50 research outputs found
A novel design for an RF MEMS resistive switch on PCB substrate
No full textCopyright @ 2008 Stimulation Action on MEM
Novel Targets of FASD Pathogenesis in the Developing Hippocampus
No full textPrenatal alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), characterized by a myriad of developmental impairments affecting behavior and cognition. Studies show many of these functional impairments are associated with the hippocampus, a structure exhibiting exquisite vulnerability to developmental alcohol exposure and critically implicated in learning and memory, however mechanisms underlying alcohol-induced hippocampal deficits remain poorly understood. Utilizing a high-throughput RNA-Seq approach to address the neurobiological and molecular basis of prenatal alcohol-induced hippocampal functional deficits, we hypothesized that chronic binge prenatal alcohol exposure alters gene expression and global molecular pathways in the fetal hippocampus. Timed-pregnant Sprague Dawley rats were randomly assigned to a pair-fed control (PF) or binge-alcohol treatment (ALC) group on gestational day (GD) 4. ALC dams acclimatized from GD 5-10 with a daily treatment of 4.5 g/kg alcohol and subsequently received 6 g/kg on GDs 11-20. PF dams received a once-daily maltose dextrin gavage on GDs 5-20, isocalorically matching ALC counterparts.
On GD 21, bilateral hippocampi were dissected, flash frozen, and stored at -80��C. Total RNA was then isolated from homogenized tissues. Samples were normalized to ~4nM and pooled equally. Sequencing was performed by Illumina NextSeq 500 on a 75 cycle, single end sequencing run. RNA-Seq identified 13,388 genes, of these, 76 genes showed a significant difference (P 2) in expression between the PF and ALC groups. 49 genes showed sex-dependent dysregulation, of which, 23 were significantly altered in ALC-exposed females, 26 were altered in ALC-exposed males, and 2 were altered in both ALC-exposed males and females compared with PF offspring. We conclude that chronic binge alcohol exposure during pregnancy dysregulates fetal hippocampal gene expression in a sex-specific manner. Identification of subtle, transcriptome-level dysregulation in hippocampal molecular pathways offers potential mechanistic insights underlying FASD pathogenesis
THE ROLE OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 6 IN PLACENTAL DEVELOPMENT UNDER GESTATIONAL DIABETES
No full textAbnormal placenta development has been indicated in preeclampsia and gestational diabetes (GDM), which are both common yet serious complications in approximately 10% of pregnancies. Proprotein convertase subtilisin/kexin-6 (PCSK6) is a protease that processes precursor proteins into active forms. Based on previous reports of PCSK6 expression in the placenta, involvement in embryonic development and vascular remodeling, we hypothesized that PCSK6 plays an important role in placenta development. Our WT placentas had a dynamic expression of PCSK6 in glycogen trophoblast cells (GlyT). In mouse hyperglycemic (HG) pregnancies, PCSK6 protein levels were decreased which led us to further pursue the interaction of PCSK6 and HG. The current study applied a PCSK6 transgenic mouse model consisting of four groups: WT and PCSK6 knockout (KO) placentas from normoglycemic (NG) and HG pregnancies. Histological examination of placenta disclosed that HG, but not PCSK6 KO, increased GlyT area within the junctional zone via differentiation. The spiral arteries (SpAs) in PCSK6 KO placentas, under NG and HG conditions, had decreased inner to outer diameter ratios and reduced trophoblast giant cell association compared to the WT placentas. Consistently, PCSK6 KO placentas over-phosphorylate ��-catenin, a key protein to regulate transcription of migratory proteins. In the labyrinth, PCSK6 KO affected fetal capillary area while HG affected maternal lacunae area. PCSK6 KO-HG placentas had increased interhaemal membrane thickness. From these factors, the calculated diffusion capacity was increased in PCSK6 KO under NG but decreased under HG. In summary, our study demonstrated that PCSK6 is involved in SpA remodeling and glucose-dependent angiogenesis. Our study indicated a potential role of PCSK6 in preeclampsia and GDM related placenta dysfunctions. Future study will focus on understanding the molecular mechanisms underlying how PCSK6 deletion disrupted normal placenta development and function
Mechanisms underlying fetal alcohol spectrum disorders: ovine model
No full textMaternal alcohol abuse during pregnancy can result in a range of structural and
functional abnormalities that include lifelong physical, mental, behavioral and learning
disabilities, now collectively termed as Fetal Alcohol Spectrum Disorders (FASD). The
incidence of FASD is now estimated be as high as 10 per 1000 live births. Each year,
40,000 babies are born with FASD in the United States at an estimated cost of 6 billion. Because of the magnitude of this
problem and because the incidence has not decreased in spite intensive efforts to educate
women to not abuse alcohol during pregnancy, ways to prevent or mitigate the effects of
prenatal alcohol exposure must be explored in addition to education. Therefore, we
wished to identify the precise mechanisms by which alcohol mediates the
neurodevelopmental damage in order to develop intervention/amelioration strategies.
The present study was conducted using an ovine model system. The large body
mass of the ovine fetus, the longer gestation that is more similar to that of humans, and
that all three trimester equivalents occur in utero, make the sheep an excellent model to
study the effects of alcohol on the developing fetus. Our study establishes that maternal alcohol exposure does not result in fetal cerebral hypoxia. Instead, alcohol results in
hypercapnea and acidemia leading to a cascade of events in the maternal and fetal
compartments that include deficits in the levels of glutamine and glutamine-related
amino acids, alterations in endocrine axes, oxidative stress, alteration in cardiovascular
homeostasis and fetal neuronal loss. Further, we demonstrate that inhibiting the novel
two-pore domain acid sensitive potassium channel (TASK) expressed in the cerebellar
granule cells and the peripheral and central chemoreceptors may prove to a be potential
therapeutic strategy. Preventive strategies that are safe to use in pregnant women and
that involve glutamine-related pathways are also suggested. Finally, the study also
establishes the beneficial effects of moderate alcohol consumption on the fetal skeletal
system
Developmental Outcomes of Prenatal E-cig Aerosol Vaping
No full textElectronic cigarettes (e-cigs) are tobacco products that have become popular among youth and young adults due to targeted advertising and misconceptions about their safety. The unfounded perception that e-cigs are less harmful than traditional cigarettes may result in the use of e-cigs during pregnancy. There are limited studies evaluating the effects of e-cig aerosol exposure on pregnancy in animal models and only a single report of gestational e-cig exposure in humans. To examine the impact of prenatal e-cig aerosol exposure on pregnancy and development we utilized a pregnant Sprague-Dawley rat model combined with a chronic, whole-body, environmental exposure to e-cig aerosols generated by commercially available e-cig atomizers. We found that exposure to e-cig aerosols containing nicotine significantly reduced fetal and neonatal growth, but aerosols without nicotine did not. Growth restriction was accompanied by reduced blood flow in the maternal uterine artery and fetal umbilical artery. Analysis of signature amino acid profile revealed altered concentrations in maternal and fetal plasma of animals exposed to e-cig aerosols with nicotine. Amino acid concentrations in the fetal lungs were altered by e-cig aerosols regardless of nicotine. RNA sequencing of fetal lung transcriptome showed altered expression after exposure to e-cig aerosols with and without nicotine. E-cig aerosols containing nicotine altered neonatal lung morphology and produced trends in respiratory mechanics that may increase the workload of breathing. Interestingly, e-cig aerosols with and without nicotine reduced the area of the pressure-volume loop during forced oscillation techniques which may indicate increased atelectasis in neonatal lungs. The effects of prenatal e-cig aerosol exposure were more pronounced in animals exposed to aerosols containing nicotine, however, e-cig aerosols without nicotine were also found to effect the physiology of pregnancy. Further studies will be required to identify molecular mechanisms of e-cig aerosol induced alterations to pregnancy and development. The data presented in these studies lay a foundation for our understanding of prenatal exposure to e-cig aerosols by providing evidence that e-cig vaping during pregnancy can have deleterious outcomes for the developing offspring
2-D DIGE uterine endothelial proteomic profile for maternal chronic binge-like alcohol exposure
No full textUntargeted and Targeted Blood Lipidomic Signature Profile of Gestational Alcohol Exposure
No full textAlcohol consumption has a close relationship with blood lipid levels in a nonpregnant state, with a myriad of effects on the liver; however, little is known about the interaction of alcohol and lipids in the context of fetal alcohol spectrum disorders (FASD). We herein aimed to determine the effect of alcohol on the lipid profile in a pregnant rat model, with a focus on FASD. Dry blood spots (50 µL) were obtained from rat maternal blood collected on gestational day (GD) 20, two hours after the last binge alcohol exposure (4.5 g/kg, GD 5–10; 6 g/kg, GD 11–20). The samples were then analyzed using high-throughput untargeted and targeted lipid profiling via liquid chromatography-tandem mass spectrometry (LC-MS/MS). In untargeted lipidomics, 73 of 315 identified lipids were altered in the alcohol group compared to the pair-fed controls; 67 were downregulated and 6 were upregulated. In targeted analysis, 57 of the 260 studied lipid subspecies were altered, including Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylglycerol (PG), Phosphatidic Acid (PA), Phosphatidylinositol (PI), and Phosphatidylserine (PS); 36 of these were downregulated and 21 lipid subspecies were upregulated. These findings suggest alcohol-induced dysregulation of lipids in the maternal blood of rats and provide novel insights into possible FASD mechanisms
Chronic binge ethanol-mediated acidemia reduces availability of glutamine and related amino acids in maternal plasma of pregnant sheep
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