduced BNC numbers, placental antiapoptotic (proliferating cell nuclear antigen), and increased proapoptotic factors (Bax, p53), associated with a temporarily decrease in fetal growth. At 125 dG, BNC numbers and apoptotic markers were restored to normal. In males, ovine placental lactogen-protein levels after DEX were increased at 50 dG, but at 100 and 140 dG significantly decreased compared to controls. In contrast to females, these changes were independent of altered BNC numbers or apoptotic markers. Early DEX was associated with sex-specific, transient alterations in BNC numbers, which may contribute to changes in placental and fetal development. Furthermore, in females, altered placental apoptosis markers may be involved.

Synthetic glucocorticoid reduces human placental system a transport in women treated with antenatal therapy.

CONTEXT: Synthetic glucocorticoids (sGCs) are routinely given to women with threatened preterm labor and have been linked to fetal growth restriction and developmental programming. Reductions in fetal growth are likely to be mediated by placental dysfunction, including altered nutrient transport. sGCs modify the system A neutral amino acid transporter in vitro, but there are no in vivo comparable data in human placenta. OBJECTIVE: Because ∼ 30% of women who receive sGCs carry to term, our objective was to examine the short- and longer-term consequences of antenatal sGCs on placental system A transport. METHODS AND PATIENTS: Placental tissue was collected from women treated with sGCs between 24 hours and 14 days before delivery (24h-14d), 14 days after treatment but before term (14d-term), or at term, compared with healthy term (control) deliveries to measure system A-mediated activity (Na(+)-dependent [(14)C]methylaminoisobutyric acid uptake per gram placenta) and mRNA expression. RESULTS: After sGC treatment, system A activity was significantly reduced at term compared with both sGC placentas delivered 24h-14d and compared with controls. Placentae from women treated with sGCs who delivered between 14d-term also had significantly reduced system A activity compared with 24h-14d placentas. SLC38A1 and SLC38A2 mRNA expression was unaffected. However, SLC38A4 was significantly reduced by sGCs at term compared with placentas delivered between 14d-term. CONCLUSION: We conclude that women who are at risk of preterm labor and receive sGCs but deliver at term have significantly reduced placental system A amino acid transporter activity. Altered placental transporter function could affect fetal growth and may contribute to developmental programming reported in both animal and clinical studies.

How to build a healthy heart from scratch.

By any of several measures, the health of the American population has been worsening over the last two decades. Obesity, type 2 diabetes and heart failure have risen dramatically. All the while, the average birthweight at all gestational ages has declined. The relationship between robust growth in the womb and lifelong health is now well established. Likewise, babies born at the low end of the birthweight scale are known to have highly elevated risks for ischemic heart disease, hypertension, stroke and metabolic disease. The biological mechanisms by which developmental plasticity becomes a risk for cardiovascular disease are only now being understood. Translating from animal and human studies, low birthweight babies are likely to have endothelial dysfunction, fewer nephrons, fewer pancreatic beta cells, less vascular elastin, fewer cardiomyocytes, increased sympathetic tone and liver-derived dyslipidemias. Only in the past few years, however, has it become known that maternal and placenta phenotypes are associated with adult onset cardiovascular disease. Helsinki Birth Cohort studies have been especially important in the discovery of these relationships. Sudden cardiac death is associated with a thin placenta and heart failure is associated with a small placenta in short mothers. Coronary heart disease is associated with three combinations of maternal-placental phenotypes. Because the diet is important in providing nutrients for the development of the female body before pregnancy and for providing nutrients during pregnancy, there is increasing evidence that the western diet is an underlying cause for the increase in metabolic disease in the American population. A large segment of the American population suffers from high calorie malnutrition. Scientists in this field now have a responsibility to educate the public on the topic of nutrition and health. This chapter honors Lawrence Longo for decades of work in bringing health to pregnant women and their babies.

Probiotic Lactobacillus rhamnosus GR-1 supernatant prevents lipopolysaccharide-induced preterm birth and reduces inflammation in pregnant CD-1 mice.

OBJECTIVE: The objective of this study was to determine the effect of probiotic Lactobacillus rhamnosus GR-1 supernatant (GR-1 SN) on lipopolysaccharide-induced preterm birth (PTB) and outputs of cytokines, chemokines, and progesterone in pregnant CD-1 mice. STUDY DESIGN: We compared PTB rates after intrauterine injection of lipopolysaccharide with and without previous GR-1 SN treatment. Cytokines and chemokines in the maternal plasma, myometrium, placenta, and amniotic fluid were examined with multiplex assay, and circulating maternal progesterone was measured with enzyme-linked immunoassay. Statistical significance was assessed with 2-tailed 1-way analysis of variance or analysis of variance on ranks. Fetal sex ratios in mice that delivered preterm were compared with those that delivered at term after lipopolysaccharide and GR-1 SN treatments. RESULTS: GR-1 SN reduced lipopolysaccharide-induced PTB by 43%. GR-1 SN significantly decreased the lipopolysaccharide-induced production of interleukin (IL)-1ß, -6, and -12p40, tumor necrosis factor-α, CCL4, and CCL5 in maternal plasma; IL-6, -12p70, -17, and -13 and tumor necrosis factor-α in myometrium; IL-6, -12p70, and -17 in placenta; and IL-6, tumor necrosis factor-α, CCL3, and CCL4 in amniotic fluid. Maternal plasma progesterone was reduced significantly after lipopolysaccharide injection with and without GR-1 SN pretreatment. There was no difference in fetal sex ratios between mice that delivered preterm and those that did not after lipopolysaccharide and GR-1 SN treatments. CONCLUSION: The supernatant of probiotic L rhamnosus GR-1 attenuated lipopolysaccharide-induced inflammation and PTB in vivo. GR-1 SN may confer therapeutic benefits in the prevention of infection-associated PTB by controlling systemic and intrauterine inflammation.

Lipopolysaccharide-Induced Profiles of Cytokine, Chemokine, and Growth Factors Produced by Human Decidual Cells Are Altered by Lactobacillus rhamnosus GR-1 Supernatant.

The aim of this study was to assess the effects of bacterial lipopolysaccharide (LPS) and Lactobacillus rhamnosus GR-1 supernatant (GR-1SN) on secretion profiles of cytokines, chemokines, and growth factors from primary cultures of human decidual cells. Lipopolysaccharide significantly increased the output of proinflammatory cytokines (interleukin [IL]-1B, IL-2, IL-6, IL-12p70, IL-15, IL-17A, interferon gamma [IFN-γ], and tumor necrosis factor [TNF]); anti-inflammatory cytokines (IL-1RN, IL-4, IL-9, and IL-10); chemokines (IL-8, eotaxin, IFN-inducible protein 10 [IP-10], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1α [MIP-1α], macrophage inflammatory protein-1ß [MIP-1ß], and regulated on activation normal T cell expressed and secreted [RANTES]); and growth factors (granulocyte colony-stimulating factor [CSF] 3, CSF-2, and vascular endothelial growth factor A [VEGFA]). Lactobacillus rhamnosus GR-1SN alone significantly increased CSF-3, MIP-1α MIP-1ß, and RANTES but decreased IL-15 and IP-10 output. The GR-1SN also significantly or partially reduced LPS-induced proinflammatory cytokines TNF, IFN-γ, IL-1ß, IL-2 IL-6, IL-12p70, IL-15, IL-17, and IP-10; partially reduced LPS-induced anti-inflammatory cytokines IL-1RN, IL-4 and IL-10, and LPS-induced VEGFA output but did not affect CSF-3, MIP-1α, MIP-1ß, MCP-1, IL-8, and IL-9. Our results demonstrate that GR-1SN attenuates the inflammatory responses to LPS by human decidual cells, suggesting its potential role in ameliorating intrauterine infection.

Proliferative action of the androgen receptor in human uterine myometrial cells--a key regulator for myometrium phenotype programming.

CONTEXT: During pregnancy, the myometrium undergoes a phenotype programming starting from an early proliferative stage, to an intermediate synthetic stage, to a late contractile stage, after which the cells commit to labor. Steroid receptors play important roles in regulating myometrial cell phenotype during pregnancy, although detailed mechanisms are not fully defined. OBJECTIVE: The aim of the study was to investigate the expression and function of the androgen receptor (AR) in myometrial cells during pregnancy. DESIGN AND SETTING: Human primary myometrial cells, immortalized myometrial cells, rat pregnant and tubal ligation models were used. Immunohistochemistry, Western blot and real-time PCR, cell proliferation, and flow cytometry assays were applied. RESULTS: The AR is highly expressed in the proliferative stage of pregnancy, starts to decrease in the synthetic stage, and reaches the lowest levels in the contractile stage. Both the mechanical stretch by the growing fetus and the decreased ratio of progestin:estrogen are responsible for AR protein reduction. AR regulates myometrial cell proliferation ligand-independently. Decreased AR expression delays the G(1)-S phase transition of human myometrial cell cycling and reduces expression of several cyclins. These AR actions are mediated through reducing IGF-I receptor protein stability, thus weakening PI3K/Akt signal cascade downstream of IGF-I. AR is required for IGF-I receptor protein stability by preventing the IGF-I receptor from ubiquitylation and protein degradation through both proteosomal and lysosomal pathways. CONCLUSION: AR is a key regulator for myometrial cell proliferation, suggesting its critical role in myometrium phenotype programming during pregnancy.

Effects of tail docking and castration on stress responses in lambs and the influence of prenatal glucocorticoid treatment.

It is common practice in Australian agriculture to remove the tails of lambs to prevent infection and to castrate males to prevent behavioural problems and unwanted reproduction. We have studied the pain and stress responses to these interventions by measuring changes in the hypothalamic-pituitary-adrenal (HPA) axis and ß-endorphin levels. Further, we have evaluated the effects of prenatal exposure to dexamethasone, which is known to affect the developing HPA axis. In control animals that had received prenatal saline treatment, plasma cortisol and adrenocorticotrophin (ACTH) levels increased after the interventions in both females and males. Plasma ß-endorphin levels also increased after the interventions, but the responses were less consistent. Prenatal dexamethasone exposure early in pregnancy (dexamethasone 0.14 mg kg(-1) ewe weight injection commenced on day 40 of pregnancy for four consecutive intramuscular injections at 12-hourly intervals) blunted the cortisol response to tail docking in female offspring, but not to combined tail docking and castration in males. It had no effect on ACTH or ß-endorphin responses in either sex. These findings describe the stress responses to these common agricultural interventions and suggest that long-term development of the HPA axis in females is altered by prenatal exposure to dexamethasone.

SGI 2012: advances in reproductive health research.

The 59th Annual Meeting of the Society for Gynecologic Investigation was held in San Diego, (CA, USA) on 21-24 March 2012, with a record number of registrants (over 1300) and submitted abstracts. The main 3-day meeting was preceded by a day of satellite meetings, covering topics such as placental function, endometrial bleeding and global issues for preterm birth. The meeting was opened by the President of the Society for Gynecologic Investigation for 2011-2012, Stephen J Lye, from the University of Toronto (ON, Canada), with 13 past presidents of the society (including this writer) in attendance.

Expression and function of myometrial PSF suggest a role in progesterone withdrawal and the initiation of labor.

Progesterone (P4), acting through its receptor (PR), is essential for the maintenance of pregnancy. P4 acts by suppressing uterine contractility and the expression of contraction-associated proteins (CAP) such as connexin 43 (Cx43). P4 levels must be reduced or its actions blocked to allow the increased expression of CAP genes and the initiation of labor. Although the importance of progesterone in pregnancy has been known for about 80 yr, the fundamental mechanisms by which P4/PR maintains myometrial quiescence and by which this signaling is blocked at term labor remain to be determined. In this manuscript, we demonstrate that ligand-bound PR interacts with the Cx43 gene promoter through activator protein-1 transcription factors. We show that the ability of PR to repress Cx43 transcription is conferred through the recruitment of the PR coregulator, polypyrimidine tract binding protein-associated splicing factor (PSF), and the further recruitment of the yeast switch independent 3 homolog A/histone deacetylase corepressor complex. PSF expression is elevated during pregnancy but falls toward term as a result of increased mechanical stretch of the myometrium and a rise in the concentrations of circulating estrogen. These data together indicate that PSF is a critical regulator of P4/PR signaling and labor. We suggest that decreased PSF at term may result in a de-repression of PR transcriptional control of CAP genes and thereby contributes to a functional withdrawal of progesterone at term labor.

Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning.

Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring.

The effects of dexamethasone treatment in early gestation on hypothalamic-pituitary-adrenal responses and gene expression at 7 months of postnatal age in sheep.

We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic-pituitary-adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3ß hydroxysteroid dehydrogenase, and 11ß hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic-pituitary-adrenal axis at 7 months of age.

Effect of maternal age and growth on placental nutrient transport: potential mechanisms for teenagers' predisposition to small-for-gestational-age birth?

Teenagers have an increased risk of delivering small-for-gestational-age (SGA) infants. Young maternal age and continued skeletal growth have been implicated as causal factors. In growing adolescent sheep, impaired placental development and nutrient transfer cause reduced birth weight. In human pregnancies, SGA is associated with reduced placental amino acid transport. Maternal growth has no effect on placental morphology or cell turnover, but growing teenagers have higher birth weight:placental weight ratios than nongrowing teenagers. We hypothesized that placental nutrient transporter activity would be affected by maternal age and/or growth status. Placentas from teenagers and adults were collected. Teenagers were defined as growing or nongrowing based on knee height measurements. System A amino acid transporter activity was quantified as sodium-dependent uptake of [(14)C]methylaminoisobutyric acid into placental fragments. Teenagers had lower placental system A activity than adults (P < 0.05). In adults, placental system A activity was lower in SGA infants than appropriate-for-gestational-age (AGA) infants (P < 0.05). In teenagers, AGA and SGA infants had lower placental system A activity than AGA infants born to adults (P < 0.05). Placental system A activity was higher in growing teenagers than in nongrowing teenagers (P < 0.001). Placental mRNA expression of system A transporter isoforms SLC38A1 and -2 was lower in teenagers than in adults (P < 0.05) but did not differ between growing and nongrowing teenagers. There was no difference in transporter protein expression/localization between cohorts. Teenagers have inherently reduced placental transport, which may underlie their susceptibility to delivering SGA infants. Growing teenagers appear to overcome this susceptibility by stimulating the activity, but not expression, of system A transporters.

Antenatal dexamethasone treatment in midgestation reduces system A-mediated transport in the late-gestation murine placenta.

Clinically, approximately 30% of women who receive synthetic glucocorticoids (sGC) for risk of preterm labor carry to term. In vitro studies have shown that sGC acutely regulate the placental system A amino acid transporter, but there are no comparable data in vivo. Hence, the objective of our study was to examine the acute [embryonic day (E)15.5] and longer-term (E17.5 and E18.5) consequences of midgestation antenatal sGC [dexamethasone (DEX); 0.1 mg/kg on E13.5 and E14.5] on placental system A-mediated transfer in the mouse (measured in vivo as maternal-fetal unidirectional (14)C-methylaminoisobutyric acid transfer per gram of placenta). System A transfer and Slc38a mRNA expression significantly increased from E12.5 to E18.5 (P < 0.05), corresponding to increased fetal growth. DEX treatment had no acute effect at E15.5 or longer-term effect at E17.5 but significantly decreased system A-mediated transfer before term (E18.5; P < 0.05) in placentae of male and female fetuses. There was no effect of DEX on Slc38a gene expression. Administration of DEX in this regime had no effect on birth weight. We conclude that sGC treatment in midgestation leads to a substantial decrease in placental system A-mediated transport in late gestation, suggesting that prenatal sGC therapy may lead to a reduction in availability of neutral amino acids to the fetus if gestation persists to term.