Early treatment of the pregnant guinea pig with IGFs promotes placental transport and nutrient partitioning near term

Appropriate partitioning of nutrients between the mother and conceptus is a major determinant of pregnancy success, with placental transfer playing a key role. Insulin-like growth factors (IGFs) increase in the maternal circulation during early pregnancy and are predictive of fetal and placental growth. We have previously shown in the guinea pig that increasing maternal IGF abundance in early to midpregnancy enhances fetal growth and viability near term. We now show that this treatment promotes placental transport to the fetus, fetal substrate utilization, and nutrient partitioning near term. Pregnant guinea pigs were infused with IGF-I, IGF-II (both 1 mg.kg-1.day-1) or vehicle subcutaneously from days 20-38 of pregnancy (term=69 days). Tissue uptake and placental transfer of the nonmetabolizable radio analogs [3H]methyl-D-glucose (MG) and [14C]aminoisobutyric acid (AIB) in vivo was measured on day 62. Early pregnancy exposure to elevated maternal IGF-I increased placental MG uptake by>70% (P=0.004), whereas each IGF increased fetal plasma MG concentrations by 40-50% (P<0.012). Both IGFs increased fetal tissue MG uptake (P<0.048), whereas IGF-I also increased AIB uptake by visceral organs (P=0.046). In the mother, earlier exposure to either IGF increased AIB uptake by visceral organs (P<0.014), whereas IGF-I also enhanced uptake of AIB by muscle (P=0.044) and MG uptake by visceral organs (P=0.016) and muscle (P=0.046). In conclusion, exogenous maternal IGFs in early pregnancy sustainedly increase maternal substrate utilization, placental transport of MG to the fetus, and fetal utilization of substrates near term. This was consistent with the previously observed increase in fetal growth and survival following IGF treatment.     

Fetal baboons convert 18:3n-3 to 22:6n-3 in vivo. A stable isotope tracer study

Using [13C]-tracers and direct fetal doses, we show for the first time that the fetal primate converts alpha-linolenic acid (18:3) to docosahexaenoic acid (22:6) in vivo, and we estimate the relative bioefficacy of the two substrates for brain 22:6 accretion. Pregnant female baboons consumed a diet free of long chain polyunsaturates (LCP), with n-6/n-3 ratio of 10/1. In the third trimester of pregnancy (normal gestation = 182 days), they were instrumented with chronic indwelling catheters in the maternal femoral artery and the fetal jugular artery. Doses of either [U-13C]-18:3 (18:3*, n = 3) or [U-13C]-22:6 (22:6*, n = 2) were administered directly to the fetus. Blood was collected from fetus and mother, and the fetus was taken by cesarean section when electromyographic activity indicated that parturition was imminent. Fetal liver, brain, retina, and retinal pigment epithelium (RPE) were collected, and (13)C fatty acids determined. In 18:3*- dosed animals, labeled n-3 LCP were detected in fetal plasma at 1 day post-dose and peaked at 2;-3 days; brain 22:6* was constant at 3, 5, and 9 days post-dose, at 0.57 +/- 0.03 percent of dose (%Dose). In 22:6*- dosed animals, brain 22:6* was similar at 3 and 9 days post-dose (4.64 +/- 0.43%Dose). From these data, we estimate that preformed 22:6 in the fetal bloodstream is 8-fold more efficacious for brain 22:6 accretion than is 18:3. Retina 22:6* was stable at about 0.0008%Dose from 3 to 9 days in 18:3-dosed animals, but RPE 22:6* dropped over the period; brain results were consistent with these observations. Liver showed about 0.5%Dose in 22:6* and in intermediary n-3 fatty acid metabolites 20:5* and 22:5* at 3 days post-dose, and declined afterward. Back-transfer of labeled fatty acids to the maternal bloodstream was measurable but not sufficient to compromise the quantitative conversion data in fetuses. We conclude 1) primate fetuses have the capacity to convert 18:3 to 22:6 in vivo; 2) fetal brain 22:6* as %Dose plateaus by 3 days post-dose; 3) fetal plasma 22:6 is about 8-fold more effective as a substrate for brain 22:6 accretion compared with 18:3; and 4) the fetal liver is likely to be an important site of 18:3 to 22:6 conversion.     

The significance of telomeric aggregates in the interphase nuclei of tumor cells

Telomeres are TTAGGG repetitive motifs found at the ends of vertebrate chromosomes. In humans, telomeres are protected by shelterin, a complex of six proteins (de Lange [2005] Genes Dev. 19: 2100-2110). Since (Müller [1938] Collecting Net. 13: 181-198; McClintock [1941] Genetics 26: 234-282), their function in maintaining chromosome stability has been intensively studied. This interest, especially in cancer biology, stems from the fact that telomere dysfunction is linked to genomic instability and tumorigenesis (Gisselsson et al. [2001] Proc. Natl. Acad. Sci. USA 98: 12683-12688; Deng et al. [2003] Genes Chromosomes Cancer 37: 92-97; DePinho and Polyak [2004] Nat. Genetics 36: 932-934; Meeker et al. [2004] Clin. Cancer Res. 10: 3317-3326). In the present overview, we will discuss the role of telomeres in genome stability, recent findings on three-dimensional (3D) changes of telomeres in tumor interphase nuclei, and outline future avenues of research.     

Molecular mechanisms of congenital heart block

Autoantibody-associated congenital heart block (CHB) is a passively acquired autoimmune condition associated with maternal anti-Ro/SSA antibodies and primarily affecting electric signal conduction at the atrioventricular node in the fetal heart. CHB occurs in 1–2% of anti-Ro/SSA antibody-positive pregancies and has a recurrence rate of 12–20% in a subsequent pregnancy. Despite the long-recognized association between maternal anti-Ro/SSA autoantibodies and CHB, the molecular mechanisms underlying CHB pathogenesis are not fully understood, but several targets for the maternal autoantibodies in the fetal heart have been suggested. Recent studies also indicate that fetal susceptibility genes determine whether an autoantibody-exposed fetus will develop CHB or not, and begin to identify such genes. In this article, we review the different lines of investigation undertaken to elucidate the molecular pathways involved in CHB development and reflect on the hypotheses put forward to explain CHB pathogenesis as well as on the questions left unanswered and that should guide future studies.     

Transfer of maternal cholesterol to embryo and fetus in pregnant mice

Cholesterol is essential for antenatal development. However, the transport of maternal cholesterol to the embryo has not been sufficiently studied, and that to the fetus is still controversial. To this end, a 1 mg dose of [3,4-(13)C(2)]cholesterol was injected daily into pregnant mice and the labeled cholesterol was measured by gas chromatography-mass spectrometry. After venous injections from days 10 to 17 of gestation, [(13)C]cholesterol levels in total ((12)C and (13)C) cholesterol were increased to 5.1% and 2.8% in maternal and fetal plasma, respectively. Labeled cholesterol was identified in the liver, kidneys, and intestines, but not in the brain, of the fetus. After injections from days 1 to 8, [(13)C]cholesterol levels were increased to 12.4% and 8.0% of total cholesterol in maternal plasma and the embryo, respectively. The level of 11.5% in the yolk sac was higher than that in the embryo. Intrauterine transfer of maternal cholesterol to the embryo as well as the fetus was evident in mice, and both the placenta and the yolk sac appear to be sites of intermediate passage in murine pregnancy.     

Steady-state maternal and fetal plasma concentrations of glyceryl trinitrate (GTN) in the preterm sheep

The administration of glyceryl trinitrate (GTN; nitroglycerin) is increasing during preterm pregnancies, yet its disposition and, importantly, the extent of fetal exposure remain to be elucidated. When used as a tocolytic (pharmacological agent that stops uterine contractions), it is administered transdermally (24-48 h). Here, we quantified the maternal and fetal steady-state plasma concentrations of maternal intravenous GTN in preterm sheep and continuously monitored maternal and fetal vascular parameters to observe possible dose-dependent vascular effects. Preterm (120 days gestation) pregnant sheep (n = 6) were instrumented with maternal femoral arterial (MA) and venous (MV) and fetal femoral arterial (FA) and umbilical venous (UV) polyethylene blood-sampling catheters. During maternal GTN infusion (3.0 micro g.kg-1.min-1, 60-min duration) the steady-state GTN concentrations ([GTN]) were as follows: MA, 98.6 +/- 9.0 nM; UV, 17.4 +/- 7.6 nM; and FA, <5 nM. There were no changes in maternal and fetal mean arterial pressure and heart rate or in uterine activity. Overall, the steady-state [GTN] was established by 5 min, and the UV/MA ratio of [GTN] was 0.18. The FA [GTN] (<5 nM) indicates that the fetus cleared essentially all GTN in the UV, and the maternal and fetal heart rate and mean arterial pressure appear to be independent of maternal GTN infusion.     

Environmental stimuli and intestinal stem cell behavior

Comment on: Wong VWY, et al. Nat Cell Biol 2012; 14:401-8.     

Heparan sulfate proteoglycan specificity during axon pathway formation in the Drosophila embryo

Axon guidance is influenced by the presence of heparan sulfate (HS) proteoglycans (HSPGs) on the surface of axons and growth cones (Hu, [2001]: Nat Neurosci 4:695-701; Irie et al. [2002]: Development 129:61-70; Inatani et al. [2003]: Science 302:1044-1046; Johnson et al. [2004]: Curr Biol 14:499-504; Steigemann et al. [2004]: Curr Biol 14:225-230). Multiple HSPGs, including Syndecans, Glypicans and Perlecans, carry the same carbohydrate polymer backbones, raising the question of how these molecules display functional specificity during nervous system development. Here we use the Drosophila central nervous system (CNS) as a model to compare the impact of eliminating Syndecan (Sdc) and/or the Glypican Dally-like (Dlp). We show that Dlp and Sdc share a role in promoting accurate patterns of axon fasciculation in the lateral longitudinal neuropil; however, unlike mutations in sdc, which disrupt the ability of the secreted repellent Slit to prevent inappropriate passage of axons across the midline, mutations in dlp show neither midline defects nor genetic interactions with Slit and its Roundabout (Robo) receptors at the midline. Dlp mutants do show genetic interactions with Slit and Robo in lateral fascicle formation. In addition, simultaneous loss of Dlp and Sdc demonstrates an important role for Dlp in midline repulsion, reminiscent of the functional overlap between Robo receptors. A comparison of HSPG distribution reveals a pattern that leaves midline proximal axons with relatively little Dlp. Finally, the loss of Dlp alters Slit distribution distal but not proximal to the midline, suggesting that distinct yet overlapping pattern of HSPG expression provides a spatial system that regulates axon guidance decisions.     

The familial Parkinson Disease gene PARK2 is a multisite tumor suppressor on chromosome 6q25.2-27 that regulates cyclin E

Comment on: Veeriah S, et al. Nat Genet 2009; [Epub ahead of print].     

A possible crosstalk between DNA repair pathways and angiogenesis

Comment on: Economopoulou M, et al. Nat Med 2009; 15:553-58.     

Over the barrier and through the blood: To CNS delivery we go

Comment on: Foust KD, et al. Nat Biotechnol 2009; 27:59-65.     

Effect of maternal glucose concentration on uteroplacental glucose consumption and transfer in pregnant sheep

The present study was designed to measure the relationships between maternal arterial glucose concentration [( GI]A) and fetal arterial glucose concentration [( GI]a), uteroplacental glucose consumption (UPGC), and the rate of uteroplacental glucose transfer to the fetus (UPGT) in pregnant sheep in late gestation. [GI]A was controlled by a glucose clamp technique and the glucose flux rates of the uteroplacenta were quantified by the Fick principle. [GI]A varied from 1.81 to 154.7 mg/dl; [GI]a was directly related to [GI]A: [GI]a = 0.374 [GI]A + 1.81, r = 0.873, P less than 0.001. Fetal arterial blood oxygen content decreased with [GI]A (P less than 0.05) and fetal arterial blood lactate concentration increased with [GI]A (P less than 0.001). There was no significant effect of [GI]A on the rates of uteroplacental lactate production, uteroplacental oxygen consumption, fetal oxygen consumption, or uterine or umbilical blood flow. Both UPGC and UPGT were directly related to [GI]A: UPGC = -2.221 x 10(-3) chi 2 + 0.646 x -6.016, r = 0.80; UPGT = -1.208 x 10(-3) chi 2 + 0.405 x -2.416, r = 0.90. UPGC and UPGT were approximately parallel over the range of [GI]A studied (UPGC = 1.19 UPGT + 3.79, r = 0.764). These results demonstrate the importance of UPGC to maternal-fetal glucose homeostasis and indicate that factors regulating uteroplacental glucose consumption and transfer to the fetus become limiting at comparable levels of [GI]A and [GI]a. The estimated kinetic constants for UPGC represent the metabolism of glucose by the uteroplacental tissues, but the estimated kinetic constants for UPGT represent the metabolism of glucose by the fetus as well as the transfer of glucose by the uteroplacenta to the fetus.     

Pregnancy and viral infections: Mechanisms of fetal damage,diagnosis and prevention of neonatal adverse outcomes from cytomegalovirus to SARS-CoV-2 and Zika virus

Some maternal infections, contracted before or during pregnancy, can be transmitted to the fetus, during gestation (congenital infection), during labor and childbirth (perinatal infection) and through breastfeeding (postnatal infection). The agents responsible for these infections can be viruses, bacteria, protozoa, fungi. Among the viruses most frequently responsible for congenital infections are Cytomegalovirus (CMV), Herpes simplex 1–2, Herpes virus 6, Varicella zoster. Moreover Hepatitis B and C virus, HIV, Parvovirus B19 and non-polio Enteroviruses when contracted during pregnancy may involve the fetus or newborn at birth. Recently, new viruses have emerged, SARS-Cov-2 and Zika virus, of which we do not yet fully know the characteristics and pathogenic power when contracted during pregnancy.Viral infections in pregnancy can damage the fetus (spontaneous abortion, fetal death, intrauterine growth retardation) or the newborn (congenital anomalies, organ diseases with sequelae of different severity). Some risk factors specifically influence the incidence of transmission to the fetus: the timing of the infection in pregnancy, the order of the infection, primary or reinfection or chronic, the duration of membrane rupture, type of delivery, socio-economic conditions and breastfeeding. Frequently infected neonates, symptomatic at birth, have worse outcomes than asymptomatic. Many asymptomatic babies develop long term neurosensory outcomes.The way in which the virus interacts with the maternal immune system, the maternal-fetal interface and the placenta explain these results and also the differences that are observed from time to time in the fetal?neonatal outcomes of maternal infections. The maternal immune system undergoes functional adaptation during pregnancy, once thought as physiological immunosuppression. This adaptation, crucial for generating a balance between maternal immunity and fetus, is necessary to promote and support the pregnancy itself and the growth of the fetus. When this adaptation is upset by the viral infection, the balance is broken, and the infection can spread and lead to the adverse outcomes previously described. In this review we will describe the main viral harmful infections in pregnancy and the potential mechanisms of the damages on the fetus and newborn.     

Quantitative and theoretical analyses of the relation between older brothers and homosexuality in men

Meta-analysis of aggregate data from 14 samples representing 10,143 male subjects shows that homosexuality in human males is predicted by higher numbers of older brothers, but not by higher numbers of older sisters, younger brothers, or younger sisters. The relation between number of older brothers and sexual orientation holds only for males. This phenomenon has therefore been called the fraternal birth order effect. Research on birth order, birth weight, and sexual orientation suggests that the developmental pathway to homosexuality initiated by older brothers operates during prenatal life. Calculations assuming a causal relation between older brothers and sexual orientation have estimated the proportion of homosexual men who owe their sexual orientation to fraternal birth order at 15% in one study and 29% in another. The maternal immune hypothesis proposes that the fraternal birth order effect reflects the progressive immunization of some mothers to male-specific antigens by each succeeding male fetus and the increasing effects of such immunization on sexual differentiation of the brain in each succeeding male fetus. There are at least three possible mechanisms by which the mother's immune response could influence the fetus: the transfer of anti-male antibodies across the placenta from the maternal into the fetal compartment, the transfer of maternal cytokines across the placenta, and maternal immune reactions affecting the placenta itself. This hypothesis is consistent with recent studies showing that the quantity of fetal cells that enter the maternal circulation is greater than previously thought, and that the number of male-specific proteins encoded by Y-chromosome genes is greater than previously thought.     

Maternal omega-3 fatty acids maintained positive maternal lipids and cytokines profile,and improved pregnancy outcomes of C57BL/6 mice

Omega (n)-3 polyunsaturated fatty acids (PUFA) are known to regulate lipid metabolism and inflammation; however, the regulation of maternal lipid metabolism and cytokines profile by n-3 PUFA during different gestation stages, and its impact on fetal sustainability is not known. We investigated the effects of maternal diet varying in n-3 PUFA prior to, and during gestation, on maternal metabolic profile, placental inflammatory cytokines, and fetal outcomes. Female C57BL/6 mice were fed either a high, low or very low (9, 3 or 1% w/w n-3 PUFA) diet, containing n-6:n-3 PUFA of 5:1, 20:1 and 40:1, respectively for two weeks before mating, and throughout pregnancy. Animals were sacrificed prior to mating (NP), and during pregnancy at gestation days 6.5, 12.5 and 18.5. Maternal metabolic profile, placental cytokines and fetal outcomes were determined. Our results show for the first time that a maternal diet high in n-3 PUFA prevented dyslipidemia in NP mice, and maintained the expected lipid profile during pregnancy. However, females fed the very low n-3 PUFA diet became hyperlipidemic prior to pregnancy, and carried this profile into pregnancy. Maternal diet high in n-3 PUFA maintained maternal plasma progesterone and placental pro-inflammatory cytokines profile, and sustained fetal numbers throughout pregnancy, while females fed the low and very-low n-3 PUFA diet had fewer fetuses. Our findings demonstrate the importance of maternal diet before, and during pregnancy, to maintain maternal metabolic profile and fetus sustainability. These findings are important when designing dietary strategies to optimize maternal metabolism during pregnancy for successful pregnancy outcome.     

Uncovering a tumor-suppressor function for Drosophila Polycomb group genes

Comment on: Martinez AM, et al. Nat Genet 2009; 41:1076-82.     

Eaters of the dead: Glial precursors clear neuron corpses during development

Comment on: Wu HH, et al. Nat Neurosci 2009; 12:1534-41.     

Pathogenic role of interleukin-21 in psoriasis

Comment on: Caruso R, et al. Nat Med 2009; 15:1013-5.     

You are what you express: Glutamatergic neurogenesis in the adult SVZ

Comment on: Brill MS, et al. Nat Neurosci 2009; 12:1524-33.     

Administration of recombinant human stem cell factor (rhSCF) and granulocyte-colony stimulating factor (rhG-CSF) to maternal and fetal rhesus monkeys (Macaca mulatta).

Studies with recombinant human stem cell factor (rhSCF) and granulocyte-colony stimulating factor (rhG-CSF) have suggested significant clinical utility although little is known regarding the effect of these cytokines when administered during pregnancy. rhSCF (25 microg/kg/day)+/-rhG-CSF (50 microg/kg/day) were administered chronically to gravid rhesus monkeys ( n =12) or directly to the rhesus fetus ( n=2) during the second and third trimesters. Maternal/fetal blood samples were collected to assess circulating SCF/G-CSF levels and complete blood counts compared to non-treated animals (n=40). Fetal endogenous SCF levels were four-fold greater than the dam (fetus approximately 2500 pg/ml, dam approximately 500 pg/ml), whereas circulating G-CSF was similar in the fetal/maternal compartments ( approximately 50-100 pg/ml). There were no adverse effects detected in the fetus or dam as a result of SCF+/-G-CSF administration. Although high levels of SCF and G-CSF were achieved in the maternal circulation with maternal administration (SCF: 7000-15 000 pg/ml; G-CSF: 7000-54 000 pg/ml), there was little evidence of placental transport or effects on fetal haematopoiesis. In contrast, direct fetal administration of SCF+G-CSF resulted in a rapid rise in fetal neutrophil counts. These studies have shown the monkey to be an excellent model for studying haematopoietic interventions during gestation, and suggest the best approach for achieving haematopoietic changes in the fetus and newborn is by direct in utero administration.