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Sample records for altered phosphatidylserine exposure

  1. 4.1R-deficient human red blood cells have altered phosphatidylserine exposure pathways and are deficient in CD44 and CD47 glycoproteins

    PubMed Central

    Jeremy, Kris P.; Plummer, Zoe E.; Head, David J.; Madgett, Tracey E.; Sanders, Kelly L.; Wallington, Amanda; Storry, Jill R.; Gilsanz, Florinda; Delaunay, Jean; Avent, Neil D.

    2009-01-01

    Background Protein 4.1R is an important component of the red cell membrane skeleton. It imparts structural integrity and has transmembrane signaling roles by direct interactions with transmembrane proteins and other membrane skeletal components, notably p55 and calmodulin. Design and Methods Spontaneous and ligation-induced phosphatidylserine exposure on erythrocytes from two patients with 4.1R deficiency were studied, using CD47 glycoprotein and glycophorin C as ligands. We also looked for protein abnormalities in the 4.1R - based multiprotein complex. Results Phosphatidylserine exposure was significantly increased in 4.1R-deficient erythrocytes obtained from the two different individuals when ligands to CD47 glycoprotein were bound. Spontaneous phosphatidylserine exposure was normal. 4.1R, glycophorin C and p55 were missing or sharply reduced. Furthermore there was an alteration or deficiency of CD47 glycoprotein and a lack of CD44 glycoprotein. Based on a recent study in 4.1R-deficient mice, we found that there are clear functional differences between interactions of human red cell 4.1R and its murine counterpart. Conclusions Glycophorin C is known to bind 4.1R, and we have defined previously that it also binds CD47. From our evidence, we suggest that 4.1R plays a role in the phosphatidylserine exposure signaling pathway that is of fundamental importance in red cell turnover. The linkage of CD44 to 4.1R may be relevant to this process. PMID:19794081

  2. Erythrocyte phosphatidylserine exposure in β-thalassemia.

    PubMed

    Ibrahim, Hamdy A; Fouda, Manal I; Yahya, Raida S; Abousamra, Nashwa K; Abd Elazim, Rania A

    2014-06-01

    [ABS]Phospholipid asymmetry is well maintained in erythrocyte (RBC) membranes with phosphatidylserine (PS) exclusively present in the inner leaflet. Eryptosis, the suicidal death of RBCs, is characterized by cell shrinkage, membrane blebbing, and cell membrane phospholipids scrambling with PS exposure at the cell surface. Erythrocytes exposing PS are recognized, bound, engulfed, and degraded by macrophages. Eryptosis thus fosters clearance of affected RBCs from circulating blood, which may aggravate anemia in pathological conditions. Thalassemia patients are more sensitive to the eryptotic depletion and osmotic shock which may affect RBC membrane phospholipid asymmetry. We aimed in this work to determine the RBC PS exposure in splenectomized and nonsplenectomized β-thalassemia major (β-TM) patients and correlate it with the clinical presentation and laboratory data. RBCs were stained for annexin V to detect phosphatidylserine (PS) exposure in 46 β-TM patients (27 splenectomized and 19 nonsplenectomized) compared to 17 healthy subjects as a control group. We observed a significant increase in RBC PS exposure in β-TM patients compared to control group (P = .0001). Erythrocyte PS exposure was significantly higher in splenectomized β-TM patients compared with nonsplenectomized β-TM patients (P = .001). No correlation was found between RBC PS exposure and clinical or hematological data of β-TM patients, but there was a positive correlation between RBC PS exposure and ferritin level in β-TM patients have higher levels of RBC PS exposure, and splenectomy was shown to aggravate RBC PS exposure without aggravation of anemia.

  3. An Apoptotic 'Eat Me' Signal: Phosphatidylserine Exposure.

    PubMed

    Segawa, Katsumori; Nagata, Shigekazu

    2015-11-01

    Apoptosis and the clearance of apoptotic cells are essential processes in animal development and homeostasis. For apoptotic cells to be cleared, they must display an 'eat me' signal, most likely phosphatidylserine (PtdSer) exposure, which prompts phagocytes to engulf the cells. PtdSer, which is recognized by several different systems, is normally confined to the cytoplasmic leaflet of the plasma membrane by a 'flippase'; apoptosis activates a 'scramblase' that quickly exposes PtdSer on the cell surface. The molecules that flip and scramble phospholipids at the plasma membrane have recently been identified. Here we discuss recent findings regarding the molecular mechanisms of apoptotic PtdSer exposure and the clearance of apoptotic cells.

  4. Stimulation of erythrocyte phosphatidylserine exposure by mercury ions

    SciTech Connect

    Eisele, Kerstin; Lang, Philipp A.; Kempe, Daniela S.; Klarl, Barbara A.; Niemoeller, Olivier; Wieder, Thomas; Huber, Stephan M.; Duranton, Christophe; Lang, Florian . E-mail: florian.lang@uni-tuebingen.de

    2006-01-15

    The sequelae of mercury intoxication include induction of apoptosis. In nucleated cells, Hg{sup 2+}-induced apoptosis involves mitochondrial damage. The present study has been performed to elucidate effects of Hg{sup 2+} in erythrocytes which lack mitochondria but are able to undergo apoptosis-like alterations of the cell membrane. Previous studies have documented that activation of a Ca{sup 2+}-sensitive erythrocyte scramblase leads to exposure of phosphatidylserine at the erythrocyte surface, a typical feature of apoptotic cells. The erythrocyte scramblase is activated by osmotic shock, oxidative stress and/or energy depletion which increase cytosolic Ca{sup 2+} activity and/or activate a sphingomyelinase leading to formation of ceramide. Ceramide sensitizes the scramblase to Ca{sup 2+}. The present experiments explored the effect of Hg{sup 2+} ions on erythrocytes. Phosphatidylserine exposure after mercury treatment was estimated from annexin binding as determined in FACS analysis. Exposure to Hg{sup 2+} (1 {mu}M) indeed significantly increased annexin binding from 2.3 {+-} 0.5% (control condition) to 23 {+-} 6% (n = 6). This effect was paralleled by activation of a clotrimazole-sensitive K{sup +}-selective conductance as measured by patch-clamp recordings and by transient cell shrinkage. Further experiments revealed also an increase of ceramide formation by {approx}66% (n = 7) after challenge with mercury (1 {mu}M). In conclusion, mercury ions activate a clotrimazole-sensitive K{sup +}-selective conductance leading to transient cell shrinkage. Moreover, Hg{sup 2+} increases ceramide formation. The observed mechanisms could similarly participate in the triggering of apoptosis in nucleated cells by Hg{sup 2+}.

  5. Phosphatidylserine metabolism modification precedes manganese-induced apoptosis and phosphatidylserine exposure in PC12 cells.

    PubMed

    Ferrara, G; Gambelunghe, A; Mozzi, R; Marchetti, M C; Migliorati, G; Muzi, G; Buratta, S

    2013-12-01

    Long-term exposure to high manganese (Mn) levels can lead to Parkinson-like neurological disorders. Molecular mechanisms underlying Mn cytotoxicity have been not defined. It is known that Mn induces apoptosis in PC12 cells and that this involves the activation of some signal transduction pathways. Although the role of phospholipids in apoptosis and signal transduction is well-known, the membrane phospholipid component in Mn-related damage has not yet been investigated. Phosphatidylserine (PS) facilitates protein translocation from cytosol to plasma membrane and PS exposure on the cell surface allows macrophage recognition of apoptotic cells. This study investigates the effects of MnCl2 on PS metabolism in PC12 cells, relating them to those on cell apoptosis. Apoptosis induction decreased PS radioactivity of PC12 cells incubated with radioactive serine. MnCl2 reduced PS radioactivity even under conditions that did not affect cell viability or PS exposure, suggesting that the effects on PS metabolism may represent an early event in cell apoptosis. Thus the latter conditions that also induced a greater PS decarboxylation were utilized for further investigating on the effects on PS synthesis, by measuring the activity and expression of PS-synthesizing enzymes, in cell lysates and in total cellular membranes (TM). Compared with corresponding controls, enzyme activity of MnCl2-treated cells was lower in cell lysates and greater in TM. Evaluating the expression of two isoforms of PS-synthesizing enzyme (PSS), PSSII was increased both in cell lysate and TM, while PSSI was unchanged. MnCl2 addition to control cell lysate reduced enzyme activity. These results suggest Mn plays a dual role on PS synthesis. Once inside the cell, Mn inhibits the enzyme/s, thus accounting for reduced PS synthesis in lysates and intact cells. On the other hand, it increases PSSII expression in cell membranes. The possibility that this occurs to counteract the direct effects of Mn ions on enzyme

  6. Phosphatidylserine exposure is required for ADAM17 sheddase function

    PubMed Central

    Sommer, Anselm; Kordowski, Felix; Büch, Joscha; Maretzky, Thorsten; Evers, Astrid; Andrä, Jörg; Düsterhöft, Stefan; Michalek, Matthias; Lorenzen, Inken; Somasundaram, Prasath; Tholey, Andreas; Sönnichsen, Frank D.; Kunzelmann, Karl; Heinbockel, Lena; Nehls, Christian; Gutsmann, Thomas; Grötzinger, Joachim; Bhakdi, Sucharit; Reiss, Karina

    2016-01-01

    ADAM17, a prominent member of the ‘Disintegrin and Metalloproteinase' (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Here we present evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase activity. PS exposure is tightly coupled to substrate shedding provoked by diverse ADAM17 activators. PS dependency is demonstrated in the following: (a) in Raji cells undergoing apoptosis; (b) in mutant PSA-3 cells with manipulatable PS content; and (c) in Scott syndrome lymphocytes genetically defunct in their capacity to externalize PS in response to intracellular Ca2+ elevation. Soluble phosphorylserine but not phosphorylcholine inhibits substrate cleavage. The isolated membrane proximal domain (MPD) of ADAM17 binds to PS but not to phosphatidylcholine liposomes. A cationic PS-binding motif is identified in this domain, replacement of which abrogates liposome-binding and renders the protease incapable of cleaving its substrates in cells. We speculate that surface-exposed PS directs the protease to its targets where it then executes its shedding function. PMID:27161080

  7. Chloride channels are necessary for full platelet phosphatidylserine exposure and procoagulant activity.

    PubMed

    Harper, M T; Poole, A W

    2013-12-19

    Platelets enhance thrombin generation at sites of vascular injury by exposing phosphatidylserine during necrosis-like cell death. Anoctamin 6 (Ano6) is required for Ca(2+)-dependent phosphatidylserine exposure and is defective in patients with Scott syndrome, a rare bleeding disorder. Ano6 may also form Cl(-) channels, though the role of Cl(-) fluxes in platelet procoagulant activity has not been explored. We found that Cl(-) channel blockers or removal of extracellular Cl(-) inhibited agonist-induced phosphatidylserine exposure. However, this was not due to direct inhibition of Ca(2+)-dependent scrambling since Ca(2+) ionophore-induced phosphatidylserine exposure was normal. This implies that the role of Ano6 in Ca(2+-)dependent PS exposure is likely to differ from any putative function of Ano6 as a Cl(-) channel. Instead, Cl(-) channel blockade inhibited agonist-induced Ca(2+) entry. Importantly, Cl(-) channel blockers also prevented agonist-induced membrane hyperpolarization, resulting in depolarization. We propose that Cl(-) entry through Cl(-) channels is required for this hyperpolarization, maintaining the driving force for Ca(2+) entry and triggering full phosphatidylserine exposure. This demonstrates a novel role for Cl(-) channels in controlling platelet death and procoagulant activity.

  8. Beta2-microglobulin causes abnormal phosphatidylserine exposure in human red blood cells.

    PubMed

    Pavone, Barbara; Bucci, Sonia; Sirolli, Vittorio; Merlini, Giampaolo; Del Boccio, Piero; Di Rienzo, Marianna; Felaco, Paolo; Amoroso, Luigi; Sacchetta, Paolo; Di Ilio, Carmine; Federici, Giorgio; Urbani, Andrea; Bonomini, Mario

    2011-03-01

    The exposure of the aminophospholipid phosphatidylserine on the external leaflet of red blood cell plasma membrane can have several pathophysiological consequences with particular regard to the processes of cell phagocytosis, haemostasis and cell-cell interaction. A significant increase in phosphatidylserine-exposing erythrocytes has been reported in chronic haemodialysis patients and found to be strongly influenced by the uraemic milieu. To identify uraemic compound(s) enhancing phosphatidylserine externalization in erythrocytes, we fractionated by chromatographic methods the ultrafiltrate obtained during dialysis, and examined by flow cytometry the effect of the resulting fractions on phosphatidylserine exposure in human red cells. Chromatographic procedures disclosed a homogeneous fraction able to increase erythrocyte phosphatidylserine exposure. The inducer of such externalization was identified by monodimensional gel electrophoresis and mass spectrometry investigations as beta2-microglobulin. To confirm the beta2-microglobulin effect and to examine the influence of protein glycation (as it occurs in uraemia) on phosphatidylserine erythrocyte exposure, erythrocytes from normal subjects were incubated with recombinant beta2-microglobulin (showing no glycation sites at mass analysis), commercial beta2-microglobulin (8 glycation sites), or with in vitro glycated recombinant beta2-microglobulin (showing multiple glycation sites). Elevated concentrations of beta2-microglobulin (corresponding to plasma levels reached in dialysis patients) increased slightly but significantly the protein's ability to externalize phosphatidylserine on human erythrocytes. Such an effect was markedly enhanced by glycated forms of the protein. Beta2-microglobulin is recognized as a surrogate marker of middle-molecule uraemic toxins and represents a key component of dialysis-associated amyloidosis. Our study adds further evidence to the potential pathophysiologic consequences of beta2

  9. Transient receptor potential channels function as a coincidence signal detector mediating phosphatidylserine exposure.

    PubMed

    Harper, Matthew T; Londoño, Juan E Camacho; Quick, Kathryn; Londoño, Julia Camacho; Flockerzi, Veit; Philipp, Stephan E; Birnbaumer, Lutz; Freichel, Marc; Poole, Alastair W

    2013-06-25

    Blood platelet aggregation must be tightly controlled to promote clotting at injury sites but avoid inappropriate occlusion of blood vessels. Thrombin, which cleaves and activates Gq-coupled protease-activated receptors, and collagen-related peptide, which activates the receptor glycoprotein VI, stimulate platelets to aggregate and form thrombi. Coincident activation by these two agonists synergizes, causing the exposure of phosphatidylserine on the cell surface, which is a marker of cell death in many cell types. Phosphatidylserine exposure is also essential to produce additional thrombin on platelet surfaces, which contributes to thrombosis. We found that activation of either thrombin receptors or glycoprotein VI alone produced a calcium signal that was largely dependent only on store-operated Ca(2+) entry. In contrast, experiments with platelets from knockout mice showed that the presence of both ligands activated nonselective cation channels of the transient receptor potential C (TRPC) family, TRPC3 and TRPC6. These channels principally allowed entry of Na(+), which coupled to reverse-mode Na(+)/Ca(2+) exchange to allow calcium influx and thereby contribute to Ca(2+) signaling and phosphatidylserine exposure. Thus, TRPC channels act as coincidence detectors to coordinate responses to multiple signals in cells, thereby indirectly mediating in platelets an increase in intracellular calcium concentrations and exposure of prothrombotic phosphatidylserine.

  10. Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

    PubMed Central

    Suzuki, Jun; Imanishi, Eiichi; Nagata, Shigekazu

    2016-01-01

    Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG−/−NPTN−/− cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG’s association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling. PMID:27503893

  11. CIRCULATING MICROPARTICLES, BLOOD CELLS, AND ENDOTHELIUM INDUCE PROCOAGULANT ACTIVITY IN SEPSIS THROUGH PHOSPHATIDYLSERINE EXPOSURE.

    PubMed

    Zhang, Yan; Meng, Huan; Ma, Ruishuang; He, Zhangxiu; Wu, Xiaoming; Cao, Muhua; Yao, Zhipeng; Zhao, Lu; Li, Tao; Deng, Ruijuan; Dong, Zengxiang; Tian, Ye; Bi, Yayan; Kou, Junjie; Thatte, Hemant S; Zhou, Jin; Shi, Jialan

    2016-03-01

    Sepsis is invariably accompanied by altered coagulation cascade; however, the precise role of phosphatidylserine (PS) in inflammation-associated coagulopathy in sepsis has not been well elucidated. We explored the possibility of exposed PS on microparticles (MPs), blood cells, as well as on endothelium, and defined its role in procoagulant activity (PCA) in sepsis. PS-positive MPs and cells were detected by flow cytometry, while PCA was assessed with clotting time, purified coagulation complex, and fibrin formation assays. Plasma levels of PS MPs derived from platelets, leukocytes (including neutrophils, monocytes, and lymphocytes), erythrocytes, and endothelial cells were elevated by 1.49-, 1.60-, 2.93-, and 1.53-fold, respectively, in septic patients. Meanwhile, PS exposure on blood cells was markedly higher in septic patients than in controls. Additionally, we found that the endothelial cells (ECs) treated with septic serum in vitro exposed more PS than with healthy serum. Isolated MPs/blood cells from septic patients and cultured ECs treated with septic serum in vitro demonstrated significantly shortened coagulation time, greatly enhanced intrinsic/extrinsic FXa generation, and increased thrombin formation. Importantly, confocal imaging of MPs or septic serum-treated ECs identified binding sites for FVa and FXa to form prothrombinase, and further supported fibrin formation in the area where PS exposure was abundant. Pretreatment with lactadherin blocked PS on MPs/blood cells/ECs, prolonged coagulation time by at least 25%, reduced FXa/thrombin generation, and inhibited fibrin formation by approximately 85%. Our findings suggest a key role for PS exposed on MPs, blood cells, and endothelium in augmenting coagulation in sepsis. Therefore, therapies targeting PS may be of particular importance.

  12. The cholesterol content of the erythrocyte membrane is an important determinant of phosphatidylserine exposure.

    PubMed

    van Zwieten, Rob; Bochem, Andrea E; Hilarius, Petra M; van Bruggen, Robin; Bergkamp, Ferry; Hovingh, G Kees; Verhoeven, Arthur J

    2012-12-01

    Maintenance of the asymmetric distribution of phospholipids across the plasma membrane is a prerequisite for the survival of erythrocytes. Various stimuli have been shown to induce scrambling of phospholipids and thereby exposure of phosphatidylserine (PS). In two types of patients, both with aberrant plasma cholesterol levels, we observed an aberrant PS exposure in erythrocytes upon stimulation. We investigated the effect of high and low levels of cholesterol on the ATP-dependent flippase, which maintains phospholipid asymmetry, and the ATP-independent scrambling activity, which breaks down phospholipid asymmetry. We analyzed erythrocytes of a patient with spur cell anemia, characterized by elevated plasma cholesterol, and the erythrocytes of Tangier disease patients with very low levels of plasma cholesterol. In normal erythrocytes, loaded with cholesterol or depleted of cholesterol in vitro, the same analyses were performed. Changes in the cholesterol/phospholipid ratio of erythrocytes had marked effects on PS exposure upon cell activation. Excess cholesterol profoundly inhibited PS exposure, whereas cholesterol depletion led to increased PS exposure. The activity of the ATP-dependent flippase was not changed, suggesting a major influence of cholesterol on the outward translocation of PS. The effects of cholesterol were not accompanied by eminent changes in cytoskeletal and membrane proteins. These findings emphasize the importance of cholesterol exchange between circulating plasma and the erythrocyte membrane as determinant for phosphatidylserine exposure in erythrocytes.

  13. 14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function

    PubMed Central

    Schoenwaelder, Simone M.; Darbousset, Roxane; Cranmer, Susan L.; Ramshaw, Hayley S.; Orive, Stephanie L.; Sturgeon, Sharelle; Yuan, Yuping; Yao, Yu; Krycer, James R.; Woodcock, Joanna; Maclean, Jessica; Pitson, Stuart; Zheng, Zhaohua; Henstridge, Darren C.; van der Wal, Dianne; Gardiner, Elizabeth E.; Berndt, Michael C.; Andrews, Robert K.; James, David E.; Lopez, Angel F.; Jackson, Shaun P.

    2016-01-01

    The 14-3-3 family of adaptor proteins regulate diverse cellular functions including cell proliferation, metabolism, adhesion and apoptosis. Platelets express numerous 14-3-3 isoforms, including 14-3-3ζ, which has previously been implicated in regulating GPIbα function. Here we show an important role for 14-3-3ζ in regulating arterial thrombosis. Interestingly, this thrombosis defect is not related to alterations in von Willebrand factor (VWF)–GPIb adhesive function or platelet activation, but instead associated with reduced platelet phosphatidylserine (PS) exposure and procoagulant function. Decreased PS exposure in 14-3-3ζ-deficient platelets is associated with more sustained levels of metabolic ATP and increased mitochondrial respiratory reserve, independent of alterations in cytosolic calcium flux. Reduced platelet PS exposure in 14-3-3ζ-deficient mice does not increase bleeding risk, but results in decreased thrombin generation and protection from pulmonary embolism, leading to prolonged survival. Our studies define an important role for 14-3-3ζ in regulating platelet bioenergetics, leading to decreased platelet PS exposure and procoagulant function. PMID:27670677

  14. Isolation and characterization of a Chinese hamster ovary cell mutant with altered regulation of phosphatidylserine biosynthesis

    SciTech Connect

    Hasegawa, K.; Kuge, O.; Nishijima, M.; Akamatsu, Y. )

    1989-11-25

    We have screened approximately 10,000 colonies of Chinese hamster ovary (CHO) cells immobilized on polyester cloth for mutants defective in (14C)ethanolamine incorporation into trichloroacetic acid-precipitable phospholipids. In mutant 29, discovered in this way, the activities of enzymes involved in the CDP-ethanolamine pathway were normal; however, the intracellular pool of phosphorylethanolamine was elevated, being more than 10-fold that in the parental CHO-K1 cells. These results suggested that the reduced incorporation of (14C)ethanolamine into phosphatidylethanolamine in mutant 29 was due to dilution of phosphoryl-(14C)ethanolamine with the increased amount of cellular phosphorylethanolamine. Interestingly, the rate of incorporation of serine into phosphatidylserine and the content of phosphatidylserine in mutant 29 cells were increased 3-fold and 1.5-fold, respectively, compared with the parent cells. The overproduction of phosphorylethanolamine in mutant 29 cells was ascribed to the elevated level of phosphatidylserine biosynthesis, because ethanolamine is produced as a reaction product on the conversion of phosphatidylethanolamine to phosphatidylserine, which is catalyzed by phospholipid-serine base-exchange enzymes. Using both intact cells and the particulate fraction of a cell extract, phosphatidylserine biosynthesis in CHO-K1 cells was shown to be inhibited by phosphatidylserine itself, whereas that in mutant 29 cells was greatly resistant to the inhibition, compared with the parental cells. As a conclusion, it may be assumed that mutant 29 cells have a lesion in the regulation of phosphatidylserine biosynthesis by serine-exchange enzyme activity, which results in the overproduction of phosphatidylserine and phosphorylethanolamine as well.

  15. Phosphatidylserine exposure and other apoptotic-like events in Bernard-Soulier syndrome platelets.

    PubMed

    Rand, Margaret L; Wang, Hong; Bang, K W Annie; Teitel, Jerome M; Blanchette, Victor S; Freedman, John; Nurden, Alan T

    2010-08-01

    In the Bernard-Soulier syndrome (BSS), the giant platelets are said to have increased phosphatidylserine (PS) surface exposure in the resting state and shortened survival in the circulation. When normal platelets are activated, they undergo many biochemical and morphological changes, some of which are apoptotic. Herein, we investigated apoptotic-like events in BSS platelets upon activation, specifically, PS exposure, microparticle (MP) formation, cell shrinkage, and loss of mitochondrial inner membrane potential (DeltaPsi(m)). Platelets from two unrelated BSS patients were examined in whole blood; agonists used were collagen, thrombin, PAR1- or PAR4-activating peptides (APs), or combinations of collagen with thrombin, and the PAR-APs. Flow cytometry was used to measure PS exposure (annexin A5 binding), platelet-derived MPs (forward scatter; events <0.75 microm size), and DeltaPsi(m) (TMRM fluorescence). PS exposure was increased on resting and activated BSS platelets, and this was independent of the platelet size. MP formation by BSS platelets was generally enhanced. Cell shrinkage occurred on activation to form smaller, PS-exposing platelets in BSS and controls. A proportion of PS-exposing BSS and control platelets exhibited DeltaPsi(m) loss, but unlike controls, there was also loss of DeltaPsi(m) in the BSS platelets not exposing PS. Thus, BSS platelets undergo apoptotic-like events upon activation, with PS exposure and MP formation being enhanced. These events may play a role in the shortened survival in BSS, as well as affecting thrombin generation.

  16. TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets.

    PubMed

    Fujii, Toshihiro; Sakata, Asuka; Nishimura, Satoshi; Eto, Koji; Nagata, Shigekazu

    2015-10-13

    Phosphatidylserine (PtdSer) exposure on the surface of activated platelets requires the action of a phospholipid scramblase(s), and serves as a scaffold for the assembly of the tenase and prothrombinase complexes involved in blood coagulation. Here, we found that the activation of mouse platelets with thrombin/collagen or Ca(2+) ionophore at 20 °C induces PtdSer exposure without compromising plasma membrane integrity. Among five transmembrane protein 16 (TMEM16) members that support Ca(2+)-dependent phospholipid scrambling, TMEM16F was the only one that showed high expression in mouse platelets. Platelets from platelet-specific TMEM16F-deficient mice exhibited defects in activation-induced PtdSer exposure and microparticle shedding, although α-granule and dense granule release remained intact. The rate of tissue factor-induced thrombin generation by TMEM16F-deficient platelets was severely reduced, whereas thrombin-induced clot retraction was unaffected. The imaging of laser-induced thrombus formation in whole animals showed that PtdSer exposure on aggregated platelets was TMEM16F-dependent in vivo. The phenotypes of the platelet-specific TMEM16F-null mice resemble those of patients with Scott syndrome, a mild bleeding disorder, indicating that these mice may provide a useful model for human Scott syndrome.

  17. Phosphatidylserine exposure and red cell viability in red cell aging and in hemolytic anemia

    PubMed Central

    Boas, Franz Edward; Forman, Linda; Beutler, Ernest

    1998-01-01

    Phosphatidylserine (PS) normally localizes to the inner leaflet of cell membranes but becomes exposed in abnormal or apoptotic cells, signaling macrophages to ingest them. Along similar lines, it seemed possible that the removal of red cells from circulation because of normal aging or in hemolytic anemias might be triggered by PS exposure. To investigate the role of PS exposure in normal red cell aging, we used N-hydroxysuccinimide-biotin to tag rabbit red cells in vivo, then used phycoerythrin-streptavidin to label the biotinylated cells, and annexin V-fluorescein isothiocyanate (FITC) to detect the exposed PS. Flow cytometric analysis of these cells drawn at 10-day intervals up to 70 days after biotinylation indicated that older, biotinylated cells expose more PS. Furthermore, our data match a simple model of red cell senescence that assumes both an age-dependent destruction of senescent red cells preceded by several hours of PS exposure and a random destruction of red cells without PS exposure. By using this model, we demonstrated that the exposure of PS parallels the rate at which biotinylated red cells are removed from circulation. On the other hand, using an annexin V-FITC label and flow cytometry demonstrates that exposed PS does not cause the reduced red cell life span of patients with hemolytic anemia, with the possible exception of those with unstable hemoglobins or sickle cell anemia. Thus, in some cases PS exposure on the cell surface may signal the removal of red cells from circulation, but in other cases some other signal must trigger the sequestration of cells. PMID:9501218

  18. Indolic uremic solutes enhance procoagulant activity of red blood cells through phosphatidylserine exposure and microparticle release.

    PubMed

    Gao, Chunyan; Ji, Shuting; Dong, Weijun; Qi, Yushan; Song, Wen; Cui, Debin; Shi, Jialan

    2015-10-28

    Increased accumulation of indolic uremic solutes in the blood of uremic patients contributes to the risk of thrombotic events. Red blood cells (RBCs), the most abundant blood cells in circulation, may be a privileged target of these solutes. However, the effect of uremic solutes indoxyl sulfate (IS) and indole-3-acetic acid (IAA) on procoagulant activity (PCA) of erythrocyte is unclear. Here, RBCs from healthy adults were treated with IS and IAA (mean and maximal concentrations reported in uremic patients). Phosphatidylserine (PS) exposure of RBCs and their microparticles (MPs) release were labeled with Alexa Fluor 488-lactadherin and detected by flow cytometer. Cytosolic Ca(2+) ([Ca(2+)]) with Fluo 3/AM was analyzed by flow cytometer. PCA was assessed by clotting time and purified coagulation complex assays. We found that PS exposure, MPs generation, and consequent PCA of RBCs at mean concentrations of IS and IAA enhanced and peaked in maximal uremic concentrations. Moreover, 128 nM lactadherin, a PS inhibitor, inhibited over 90% PCA of RBCs and RMPs. Eryptosis or damage, by indolic uremic solutes was due to, at least partially, the increase of cytosolic [Ca(2+)]. Our results suggest that RBC eryptosis in uremic solutes IS and IAA plays an important role in thrombus formation through releasing RMPs and exposing PS. Lactadherin acts as an efficient anticoagulant in this process.

  19. Exposure of Phosphatidylserine by Xk-related Protein Family Members during Apoptosis*

    PubMed Central

    Suzuki, Jun; Imanishi, Eiichi; Nagata, Shigekazu

    2014-01-01

    Apoptotic cells expose phosphatidylserine (PtdSer) on their surface as an “eat me” signal. Mammalian Xk-related (Xkr) protein 8, which is predicted to contain six transmembrane regions, and its Caenorhabditis elegans homolog CED-8 promote apoptotic PtdSer exposure. The mouse and human Xkr families consist of eight and nine members, respectively. Here, we found that mouse Xkr family members, with the exception of Xkr2, are localized to the plasma membrane. When Xkr8-deficient cells, which do not expose PtdSer during apoptosis, were transformed by Xkr family members, the transformants expressing Xkr4, Xkr8, or Xkr9 responded to apoptotic stimuli by exposing cell surface PtdSer and were efficiently engulfed by macrophages. Like Xkr8, Xkr4 and Xkr9 were found to possess a caspase recognition site in the C-terminal region and to require its direct cleavage by caspases for their function. Site-directed mutagenesis of the amino acid residues conserved among CED-8, Xkr4, Xkr8, and Xkr9 identified several essential residues in the second transmembrane and second cytoplasmic regions. Real time PCR analysis indicated that unlike Xkr8, which is ubiquitously expressed, Xkr4 and Xkr9 expression is tissue-specific. PMID:25231987

  20. EGF domain of coagulation factor IX is conducive to exposure of phosphatidylserine.

    PubMed

    Hidai, Chiaki; Fujiwara, Yusuke; Kokubun, Shinichiro; Kitano, Hisataka

    2017-04-01

    Lipid rafts are an initiation site for many different signals. Recently, we reported that an EGF domain in activated coagulation factor IX (EGF-F9) increases lipid raft formation and accelerates cell migration. However, the detailed mechanism is not well understood. This study aimed to evaluate the effects of EGF-F9 on the cell membrane. A431 cells (derived from human squamous cell carcinoma) were treated with recombinant EGF-F9. Cells were immunocytochemically stained with probes for lipid rafts or phosphatidylserine (PS). After 3 min of treatment with EGF-F9, cholera toxin subunit B (CTxB) binding domains emerged at the adhesive tips of filopodia. Subsequently, CTxB staining was observed on the filopodial shaft. Finally, large clusters of CTxB domains were observed at the edge of cell bodies. Markers for lipid rafts, such as caveolin-1 and a GPI anchored protein, co-localized with CTxB. Staining with annexin V and XII revealed that PS was exposed at the tips of filopodia, translocated on filopodial shafts, and co-localized with CTxB at the rafts. Immunocytochemistry showed that scramblase-1 protein was present at the filopodial tips. Our data indicates that EGF-F9 accelerates PS exposure around the filopodial adhesion complex and induces clustering of lipid rafts in the cell body. PS exposure is thought to occur on cells undergoing apoptosis. Further study of the function of the EGF-F9 motif in mediating signal transduction is necessary because it is shared by a number of proteins.

  1. Involvement of sodium in early phosphatidylserine exposure and phospholipid scrambling induced by P2X7 purinoceptor activation in thymocytes.

    PubMed

    Courageot, Marie-Pierre; Lépine, Sandrine; Hours, Michel; Giraud, Françoise; Sulpice, Jean-Claude

    2004-05-21

    Extracellular ATP (ATP(ec)), a possible effector in thymocyte selection, induces thymocyte death via purinoceptor activation. We show that ATP(ec) induced cell death by apoptosis, rather than lysis, and early phosphatidylserine (PS) exposure and phospholipid scrambling in a limited thymocyte population (35-40%). PS externalization resulted from the activation of the cationic channel P2X7 (formerly P2Z) receptor and was triggered in all thymocyte subsets although to different proportions in each one. Phospholipid movement was dependent on ATP(ec)-induced Ca(2+) and/or Na(+) influx. At physiological external Na(+) concentration, without external Ca(2+), PS was exposed in all ATP(ec)-responsive cells. In contrast, without external Na(+), physiological external Ca(2+) concentration promoted a submaximal response. Altogether these data show that Na(+) influx plays a major role in the rapid PS exposure induced by P2X7 receptor activation in thymocytes.

  2. Low level of lead can induce phosphatidylserine exposure and erythrophagocytosis: a new mechanism underlying lead-associated anemia.

    PubMed

    Jang, Won-Hee; Lim, Kyung-Min; Kim, Keunyoung; Noh, Ji-Yoon; Kang, Seojin; Chang, Youn-Kyeong; Chung, Jin-Ho

    2011-07-01

    Anemia is probably one of the most well-known toxic effects of lead. Previously, lead-induced anemia was considered to be from the inhibition of δ-aminolevulinic acid dehydratase participating in the heme biosynthesis. However, little is known whether lead could affect the destruction of erythrocyte, another important factor for anemia. In the present study, we demonstrated that lead could accelerate the splenic sequestration of erythrocytes through phosphatidylserine (PS) exposure and subsequently increased erythrophagocytosis. In freshly isolated human erythrocytes, Pb(2+)- induced PS exposure at relatively low concentrations (∼0.1 μM) by inhibiting flippase, a key aminophospholipid translocase for the maintenance of PS asymmetry and adenosine triphosphate depletion appeared to underlie this phenomenon. Abnormal shape changes of erythrocytes and microvesicle generation and other triggers for the erythrophagocytosis were also observed in the Pb(2+)-exposed erythrocytes. In vitro data showed that human macrophage indeed recognized and phagocytosis PS-exposed erythrocytes. In good accordance with these in vitro results, the oral administration of Pb(2+) increased PS exposure on erythrocytes in rat in vivo. In addition, reduction of hematocrit and hemoglobin and increased spleen weight were observed along with enhanced splenic sequestration of erythrocytes in the rats exposed to Pb(2+) subchronically for 4 weeks through drinking water. In conclusion, these results suggest that Pb(2+)-induced anemia may be explained at least in part by increased PS exposure on erythrocytes, erythrophagocytosis, and splenic sequestration.

  3. Unconventional apoptosis of polymorphonuclear neutrophils (PMN): staurosporine delays exposure of phosphatidylserine and prevents phagocytosis by MΦ-2 macrophages of PMN

    PubMed Central

    Franz, S; Muñoz, L E; Heyder, P; Herrmann, M; Schiller, M

    2015-01-01

    Apoptosis of polymorphonuclear neutrophils (PMN) and subsequent ‘silent’ removal represents an important check-point for the resolution of inflammation. Failure in PMN clearance resulting in secondary necrosis-driven tissue damage has been implicated in conditions of chronic inflammation and autoimmunity. Apoptotic PMN undergo profound biophysical changes that warrant their efficient recognition and uptake by phagocytes before fading to secondary necrosis. In this study, we demonstrate that staurosporine (STS), a non-selective but potent inhibitor of cyclin-dependent kinase and protein kinase C, exerts a drastic impact on PMN apoptosis. PMN treated with STS underwent an unconventional form of cell death characterized by a delayed exposure of aminophospholipids, including phosphatidylserine (PS) and phosphatidylethanolamine and an increased exposure of neo-glycans. STS caused an impaired cellular fragmentation and accelerated DNA fragmentation. Phagocytosis of STS-treated PMN lacking PS on their surfaces was decreased significantly, which highlights the importance of PS for the clearance of apoptotic PMN. Specific opsonization with immune complexes completely restored phagocytosis of STS-treated PMN, demonstrating the efficiency of back-up clearance pathways in the absence of PS exposure. PMID:24995908

  4. Pleiotropic actions of forskolin result in phosphatidylserine exposure in primary trophoblasts.

    PubMed

    Riddell, Meghan R; Winkler-Lowen, Bonnie; Jiang, Yanyan; Davidge, Sandra T; Guilbert, Larry J

    2013-01-01

    Forskolin is an extract of the Coleus forskholii plant that is widely used in cell physiology to raise intracellular cAMP levels. In the field of trophoblast biology, forskolin is one of the primary treatments used to induce trophoblastic cellular fusion. The syncytiotrophoblast (ST) is a continuous multinucleated cell in the human placenta that separates maternal from fetal circulations and can only expand by fusion with its stem cell, the cytotrophoblast (CT). Functional investigation of any aspect of ST physiology requires in vitro differentiation of CT and de novo ST formation, thus selecting the most appropriate differentiation agent for the hypothesis being investigated is necessary as well as addressing potential off-target effects. Previous studies, using forskolin to induce fusion in trophoblastic cell lines, identified phosphatidylserine (PS) externalization to be essential for trophoblast fusion and showed that widespread PS externalization is present even after fusion has been achieved. PS is a membrane phospholipid that is primarily localized to the inner-membrane leaflet. Externalization of PS is a hallmark of early apoptosis and is involved in cellular fusion of myocytes and macrophages. We were interested to examine whether PS externalization was also involved in primary trophoblast fusion. We show widespread PS externalization occurs after 72 hours when fusion was stimulated with forskolin, but not when stimulated with the cell permeant cAMP analog Br-cAMP. Using a forskolin analog, 1,9-dideoxyforskolin, which stimulates membrane transporters but not adenylate cyclase, we found that widespread PS externalization required both increased intracellular cAMP levels and stimulation of membrane transporters. Treatment of primary trophoblasts with Br-cAMP alone did not result in widespread PS externalization despite high levels of cellular fusion. Thus, we concluded that widespread PS externalization is independent of trophoblast fusion and, importantly

  5. Trivalent methylated arsenical-induced phosphatidylserine exposure and apoptosis in platelets may lead to increased thrombus formation

    SciTech Connect

    Bae, Ok-Nam; Lim, Kyung-Min; Chung, Jin-Ho

    2009-09-01

    Trivalent methylated metabolites of arsenic, monomethylarsonous acid (MMA{sup III}) and dimethylarsinous acid (DMA{sup III}), have been found highly reactive and toxic in various cells and in vivo animal models, suggesting their roles in the arsenic-associated toxicity. However, their effects on cardiovascular system including blood cells, one of the most important targets for arsenic toxicity, remain poorly understood. Here we found that MMA{sup III} and DMA{sup III} could induce procoagulant activity and apoptosis in platelets, which play key roles in the development of various cardiovascular diseases (CVDs) through excessive thrombus formation. In freshly isolated human platelets, treatment of MMA{sup III} resulted in phosphatidylserine (PS) exposure, a hallmark of procoagulant activation, accompanied by distinctive apoptotic features including mitochondrial membrane potential disruption, cytochrome c release, and caspase-3 activation. These procoagulant activation and apoptotic features were found to be mediated by the depletion of protein thiol and intracellular ATP, and flippase inhibition by MMA{sup III}, while the intracellular calcium increase or reactive oxygen species generation was not involved. Importantly, increased platelet procoagulant activity by MMA{sup III} resulted in enhanced blood coagulation and excessive thrombus formation in a rat in vivo venous thrombosis model. DMA{sup III} also induced PS-exposure with apoptotic features mediated by protein thiol depletion, which resulted in enhanced thrombin generation. In summary, we believe that this study provides an important evidence for the role of trivalent methylated arsenic metabolites in arsenic-associated CVDs, giving a novel insight into the role of platelet apoptosis in toxicant-induced cardiovascular toxicity.

  6. Formaldehyde-fixation of platelets for flow cytometric measurement of phosphatidylserine exposure is feasible.

    PubMed

    Rochat, Sophie; Alberio, Lorenzo

    2015-01-01

    Strong platelet activation results in a redistribution of negatively charged phospholipids from the cytosolic to the outer leaflet of the cellular membrane. Annexin V has a high affinity to negatively charged phospholipids and can be used to identify procoagulant platelets. Formaldehyde fixation can cause factitious Annexin V binding. Our aim was to evaluate a method for fixing platelets avoiding additional Annexin V binding. We induced expression of negatively charged phospholipids on the surface of a fraction of platelets by combined activation with convulxin and thrombin in the presence of Annexin V-fluorescein isothiocyanate and calcium. Aliquots of resting and activated platelets were fixed with a low concentration, calcium-free formaldehyde solution. Both native platelets and fixed platelets were analyzed by flow cytometry immediately and after a 24-h storage at 4°C. We observed that the percentage of Annexin V positive resting platelets ranged from 1.5 to 9.3% for the native samples and from 0.4 to 12.8% for the fixed samples (P=0.706, paired t-test). The amount of Annexin V positive convulxin/thrombin activated platelets varied from 12.9 to 35.4% without fixation and from 15.3 to 36.3% after formalin fixation (P=0.450). After a 24-h storage at 4°C, Annexin V positive platelets significantly increased both in the resting and in the convulxin/thrombin activated samples of native platelets (both P<0.001), while results for formalin fixed platelets did not differ from baseline values (P=0.318 for resting fixed platelets; P=0.673 for activated fixed platelets). We conclude that platelet fixation with a low concentration, calcium-free formaldehyde solution does not alter the proportion of Annexin V positive platelets. This method can be used to investigate properties of procoagulant platelets by multicolor flow-cytometric analysis requiring fixation steps.

  7. Escherichia coli α-Hemolysin Triggers Shrinkage of Erythrocytes via KCa3.1 and TMEM16A Channels with Subsequent Phosphatidylserine Exposure*

    PubMed Central

    Skals, Marianne; Jensen, Uffe B.; Ousingsawat, Jiraporn; Kunzelmann, Karl; Leipziger, Jens; Praetorius, Helle A.

    2010-01-01

    α-Hemolysin from Escherichia coli (HlyA) readily lyse erythrocytes from various species. We have recently demonstrated that this pore-forming toxin provokes distinct shrinkage and crenation before it finally leads to swelling and lysis of erythrocytes. The present study documents the underlying mechanism for this severe volume reduction. We show that HlyA-induced shrinkage and crenation of human erythrocytes occur subsequent to a significant rise in [Ca2+]i. The Ca2+-activated K+ channel KCa3.1 (or Gardos channel) is essential for the initial shrinkage, because both clotrimazole and TRAM-34 prevent the shrinkage and potentiate hemolysis produced by HlyA. Notably, the recently described Ca2+-activated Cl− channel TMEM16A contributes substantially to HlyA-induced cell volume reduction. Erythrocytes isolated from TMEM16A−/− mice showed significantly attenuated crenation and increased lysis compared with controls. Additionally, we found that HlyA leads to acute exposure of phosphatidylserine in the outer leaflet of the plasma membrane. This exposure was considerably reduced by KCa3.1 antagonists. In conclusion, this study shows that HlyA triggers acute erythrocyte shrinkage, which depends on Ca2+-activated efflux of K+ via KCa3.1 and Cl− via TMEM16A, with subsequent phosphatidylserine exposure. This mechanism might potentially allow HlyA-damaged erythrocytes to be removed from the bloodstream by macrophages and thereby reduce the risk of intravascular hemolysis. PMID:20231275

  8. Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation.

    PubMed

    van Kruchten, Roger; Mattheij, Nadine J A; Saunders, Christine; Feijge, Marion A H; Swieringa, Frauke; Wolfs, Jef L N; Collins, Peter W; Heemskerk, Johan W M; Bevers, Edouard M

    2013-03-07

    Scott syndrome, a bleeding disorder caused by defective phospholipid scrambling, has been associated with mutations in the TMEM16F gene. The role of TMEM16F in apoptosis- or agonist-induced phosphatidylserine (PS) exposure was studied in platelets from a Scott syndrome patient and control subjects. Whereas stimulation of control platelets with the BH3-mimetic ABT737 resulted in 2 distinct fractions with moderate and high PS exposure, the high PS-exposing fraction was markedly delayed in Scott platelets. High, but not moderate, PS exposure in platelets was suppressed by chelation of intracellular Ca(2+), whereas caspase inhibition completely abolished ABT737-induced PS exposure in both Scott and control platelets. On the other hand, high PS exposure induced by the Ca(2+)-mobilizing agonists convulxin/thrombin fully relied on mitochondrial depolarization and was virtually absent in Scott platelets. Finally, PS exposure induced by collagen/thrombin was partly affected in Scott platelets, and the residual PS positive fraction was insensitive to inhibition of caspases or mitochondrial depolarization. In conclusion, TMEM16F is not required for, but enhances, caspase-dependent PS exposure; convulxin-/thrombin-induced PS exposure is entirely dependent on TMEM16F, whereas collagen/thrombin-induced PS exposure results from 2 distinct pathways, one of which involves mitochondrial depolarization and is mediated by TMEM16F.

  9. Inhibitors of second messenger pathways and Ca(2+)-induced exposure of phosphatidylserine in red blood cells of patients with sickle cell disease.

    PubMed

    Gbotosho, O T; Cytlak, U M; Hannemann, A; Rees, D C; Tewari, S; Gibson, J S

    2014-07-01

    The present work investigates the contribution of various second messenger systems to Ca(2+)-induced phosphatidylserine (PS) exposure in red blood cells (RBCs) from sickle cell disease (SCD) patients. The Ca(2+) dependence of PS exposure was confirmed using the Ca(2+) ionophore bromo-A23187 to clamp intracellular Ca(2+) over 4 orders of magnitude in high or low potassium-containing (HK or LK) saline. The percentage of RBCs showing PS exposure was significantly increased in LK over HK saline. This effect was reduced by the Gardos channel inhibitors, clotrimazole and charybdotoxin. Nevertheless, although Ca(2+) loading in the presence of an outwardly directed electrochemical gradient for K(+) stimulated PS exposure, substantial exposure still occurred in HK saline. Under the conditions used inhibitors of other second messenger systems (ABT491, quinacrine, acetylsalicylic acid, 3,4-dichloroisocoumarin, GW4869 and zVAD-fmk) did not inhibit the relationship between [Ca(2+)] and PS exposure. Inhibitors of phospholipase A2, cyclooxygenase, platelet-activating factor, sphingomyelinase and caspases, therefore, were without effect on Ca(2+)-induced PS exposure in RBCs, incubated in either HK or LK saline.

  10. Identification of the Ca²⁺ entry pathway involved in deoxygenation-induced phosphatidylserine exposure in red blood cells from patients with sickle cell disease.

    PubMed

    Cytlak, U M; Hannemann, A; Rees, D C; Gibson, J S

    2013-11-01

    Phosphatidylserine (PS) exposure in red blood cells (RBCs) from sickle cell disease (SCD) patients is increased compared to levels in normal individuals and may participate in the anaemic and ischaemic complications of SCD. Exposure is increased by deoxygenation and occurs with elevation of intracellular Ca²⁺ to low micromolar levels. The Ca²⁺ entry step has not been defined but a role for the deoxygenation-induced pathway, Psickle, is postulated. Partial Psickle inhibitors 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid (SITS), 4,4'-dithiocyano-2,2'-stilbene-disulphonic acid (DIDS) and dipyridamole inhibited deoxygenation-induced PS exposure (DIDS IC50, 118 nM). Inhibitors and activators of other pathways (including these stimulated by depolarisation, benzodiazepines, glutamate and stretch) were without effect. Zn²⁺ and Gd³⁺ stimulated PS exposure to high levels. In the case of Zn²⁺, this effect was independent of oxygen (and hence HbS polymerisation and RBC sickling) but required extracellular Ca²⁺. The effect was completely abolished when Zn²⁺ (100 μM) was added to RBCs suspended in autologous plasma, implying a requirement of high levels of free Zn²⁺.

  11. Procoagulant activity induced by transcatheter closure of atrial septal defects is associated with exposure of phosphatidylserine on microparticles, platelets and red blood cells.

    PubMed

    Ding, Wenbo; Kou, Junjie; Meng, Huan; Kou, Yan; He, Zhangxiu; Cao, Muhua; Wang, Lixiu; Bi, Yayan; Thatte, Hemant S; Shi, Jialan

    2015-08-01

    The mechanism of hypercoagulable state following transcatheter closure of atrial septal defects (ASDs) remains unclear. We evaluated the exposure of phosphatidylserine (PS) on released microparticles (MPs) and also the cells of their origin from peripheral blood, and the associated increase in procoagulant activity (PCA) following transcatheter ASD closure. We demonstrate that PS(+) MP levels were elevated immediately after device implantation (P <0.002), peaked at 24hour (P <0.002), and persisted at high levels for 1-week post procedure (P <0.002). Flow cytometry analysis indicated that PS(+) MPs were mainly derived from platelets, endothelial cells, and the red blood cells (RBCs). Concomittantly, PS(+) platelet and RBC count also increased after transcatheter closure of ASDs, while PS(+) leukocytes levels remained the same. Compared to the baseline, coagulation time of PS(+) MPs, platelets, and RBCs at 24hours post procedure decreased by about 18.7% (P <0.004), 21.5% (P <0.001), and 26.8% (P <0.001), respectively. Intrinsic factor Xa and prothrombinase were produced abundantly by platelets, RBCs, and MPs leading to materialization of fibrin by 24hours. Additionally, Xase complex formation and thrombin generation was inhibited by about 74% by the addition of lactadherin to the assays. Our results thus demonstrate that PS exposure on MPs, platelets, and RBCs play an important role in hypercoagulability following transcatheter ASD closure.

  12. Sub-chronic (13-week) oral toxicity study, preceded by an in utero exposure phase and genotoxicity studies with fish source phosphatidylserine in rats.

    PubMed

    Lifshitz, Y; Levi, L; Eyal, I; Cohen, T; Tessler, S

    2015-12-01

    The safety of fish phosphatidylserine (PS) conjugated to DHA (InCog™) was examined in a series of toxicology studies as first step to support future use in infants and general population using in vitro genotoxicity tests and in a sub-chronic toxicity study with an in-utero exposure phase. PS is a major lipid in the cell membrane, active in various membrane-mediated processes. PS-DHA, present in human milk, has been suggested to be important for early brain development. Rats were exposed to diets containing 1.5%, 3% or 4.5% InCog or two control diets. Parental (F0) animals were fed throughout mating, gestation and lactation. Subsequently, a subchronic, 13-week study was conducted on the F1 animals followed by 4 weeks of recovery. The genotoxicity tests showed no mutagenicity potential. No significant toxicological findings were found in the F0 rats or the F1 pups. In the 13-weeks study, an increase in the presence of renal minimal-mild multifocal corticomedullary mineralization was noted in nine females of the high-dose group. This change was not associated with any inflammatory or degenerative changes in the kidneys. The no-observed-adverse-effect level (NOAEL) in the present study was placed at 3% in the diet (mid-dose group), equivalent to an overall intake of at least 2.1 g InCog/kg bw/day in the F1 generation.

  13. Neural alterations from lead exposure in zebrafish.

    PubMed

    Roy, Nicole M; DeWolf, Sarah; Schutt, Alexius; Wright, Ashia; Steele, Latina

    2014-01-01

    Lead was used extensively as a gas additive and pesticide, in paints, batteries, lead shot, pipes, canning and toy manufacturing. Although uses of lead have been restricted, lead persists in our environment especially in older homes, and generally in soil and water. Although extensive studies have determined that fetal and childhood exposures to lead have been associated with childhood and adolescent memory impairments and learning disabilities, there are limited studies investigating early neural and morphological effects that may lead to these behavioral and learning abnormalities. Here we utilize the zebrafish vertebrate model system to study early effects of lead exposure on the brain. We treat embryos with 0.2mM lead for 24, 48 and 72 h and analyze neural structures through live imagery and transgenic approaches. We find structural abnormalities in the hindbrain region as well as changes in branchiomotor neuron development and altered neural vasculature. Additionally, we find areas of increased apoptosis. We conclude that lead is developmentally neurotoxic to a specific region of the brain, the hindbrain and is toxic to branchiomotor neurons residing in rhombomeres 2 through 7 of the hindbrain and hindbrain central artery vasculature.

  14. Sensing phosphatidylserine in cellular membranes.

    PubMed

    Kay, Jason G; Grinstein, Sergio

    2011-01-01

    Phosphatidylserine, a phospholipid with a negatively charged head-group, is an important constituent of eukaryotic cellular membranes. On the plasma membrane, rather than being evenly distributed, phosphatidylserine is found preferentially in the inner leaflet. Disruption of this asymmetry, leading to the appearance of phosphatidylserine on the surface of the cell, is known to play a central role in both apoptosis and blood clotting. Despite its importance, comparatively little is known about phosphatidylserine in cells: its precise subcellular localization, transmembrane topology and intracellular dynamics are poorly characterized. The recent development of new, genetically-encoded probes able to detect phosphatidylserine within live cells, however, is leading to a more in-depth understanding of the biology of this phospholipid. This review aims to give an overview of the current methods for phosphatidylserine detection within cells, and some of the recent realizations derived from their use.

  15. Ribavirin-induced externalization of phosphatidylserine in erythrocytes is predominantly caused by inhibition of aminophospholipid translocase activity.

    PubMed

    Kleinegris, Marie-Claire; Koek, Ger H; Mast, Kelly; Mestrom, Eveline H C; Wolfs, Jef L N; Bevers, Edouard M

    2012-10-15

    Ribavirin in combination with interferon-α is the standard treatment for chronic hepatitis C, but often induces severe anemia forcing discontinuation of the therapy. Whereas suppression of bone marrow by interferon may impact on the production of erythrocytes, it has been suggested that accumulation of ribavirin in erythrocytes induces alterations causing an early removal of these cells by the mononuclear phagocytic system. Externalization of phosphatidylserine, which is exclusively present in the cytoplasmic leaflet of the plasma membrane, is a recognition signal for phagocytosis in particular of apoptotic cells. Here, we demonstrate that surface exposure of phosphatidylserine upon prolonged treatment of erythrocytes with ribavirin results mainly from inactivation of the aminophospholipid translocase, an ATP-dependent lipid pump, which specifically transports phosphatidylserine from the outer to the inner leaflet of the plasma membrane. Inactivation is due to severe ATP depletion, although competitive inhibition by ribavirin or its phosphorylated derivatives cannot be excluded. Phospholipid scramblase, responsible for collapse of lipid asymmetry, appears to be of minor importance as erythrocytes of patients with the Scott syndrome, lacking Ca(2+)-induced lipid scrambling, are equally sensitive to ribavirin treatment. Neither the antioxidant N-acetylcysteine nor the pan-caspase inhibitor Q-VD-OPH did affect ribavirin-induced phosphatidylserine exposure, suggesting that oxidative stress or apoptotic-related mechanisms are not involved in this process. In conclusion, we propose that spontaneous loss of lipid asymmetry, not corrected by aminophospholipid translocase activity, is the mechanism for ribavirin-induced phosphatidylserine exposure that may contribute to ribavirin-induced anemia.

  16. Structural Alterations in the Cornea from Exposure to Infrared Radiation

    DTIC Science & Technology

    1985-07-01

    mylar disks that were preformed - 4- to match the corneal curvature. The disks were attached 0 at their edges to excised corneas using cyanoacrylate ...ICFIECOP JHU/APL TG 1364 JULY 1985 (0 FINAL Technical Memorandum STRUCTURAL ALTERATIONS IN THE CORNEA FROM EXPOSURE TO INFRARED RADIATION R. A...Structural Alterations in the Cornea from Exposure to Infrared Radiation 12. PERSONAL AUTHOR(S) R. A. Farrell, R. L. McCally, C. B. Bargeron, and W. R. Green

  17. Binding of Alphaherpesvirus Glycoprotein H to Surface α4β1-Integrins Activates Calcium-Signaling Pathways and Induces Phosphatidylserine Exposure on the Plasma Membrane

    PubMed Central

    Gramatica, Andrea; Herrmann, Andreas; Osterrieder, Nikolaus

    2015-01-01

    ABSTRACT Intracellular signaling connected to integrin activation is known to induce cytoplasmic Ca2+ release, which in turn mediates a number of downstream signals. The cellular entry pathways of two closely related alphaherpesviruses, equine herpesviruses 1 and 4 (EHV-1 and EHV-4), are differentially regulated with respect to the requirement of interaction of glycoprotein H (gH) with α4β1-integrins. We show here that binding of EHV-1, but not EHV-4, to target cells resulted in a rapid and significant increase in cytosolic Ca2+ levels. EHV-1 expressing EHV-4 gH (gH4) in lieu of authentic gH1 failed to induce Ca2+ release, while EHV-4 with gH1 triggered significant Ca2+ release. Blocking the interaction between gH1 and α4β1-integrins, inhibiting phospholipase C (PLC) activation, or blocking binding of inositol 1,4,5-triphosphate (IP3) to its receptor on the endoplasmic reticulum (ER) abrogated Ca2+ release. Interestingly, phosphatidylserine (PS) was exposed on the plasma membrane in response to cytosolic calcium increase after EHV-1 binding through a scramblase-dependent mechanism. Inhibition of both Ca2+ release from the ER and scramblase activation blocked PS scrambling and redirected virus entry to the endocytic pathway, indicating that PS may play a role in facilitating virus entry directly at the plasma membrane. PMID:26489864

  18. Alterations in cognitive and psychological functioning after organic solvent exposure

    SciTech Connect

    Morrow, L.A.; Ryan, C.M.; Hodgson, M.J.; Robin, N. )

    1990-05-01

    Exposure to organic solvents has been linked repeatedly to alterations in both personality and cognitive functioning. To assess the nature and extent of these changes more thoroughly, 32 workers with a history of exposure to mixtures of organic solvents and 32 age- and education-matched blue-collar workers with no history of exposure were assessed with a comprehensive battery of neuropsychological tests. Although both groups were comparable on measures of general intelligence, significant differences were found in virtually all other cognitive domains tested (Learning and Memory, Visuospatial, Attention and Mental Flexibility, Psychomotor Speed). In addition, Minnesota Multiphasic Personality Inventories of exposed workers indicated clinically significant levels of depression, anxiety, somatic concerns and disturbances in thinking. The reported psychological distress was unrelated to degree of cognitive deficit. Finally, several exposure-related variables were associated with poorer performance on tests of memory and visuospatial ability.

  19. Beyond apoptosis: the mechanism and function of phosphatidylserine asymmetry in the membrane of activating mast cells.

    PubMed

    Rysavy, Noel M; Shimoda, Lori M N; Dixon, Alyssa M; Speck, Mark; Stokes, Alexander J; Turner, Helen; Umemoto, Eric Y

    2014-01-01

    Loss of plasma membrane asymmetry is a hallmark of apoptosis, but lipid bilayer asymmetry and loss of asymmetry can contribute to numerous cellular functions and responses that are independent of programmed cell death. Exofacial exposure of phosphatidylserine occurs in lymphocytes and mast cells after antigenic stimulation and in the absence of apoptosis, suggesting that there is a functional requirement for phosphatidylserine exposure in immunocytes. In this review we examine current ideas as to the nature of this functional role in mast cell activation. Mechanistically, there is controversy as to the candidate proteins responsible for phosphatidylserine translocation from the internal to external leaflet, and here we review the candidacies of mast cell PLSCR1 and TMEM16F. Finally we examine the potential relationship between functionally important mast cell membrane perturbations and phosphatidylserine exposure during activation.

  20. Beyond apoptosis: The mechanism and function of phosphatidylserine asymmetry in the membrane of activating mast cells

    PubMed Central

    Rysavy, Noel M.; Shimoda, Lori M. N.; Dixon, Alyssa M.; Speck, Mark; Stokes, Alexander J.; Turner, Helen; Umemoto, Eric Y.

    2014-01-01

    Loss of plasma membrane asymmetry is a hallmark of apoptosis, but lipid bilayer asymmetry and loss of asymmetry can contribute to numerous cellular functions and responses that are independent of programmed cell death. Exofacial exposure of phosphatidylserine occurs in lymphocytes and mast cells after antigenic stimulation and in the absence of apoptosis, suggesting that there is a functional requirement for phosphatidylserine exposure in immunocytes. In this review we examine current ideas as to the nature of this functional role in mast cell activation. Mechanistically, there is controversy as to the candidate proteins responsible for phosphatidylserine translocation from the internal to external leaflet, and here we review the candidacies of mast cell PLSCR1 and TMEM16F. Finally we examine the potential relationship between functionally important mast cell membrane perturbations and phosphatidylserine exposure during activation. PMID:25759911

  1. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes.

    PubMed

    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B; Rivkees, Scott A; Wendler, Christopher C

    2014-12-15

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20-60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3-65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes.

  2. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

    PubMed Central

    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

    2014-01-01

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

  3. Produced water exposure alters bacterial response to biocides.

    PubMed

    Vikram, Amit; Lipus, Daniel; Bibby, Kyle

    2014-11-04

    Microbial activity during the holding and reuse of wastewater from hydraulic fracturing operations, termed produced water, may lead to issues with corrosion, sulfide release, and fouling. Biocides are applied to control biological activity, often with limited efficacy, which is typically attributed to chemical interactions with the produced water. However, it is unknown whether there is a biologically driven mechanism to biocide tolerance in produced water. Here, we demonstrate that produced water exposure results in an enhanced tolerance against the typically used biocide glutaraldehyde and increased susceptibility to the oxidative biocide hypochlorite in a native and a model bacteria and that this altered resistance is due to the salinity of the produced water. In addition, we elucidate the genetic response of the model organism Pseudomonas fluorescens to produced water exposure to provide a mechanistic interpretation of the altered biocide resistance. The RNA-seq data demonstrated the induction of genes involved in osmotic stress, energy production and conversion, membrane integrity, and protein transport following produced water exposure, which facilitates bacterial survival and alters biocide tolerance. Efforts to fundamentally understand biocide resistance mechanisms, which enable the optimization of biocide application, hold significant implications for greening of the fracturing process through encouraging produced water recycling. Specifically, these results suggest the necessity of optimizing biocide application at the level of individual shale plays, rather than historical experience, based upon produced water characteristics and salinity.

  4. Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats

    PubMed Central

    Jolous-Jamshidi, Banafsheh; Cromwell, Howard C.; McFarland, Ashley M.; Meserve, Lee A.

    2014-01-01

    Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation–dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders. PMID:20813172

  5. Apical phosphatidylserine externalization in auditory hair cells.

    PubMed

    Shi, Xiaorui; Gillespie, Peter G; Nuttall, Alfred L

    2007-01-01

    In hair cells of the inner ear, phosphatidylserine (PS), detected with fluorescent annexin V labeling, was rapidly exposed on the external leaflet of apical plasma membranes upon dissection of the organ of Corti. PS externalization was unchanged by caspase inhibition, suggesting that externalization did not portend apoptosis or necrosis. Consistent with that conclusion, mitochondrial membrane potential and hair-cell nuclear structure remained normal during externalization. PS externalization was triggered by forskolin, which raises cAMP, and blocked by inhibitors of adenylyl cyclase. Blocking Na(+) influx by inhibiting the mechanoelectrical transduction channels and P2X ATP channels also inhibited external PS externalization. Diminished PS externalization was also seen in cells exposed to LY 294002, which blocks membrane recycling in hair cells by inhibiting phosphatidylinositol 3-kinase. These results indicate that PS exposure on the external leaflet, presumably requiring vesicular transport, results from elevation of intracellular cAMP, which can be triggered by Na(+) entry into hair cells.

  6. Prenatal exposure to MDMA alters noradrenergic neurodevelopment in the rat

    PubMed Central

    Thompson, V.B.; Koprich, J.B.; Chen, E.Y.; Kordower, J.H.; Terpstra, B.; Lipton, J.W.

    2011-01-01

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) binds with high affinity to the norepinephrine transporter (NET), making the noradrenergic system a potential target during fetal exposure. Recent data indicates that adult rats that had been prenatally exposed to MDMA display persistent deficits in working memory and attention; behaviors consistent with abnormal noradrenergic signaling in the forebrain. The present study was designed to investigate whether prenatal exposure to MDMA from embryonic days 14–20 affects the structure and/or function of the noradrenergic system of the rat on postnatal day 21. Offspring that were prenatally exposed to MDMA exhibited an increase in noradrenergic fiber density in the prelimbic region of the prefrontal cortex and the CA1 region of the hippocampus that was not accompanied by an increase in the number of noradrenergic neurons in the locus coeruleus. Direct tissue autoradiography using tritiated nisoxetine demonstrated that while NET binding was not altered in the prelimbic cortex, the dentate gyrus, or the locus coeruleus, it was increased in the CA1, CA2, and CA3 regions of the hippocampus. Basal levels of norepinephrine were increased in the prefrontal cortex and the nucleus accumbens of MDMA-exposed rats, as compared to saline-treated controls. These findings indicate that prenatal exposure to MDMA results in structural changes in the noradrenergic system as well as functional alterations in NE neurotransmission in structures that are critical in attentional processing. PMID:21978916

  7. Tributyltin exposure alters cytokine levels in mouse serum.

    PubMed

    Lawrence, Shanieek; Pellom, Samuel T; Shanker, Anil; Whalen, Margaret M

    2016-11-01

    Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, keratinocyte chemoattractant (KC), macrophage inflammatory protein 1β (MIP), MIP2 and regulated on activation normal T-cell-expressed and secreted (RANTES) was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40 and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in the serum of mice exposed to TBT for less than 24 h. Levels of IL1β, IL-12 βp40, IL-5 and IL-15 were also modulated in mouse serum, depending on the specific experiment and exposure level. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines.

  8. Radiation Exposure Alters Expression of Metabolic Enzyme Genes In Mice

    NASA Technical Reports Server (NTRS)

    Wotring, Virginia E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2010-01-01

    Most pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Because of the importance of the liver in drug metabolism it is important to understand the effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. This study is an effort to examine the effects of adaptive mechanisms that may be triggered by early exposure to low radiation doses. Using procedures approved by the JSC Animal Care & Use Committee, C57 male mice were exposed to Cs-137 in groups: controls, low dose (50 mGy), high dose (6Gy) and a fourth group that received both radiation doses separated by 24 hours. Animals were anesthetized and sacrificed 4 hours after their last radiation exposure. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted and purified (Absolutely RNA, Agilent). Quality of RNA samples was evaluated (Agilent Bioanalyzer 2100). Complementary DNA was prepared from high-quality RNA samples, and used to run RT-qPCR screening arrays for DNA Repair and Drug Metabolism (SuperArray, SABiosciences/Qiagen; BioRad Cfx96 qPCR System). Of 91 drug metabolism genes examined, expression of 7 was altered by at least one treatment condition. Genes that had elevated expression include those that metabolize promethazine and steroids (4-8-fold), many that reduce oxidation products, and one that reduces heavy metal exposure (greater than 200-fold). Of the 91 DNA repair and general metabolism genes examined, expression of 14 was altered by at least one treatment condition. These gene expression changes are likely homeostatic and could lead to development of new radioprotective countermeasures.

  9. Vanadium exposure-induced neurobehavioral alterations among Chinese workers.

    PubMed

    Li, Hong; Zhou, Dinglun; Zhang, Qin; Feng, Chengyong; Zheng, Wei; He, Keping; Lan, Yajia

    2013-05-01

    Vanadium-containing products are manufactured and widely used in the modern industry. Yet the neurobehavioral toxicity due to occupational exposure to vanadium remained elusive. This cross-sectional study was designed to examine the neurotoxic effects of occupational vanadium exposure. A total of 463 vanadium-exposed workers (exposed group) and 251 non-exposed workers (control group) were recruited from a Steel and Iron Group in Sichuan, China. A WHO-recommended neurobehavioral core test battery (NCTB) and event-related auditory evoked potentials test (P300) were used to assess the neurobehavioral functions of all study subjects. A general linear model was used to compare outcome scores between the two groups while controlling for possible confounders. The exposed group showed a statistically significant neurobehavioral alteration more than the control group in the NCTB tests. The exposed workers also exhibited an increased anger-hostility, depression-dejection and fatigue-inertia on the profile of mood states (p<0.05). Performances in the simple reaction time, digit span, benton visual retention and pursuit aiming were also poorer among exposed workers as compared to unexposed control workers (p<0.05). Some of these poor performances in tests were also significantly related to workers' exposure duration. P300 latencies were longer in the exposed group than in the control (p<0.05). Longer mean reaction times and more counting errors were also found in the exposed workers (p<0.05). Given the findings of our study and the limitations of neurobehavioral workplace testing, we found evidence of altered neurobehavioral outcomes by occupational exposure to vanadium.

  10. Altering user' acceptance of automation through prior automation exposure.

    PubMed

    Bekier, Marek; Molesworth, Brett R C

    2016-08-22

    Air navigation service providers worldwide see increased use of automation as one solution to overcome the capacity constraints imbedded in the present air traffic management (ATM) system. However, increased use of automation within any system is dependent on user acceptance. The present research sought to determine if the point at which an individual is no longer willing to accept or cooperate with automation can be manipulated. Forty participants underwent training on a computer-based air traffic control programme, followed by two ATM exercises (order counterbalanced), one with and one without the aid of automation. Results revealed after exposure to a task with automation assistance, user acceptance of high(er) levels of automation ('tipping point') decreased; suggesting it is indeed possible to alter automation acceptance. Practitioner Summary: This paper investigates whether the point at which a user of automation rejects automation (i.e. 'tipping point') is constant or can be manipulated. The results revealed after exposure to a task with automation assistance, user acceptance of high(er) levels of automation decreased; suggesting it is possible to alter automation acceptance.

  11. Embryonic ethanol exposure alters synaptic properties at zebrafish neuromuscular junctions.

    PubMed

    Sylvain, Nicole J; Brewster, Daniel L; Ali, Declan W

    2011-01-01

    Pre-natal alcohol exposure induces delays in fine and gross motor skills, and deficiencies in reflex development via mechanisms that remain to be elucidated. The purpose of the present study was to investigate the effect of embryonic ethanol exposure (16-hour exposure window with 1.5%, 2% or 2.5% EtOH) on synaptic properties at the neuromuscular junction (NMJ) in 3 day post fertilization (dpf) zebrafish larvae. Immunohistochemical studies show that exposure of embryos to 2.5% ethanol for 16 h results in motor neuron axons that display abnormal branching patterns. Co-labelling embryos with pre-synaptic markers such as SV-2 or 3A10, and the post-synaptic marker, α-bungarotoxin, which irreversibly binds to nicotinic acetylcholine receptors (nAChRs), indicates that pre- and post-synaptic sites are properly aligned even when motor neuron axons display abnormal morphology. Miniature endplate currents (mEPCs) recorded from muscle fibers revealed the presence of two types of mEPCs that we dubbed fast and slow. Ethanol treated fish experienced significant changes in the frequencies of fast and slow mEPCs, and an increase in the rise time of slow mEPCs recorded from red muscle fibers. Additionally, embryonic exposure to ethanol resulted in a significant increase in the decay time of fast mEPCs recorded from white fibers. Mean mEPC amplitude was unaffected by ethanol treatment. Together, these results indicate that zebrafish embryos exposed to ethanol may experience altered synaptic properties at the NMJ.

  12. Arsenic exposure to killifish during embryogenesis alters muscle development.

    PubMed

    Gaworecki, Kristen M; Chapman, Robert W; Neely, Marion G; D'Amico, Angela R; Bain, Lisa J

    2012-02-01

    Epidemiological studies have correlated arsenic exposure in drinking water with adverse developmental outcomes such as stillbirths, spontaneous abortions, neonatal mortality, low birth weight, delays in the use of musculature, and altered locomotor activity. Killifish (Fundulus heteroclitus) were used as a model to help to determine the mechanisms by which arsenic could impact development. Killifish embryos were exposed to three different sodium arsenite concentrations and were collected at 32 h post-fertilization (hpf), 42 hpf, 168 hpf, or < 24 h post-hatch. A killifish oligo microarray was developed and used to examine gene expression changes between control and 25-ppm arsenic-exposed hatchlings. With artificial neural network analysis of the transcriptomic data, accurate prediction of each group (control vs. arsenic-exposed embryos) was obtained using a small subset of only 332 genes. The genes differentially expressed include those involved in cell cycle, development, ubiquitination, and the musculature. Several of the genes involved in cell cycle regulation and muscle formation, such as fetuin B, cyclin D-binding protein 1, and CapZ, were differentially expressed in the embryos in a time- and dose-dependent manner. Examining muscle structure in the hatchlings showed that arsenic exposure during embryogenesis significantly reduces the average muscle fiber size, which is coupled with a significant 2.1- and 1.6-fold upregulation of skeletal myosin light and heavy chains, respectively. These findings collectively indicate that arsenic exposure during embryogenesis can initiate molecular changes that appear to lead to aberrant muscle formation.

  13. Dynamic adhesion of eryptotic erythrocytes to immobilized platelets via platelet phosphatidylserine receptors.

    PubMed

    Walker, Britta; Towhid, Syeda T; Schmid, Evi; Hoffmann, Sascha M; Abed, Majed; Münzer, Patrick; Vogel, Sebastian; Neis, Felix; Brucker, Sara; Gawaz, Meinrad; Borst, Oliver; Lang, Florian

    2014-02-01

    Glucose depletion of erythrocytes triggers suicidal erythrocyte death or eryptosis, which leads to cell membrane scrambling with phosphatidylserine exposure at the cell surface. Eryptotic erythrocytes adhere to endothelial cells by a mechanism involving phosphatidylserine at the erythrocyte surface and CXCL16 as well as CD36 at the endothelial cell membrane. Nothing has hitherto been known about an interaction between eryptotic erythrocytes and platelets, the decisive cells in primary hemostasis and major players in thrombotic vascular occlusion. The present study thus explored whether and how glucose-depleted erythrocytes adhere to platelets. To this end, adhesion of phosphatidylserine-exposing erythrocytes to platelets under flow conditions was examined in a flow chamber model at arterial shear rates. Platelets were immobilized on collagen and further stimulated with adenosine diphosphate (ADP, 10 μM) or thrombin (0.1 U/ml). As a result, a 48-h glucose depletion triggered phosphatidylserine translocation to the erythrocyte surface and augmented the adhesion of erythrocytes to immobilized platelets, an effect significantly increased upon platelet stimulation. Adherence of erythrocytes to platelets was blunted by coating of erythrocytic phosphatidylserine with annexin V or by neutralization of platelet phosphatidylserine receptors CXCL16 and CD36 with respective antibodies. In conclusion, glucose-depleted erythrocytes adhere to platelets. The adhesive properties of platelets are augmented by platelet activation. Erythrocyte adhesion to immobilized platelets requires phosphatidylserine at the erythrocyte surface and CXCL16 as well as CD36 expression on platelets. Thus platelet-mediated erythrocyte adhesion may foster thromboocclusive complications in diseases with stimulated phosphatidylserine exposure of erythrocytes.

  14. Seizures and antiepileptic drugs: does exposure alter normal brain development?

    PubMed

    Marsh, Eric D; Brooks-Kayal, Amy R; Porter, Brenda E

    2006-12-01

    Seizures and antiepileptic drugs (AEDs) affect brain development and have long-term neurological consequences. The specific molecular and cellular changes, the precise timing of their influence during brain development, and the full extent of the long-term consequences of seizures and AEDs exposure have not been established. This review critically assesses both the basic and clinical science literature on the effects of seizures and AEDs on the developing brain and finds that evidence exists to support the hypothesis that both seizures and antiepileptic drugs influence a variety of biological process, at specific times during development, which alter long-term cognition and epilepsy susceptibility. More research, both clinical and experimental, is needed before changes in current clinical practice, based on the scientific data, can be recommended.

  15. Prenatal alcohol exposure alters the patterns of facial asymmetry.

    PubMed

    Klingenberg, C P; Wetherill, L; Rogers, J; Moore, E; Ward, R; Autti-Rämö, I; Fagerlund, A; Jacobson, S W; Robinson, L K; Hoyme, H E; Mattson, S N; Li, T K; Riley, E P; Foroud, T

    2010-01-01

    Directional asymmetry, the systematic differences between the left and right body sides, is widespread in human populations. Changes in directional asymmetry are associated with various disorders that affect craniofacial development. Because facial dysmorphology is a key criterion for diagnosing fetal alcohol syndrome (FAS), the question arises whether in utero alcohol exposure alters directional asymmetry in the face. Data on the relative position of 17 morphologic landmarks were obtained from facial scans of children who were classified as either FAS or control. Shape data obtained from the landmarks were analyzed with the methods of geometric morphometrics. Our analyses showed significant directional asymmetry of facial shape, consisting primarily of a shift of midline landmarks to the right and a displacement of the landmarks around the eyes to the left. The asymmetry of FAS and control groups differed significantly and average directional asymmetry was increased in those individuals exposed to alcohol in utero. These results suggest that the developmental consequences of fetal alcohol exposure affect a wide range of craniofacial features in addition to those generally recognized and used for diagnosis of FAS.

  16. Use of Autoantigen-Loaded Phosphatidylserine-Liposomes to Arrest Autoimmunity in Type 1 Diabetes

    PubMed Central

    Pujol-Autonell, Irma; Serracant-Prat, Arnau; Cano-Sarabia, Mary; Ampudia, Rosa M.; Rodriguez-Fernandez, Silvia; Sanchez, Alex; Izquierdo, Cristina; Stratmann, Thomas; Puig-Domingo, Manuel; Maspoch, Daniel; Verdaguer, Joan; Vives-Pi, Marta

    2015-01-01

    Introduction The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes. Objective To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes. Methods A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides. Results We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion. Conclusions We conclude that this innovative immunotherapy based on the use of liposomes

  17. Hyperoxia exposure alters hepatic eicosanoid metabolism in newborn mice.

    PubMed

    Rogers, Lynette K; Tipple, Trent E; Britt, Rodney D; Welty, Stephen E

    2010-02-01

    Prematurely born infants are often treated with supraphysiologic amounts of oxygen, which is associated with lung injury and the development of diseases such as bronchopulmonary dysplasia. Complimentary responses between the lung and liver during the course of hyperoxic lung injury have been studied in adult animals, but little is known about this relationship in neonates. These studies tested the hypothesis that oxidant stress occurs in the livers of newborn mice in response to continuous hyperoxia exposure. Greater levels of glutathione disulfide and nitrotyrosine were detected in lung tissues but not liver tissues from newborn mice exposed to hyperoxia than in room air-exposed controls. However, early increases in 5-lipoxygenase and cyclooxygenases-2 protein levels and increases in total hydroxyeicosatetraenoic acid and prostaglandin levels were observed in the liver tissues of hyperoxia-exposed pups. These studies indicate that free radical oxidation occurs in the lungs of newborn pups exposed to hyperoxia, and alterations in lipid metabolism could be a primary response in the liver tissues. The findings of this study identify possible new mechanisms associated with hyperoxic lung injury in a newborn model of bronchopulmonary dysplasia and thus open opportunities for research.

  18. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes.

    PubMed

    Fadok, V A; Bratton, D L; Frasch, S C; Warner, M L; Henson, P M

    1998-07-01

    Exposure of phosphatidylserine on the outer leaflet of the plasma membrane is a surface change common to many apoptotic cells. Normally restricted to the inner leaflet, phosphatidylserine appears as a result of decreased aminophospholipid translocase activity and activation of a calcium-dependent scramblase. Phosphatidylserine exposure has several potential biological consequences, one of which is recognition and removal of the apoptotic cell by phagocytes. It is still not clear which receptors mediate PS recognition on apoptotic cells; however, several interesting candidates have been proposed. These include the Class B scavenger and thrombospondin receptor CD36, an oxLDL receptor (CD68), CD14, annexins, beta2 glycoprotein I, gas-6 and a novel activity expressed on macrophages stimulated with digestible particles such as beta-glucan. Whether PS is the sole ligand recognized by phagocytes or whether it associated with other molecules to form a complex ligand remains to be determined.

  19. Phosphatidylserine dynamics in cellular membranes.

    PubMed

    Kay, Jason G; Koivusalo, Mirkka; Ma, Xiaoxiao; Wohland, Thorsten; Grinstein, Sergio

    2012-06-01

    Much has been learned about the role of exofacial phosphatidylserine (PS) in apoptosis and blood clotting using annexin V. However, because annexins are impermeant and unable to bind PS at low calcium concentration, they are unsuitable for intracellular use. Thus little is known about the topology and dynamics of PS in the endomembranes of normal cells. We used two new probes-green fluorescent protein (GFP)-LactC2, a genetically encoded fluorescent PS biosensor, and 1-palmitoyl-2-(dipyrrometheneboron difluoride)undecanoyl-sn-glycero-3-phospho-L-serine (TopFluor-PS), a synthetic fluorescent PS analogue-to examine PS distribution and dynamics inside live cells. The mobility of PS was assessed by a combination of advanced optical methods, including single-particle tracking and fluorescence correlation spectroscopy. Our results reveal the existence of a sizable fraction of PS with limited mobility, with cortical actin contributing to the confinement of PS in the plasma membrane. We were also able to measure the dynamics of PS in endomembrane organelles. By targeting GFP-LactC2 to the secretory pathway, we detected the presence of PS in the luminal leaflet of the endoplasmic reticulum. Our data provide new insights into properties of PS inside cells and suggest mechanisms to account for the subcellular distribution and function of this phospholipid.

  20. Differential roles of tissue factor and phosphatidylserine in activation of coagulation.

    PubMed

    Spronk, Henri M H; ten Cate, Hugo; van der Meijden, Paola E J

    2014-05-01

    It has been suggested that the main physiological trigger of coagulation, tissue factor, possesses limited procoagulant activity and occurs in an inactive or so-called encrypted state. For the conversion of encrypted into decrypted tissue factor with sufficient procoagulant activity, four distinct models have been proposed: 1; dimer formation, 2; lipid rafts, 3; disulfide bonds, and 4; phosphatidylserine exposure. Pro and cons can be given for each of these mechanisms of tissue factor encryption/decryption, however, it seems most likely that two or more mechanisms act together in activating the procoagulant activity. The exposure of phosphatidylserine in the outer layer of cell membranes supports coagulation through enhanced formation of the tenase (factors IXa, VIIIa and X) and prothrombinase (factors Xa, Va and prothrombin) complexes. The proposed role for phosphatidylserine in decryption of tissue factor could contribute to the correct orientation of the tissue factor - factor VII complex. Overall, the contribution of both tissue factor and phosphatidylserine to coagulation seems distinct with tissue factor being the physiological activator and phosphatidylserine the driving force of propagation of coagulation.

  1. Phosphatidylserine biosynthesis in cultured Chinese hamster ovary cells. I. Inhibition of de novo phosphatidylserine biosynthesis by exogenous phosphatidylserine and its efficient incorporation

    SciTech Connect

    Nishijima, M.; Kuge, O.; Akamatsu, Y.

    1986-05-05

    The effect of phosphatidylserine exogenously added to the medium on de novo biosynthesis of phosphatidylserine was investigated in cultured Chinese hamster ovary cells. When cells were cultured for several generations in medium supplemented with phosphatidylserine and /sup 32/Pi, the incorporation of /sup 32/Pi into cellular phosphatidylserine was remarkably inhibited, the degree of inhibition being dependent upon the concentration of added phosphatidylserine. /sup 32/Pi uptake into cellular phosphatidylethanolamine was also partly reduced by the addition of exogenous phosphatidylserine, consistent with the idea that phosphatidylethanolamine is biosynthesized via decarboxylation of phosphatidylserine. However, incorporation of /sup 32/Pi into phosphatidylcholine, sphingomyelin, and phosphatidylinositol was not significantly affected. In contrast, the addition of either phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, or phosphatidylinositol to the medium did not inhibit endogenous biosynthesis of the corresponding phospholipid. Radiochemical and chemical analyses of the cellular phospholipid composition revealed that phosphatidylserine in cells grown with 80 microM phosphatidylserine was almost entirely derived from the added phospholipid. Phosphatidylserine uptake was also directly determined by using (/sup 3/H)serine-labeled phospholipid. Pulse and pulse-chase experiments with L-(U-/sup 14/C) serine showed that when cells were cultured with 80 microM phosphatidylserine, the rate of synthesis of phosphatidylserine was reduced 3-5-fold. Enzyme assaying of extracts prepared from cells grown with and without phosphatidylserine indicated that the inhibition of de novo phosphatidylserine biosynthesis by the added phosphatidylserine appeared not to be caused by a reduction in the level of the enzyme involved in the base-exchange reaction between phospholipids and serine.

  2. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FAILS TO ALTER BRAINSTEM AUDITORY EVOKED RESPONSE (BAERS) IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in auditory structures in the periphery and the brainstem and is altered following chlorpyrifos exposure. This study e...

  3. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FAILS TO ALTER FLASH OR PATTERN REVERSAL EVOKED POTENTIALS IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Visual disturbances are often reported following exposure to xenobiotics, and cholinesterase-inhibiting compounds have been reported to alter visual functi...

  4. Host Cell Plasma Membrane Phosphatidylserine Regulates the Assembly and Budding of Ebola Virus

    PubMed Central

    Adu-Gyamfi, Emmanuel; Johnson, Kristen A.; Fraser, Mark E.; Scott, Jordan L.; Soni, Smita P.; Jones, Keaton R.; Digman, Michelle A.; Gratton, Enrico; Tessier, Charles R.

    2015-01-01

    ABSTRACT Lipid-enveloped viruses replicate and bud from the host cell where they acquire their lipid coat. Ebola virus, which buds from the plasma membrane of the host cell, causes viral hemorrhagic fever and has a high fatality rate. To date, little has been known about how budding and egress of Ebola virus are mediated at the plasma membrane. We have found that the lipid phosphatidylserine (PS) regulates the assembly of Ebola virus matrix protein VP40. VP40 binds PS-containing membranes with nanomolar affinity, and binding of PS regulates VP40 localization and oligomerization on the plasma membrane inner leaflet. Further, alteration of PS levels in mammalian cells inhibits assembly and egress of VP40. Notably, interactions of VP40 with the plasma membrane induced exposure of PS on the outer leaflet of the plasma membrane at sites of egress, whereas PS is typically found only on the inner leaflet. Taking the data together, we present a model accounting for the role of plasma membrane PS in assembly of Ebola virus-like particles. IMPORTANCE The lipid-enveloped Ebola virus causes severe infection with a high mortality rate and currently lacks FDA-approved therapeutics or vaccines. Ebola virus harbors just seven genes in its genome, and there is a critical requirement for acquisition of its lipid envelope from the plasma membrane of the human cell that it infects during the replication process. There is, however, a dearth of information available on the required contents of this envelope for egress and subsequent attachment and entry. Here we demonstrate that plasma membrane phosphatidylserine is critical for Ebola virus budding from the host cell plasma membrane. This report, to our knowledge, is the first to highlight the role of lipids in human cell membranes in the Ebola virus replication cycle and draws a clear link between selective binding and transport of a lipid across the membrane of the human cell and use of that lipid for subsequent viral entry. PMID

  5. FINE PARTICLE EXPOSURE IS ASSOCIATED WITH ALTERED VENTRICULAR REPOLARIZATION

    EPA Science Inventory

    Exposure to fine airborne particulate matter (PM2.5) has previously been associated with cardiac events, especially in older people with cardiovascular disease and in diabetics. This study examined the cardiac effects of short-term exposures to ambient PM2.5 in a prospective pane...

  6. Efficient synthesis of phosphatidylserine in 2-methyltetrahydrofuran.

    PubMed

    Duan, Zhang-Qun; Hu, Fei

    2013-01-10

    2-Methyltetrahydrofuran has recently been described as a promising and green solvent. Herein, it was successfully used as the reaction medium for enzyme-mediated transphosphatidylation of phosphatidylcholine with L-serine with the aim of phosphatidylserine synthesis for the first time. Our results indicated that as high as 90% yield of phosphatidylserine could be achieved after 12 h combined with no byproduct (phosphatidic acid) forming. The present work accommodated a facilely and efficiently enzymatic strategy for preparing phosphatidylserine, which possessed obvious advantages over the reported processes in terms of high efficiency and environmental friendliness. This work is also a proof-of-concept opening the use of 2-methyltetrahydrofuran in biosynthesis as well.

  7. In utero and postnatal exposure to arsenic alters pulmonary structure and function

    SciTech Connect

    Lantz, R. Clark Chau, Binh; Sarihan, Priyanka; Witten, Mark L.; Pivniouk, Vadim I.; Chen, Guan Jie

    2009-02-15

    In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 {mu}m in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.

  8. Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring

    PubMed Central

    Vallaster, Markus P; Kukreja, Shweta; Bing, Xin Y; Ngolab, Jennifer; Zhao-Shea, Rubing; Gardner, Paul D; Tapper, Andrew R; Rando, Oliver J

    2017-01-01

    Paternal environmental conditions can influence phenotypes in future generations, but it is unclear whether offspring phenotypes represent specific responses to particular aspects of the paternal exposure history, or a generic response to paternal ‘quality of life’. Here, we establish a paternal effect model based on nicotine exposure in mice, enabling pharmacological interrogation of the specificity of the offspring response. Paternal exposure to nicotine prior to reproduction induced a broad protective response to multiple xenobiotics in male offspring. This effect manifested as increased survival following injection of toxic levels of either nicotine or cocaine, accompanied by hepatic upregulation of xenobiotic processing genes, and enhanced drug clearance. Surprisingly, this protective effect could also be induced by a nicotinic receptor antagonist, suggesting that xenobiotic exposure, rather than nicotinic receptor signaling, is responsible for programming offspring drug resistance. Thus, paternal drug exposure induces a protective phenotype in offspring by enhancing metabolic tolerance to xenobiotics. DOI: http://dx.doi.org/10.7554/eLife.24771.001 PMID:28196335

  9. Developmental timing of perchlorate exposure alters threespine stickleback dermal bone

    PubMed Central

    Furin, Christoff G.; von Hippel, Frank A.; Postlethwait, John; Buck, C. Loren; Cresko, William A.; O’Hara, Todd M.

    2015-01-01

    Adequate levels of thyroid hormone are critical during development and metamorphosis, and for maintaining metabolic homeostasis. Perchlorate, a common contaminant of water sources, inhibits thyroid function in vertebrates. We utilized threespine stickleback (Gasterosteus aculeatus) to determine if timing of perchlorate exposure during development impacts adult dermal skeletal phenotypes. Fish were exposed to water contaminated with perchlorate (30 mg/L or 100 mg/L) beginning at 0, 3, 7, 14, 21, 42, 154 or 305 days post fertilization until sexual maturity at one year of age. A reciprocal treatment moved stickleback from contaminated to clean water on the same schedule providing for different stages of initial exposure and different treatment durations. Perchlorate exposure caused concentration-dependent significant differences in growth for some bony traits. Continuous exposure initiated within the first 21 days post fertilization had the greatest effects on skeletal traits. Exposure to perchlorate at this early stage can result in small traits or abnormal skeletal morphology of adult fish which could affect predator avoidance and survival. PMID:25753171

  10. Specific stabilization of CFTR by phosphatidylserine.

    PubMed

    Hildebrandt, Ellen; Khazanov, Netaly; Kappes, John C; Dai, Qun; Senderowitz, Hanoch; Urbatsch, Ina L

    2017-02-01

    The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR, ABCC7) is a plasma membrane chloride ion channel in the ABC transporter superfamily. CFTR is a key target for cystic fibrosis drug development, and its structural elucidation would advance those efforts. However, the limited in vivo and in vitro stability of the protein, particularly its nucleotide binding domains, has made structural studies challenging. Here we demonstrate that phosphatidylserine uniquely stimulates and thermally stabilizes the ATP hydrolysis function of purified human CFTR. Among several lipids tested, the greatest stabilization was observed with brain phosphatidylserine, which shifted the Tm for ATPase activity from 22.7±0.8°C to 35.0±0.2°C in wild-type CFTR, and from 26.6±0.7°C to 42.1±0.2°C in a more stable mutant CFTR having deleted regulatory insertion and S492P/A534P/I539T mutations. When ATPase activity was measured at 37°C in the presence of brain phosphatidylserine, Vmax for wild-type CFTR was 240±60nmol/min/mg, a rate higher than previously reported and consistent with rates for other purified ABC transporters. The significant thermal stabilization of CFTR by phosphatidylserine may be advantageous in future structural and biophysical studies of CFTR.

  11. Acute Exposure to Particulate Matter (PM) Alters Physiologic ...

    EPA Pesticide Factsheets

    Human exposure to ambient PM from fossil-fuel emissions is linked to cardiovascular disease and death. This association strengthens in people with preexisting cardiopulmonary diseases—especially heart failure (HF). We previously examined the effects of PM on HF by exposing Spontaneously Hypertensive Heart Failure (SHHF) rats to residual oil fly ash (ROFA) after accelerating HF onset via isoproterenol (ISO) infusion. In that study, rats were exposed to PM 2 wks after ISO treatment ceased, which was more than 1 wk after ISO-cessation had induced a 9-d period of hypotension. Epidemiological evidence suggests that effects would be more pronounced if exposure coincided with the HF-like hypotensive period. We hypothesized that PM exposure shortly after cessation of ISO treatment would cause greater cardiopulmonary injury. SHHF rats were infused with ISO (n=24; 1.0 mg/kg/d sc) or saline (n=23) via osmotic pump for 5 wks and then 5 d later exposed by nose-only inhalation for 4 h to either air or 580 µg/m3 of the PM2.5 fraction of a synthetic PM (dried salt solution, MSO4) similar in composition to a well-studied ROFA and consisting of Fe, Ni and V sulfates. In ISO-pretreated rats only, MSO4 decreased pulse pressure (an indirect indicator of cardiac output), decreased systolic and diastolic blood pressures, and increased QA interval (inversely related to myocardial contractility) during inhalation exposure and caused post-inhalation pulmonary inflammation significantl

  12. Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice

    NASA Technical Reports Server (NTRS)

    Wotring, V. E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2011-01-01

    Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.

  13. Acute neuroactive drug exposures alter locomotor activity in larval zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA's prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after exposure to prototypic drugs that act on the central nervous system. MPTP (1-methyl-4phenyl- 1 ,2,3,6-...

  14. EXPOSURE OF CULTURED MYOCYTES TO ZINC RESULTS IN ALTERED BEAT RATE AND INTERCELLULAR COMMUNICATION.

    EPA Science Inventory

    Exposure of cultured myocytes to zinc results in altered beat rate and intercellular communication

    Graff, Donald W, Devlin, Robert B, Brackhan, Joseph A, Muller-Borer, Barbara J, Bowman, Jill S, Cascio, Wayne E.

    Exposure to ambient air pollution particulate matter (...

  15. ACUTE EXPOSURE TO MOLINATE ALTERS NEUROENDOCRINE CONTROL OF OVULATION IN THE RAT

    EPA Science Inventory

    Molinate, a thiocarbamate herbicide, has been shown previously to impair reproductive capability in the male rat. In a two-generation study, molinate exposure to female rats resulted in altered pregnancy outcome. However, published data is lacking on the effects of acute exposure...

  16. Prenatal cadmium exposure alters postnatal immune cell development and function

    SciTech Connect

    Hanson, Miranda L.; Holásková, Ida; Elliott, Meenal; Brundage, Kathleen M.; Schafer, Rosana; Barnett, John B.

    2012-06-01

    Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl{sub 2} (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4{sup +}FoxP3{sup +}CD25{sup +} (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8{sup +}CD223{sup +} T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can

  17. Phosphatidylserine biosynthesis in cultured Chinese hamster ovary cells. II. Isolation and characterization of phosphatidylserine auxotrophs

    SciTech Connect

    Kuge, O.; Nishijima, M.; Akamatsu, Y.

    1986-05-05

    Chinese hamster ovary (CHO) cell mutants that required exogenously added phosphatidylserine for cell growth were isolated by using the replica technique with polyester cloth, and three such mutants were characterized. Labeling experiments on intact cells with /sup 32/Pi and L-(U-/sup 14/C)serine revealed that a phosphatidylserine auxotroph, designated as PSA-3, was strikingly defective in phosphatidylserine biosynthesis. When cells were grown for 2 days without phosphatidylserine, the phosphatidylserine content of PSA-3 was about one-third of that of the parent. In extracts of the mutant, the enzymatic activity of the base-exchange reaction of phospholipids with serine producing phosphatidylserine was reduced to 33% of that in the parent; in addition, the activities of base-exchange reactions of phospholipids with choline and ethanolamine in the mutant were also reduced to 1 and 45% of those in the parent, respectively. Furthermore, it was demonstrated that the serine-exchange activity in the parent was inhibited approximately 60% when choline was added to the reaction mixture whereas that in the mutant was not significantly affected. From the results presented here, we conclude the following. There are at least two kinds of serine-exchange enzymes in CHO cells; one (serine-exchange enzyme I) can catalyze the base-exchange reactions of phospholipids with serine, choline, and ethanolamine while the other (serine-exchange enzyme II) does not use the choline as a substrate. Serine-exchange enzyme I, in which mutant PSA-3 is defective, plays a major role in phosphatidylserine biosynthesis in CHO cells. Serine-exchange enzyme I is essential for the growth of CHO cells.

  18. Exposure to bisphenol A in young adult mice does not alter ovulation but does alter the fertilization ability of oocytes.

    PubMed

    Moore-Ambriz, Teresita Rocio; Acuña-Hernández, Deyanira Guadalupe; Ramos-Robles, Brenda; Sánchez-Gutiérrez, Manuel; Santacruz-Márquez, Ramsés; Sierra-Santoyo, Adolfo; Piña-Guzmán, Belem; Shibayama, Mineko; Hernández-Ochoa, Isabel

    2015-12-15

    Follicle growth culminates in ovulation, which allows for the expulsion of fertilizable oocytes and the formation of corpora lutea. Bisphenol A (BPA) is present in many consumer products, and it has been suggested that BPA impairs ovulation; however, the underlying mechanisms are unknown. Therefore, this study first evaluated whether BPA alters ovulation by affecting folliculogenesis, the number of corpora lutea or eggs shed to the oviduct, ovarian gonadotropin responsiveness, hormone levels, and estrous cyclicity. Because it has been suggested (but not directly confirmed) that BPA exerts toxic effects on the fertilization ability of oocytes, a second aim was to evaluate whether BPA impacts the oocyte fertilization rate using an in vitro fertilization assay and mating. The possible effects on early zygote development were also examined. Young adult female C57BL/6J mice (39 days old) were orally dosed with corn oil (vehicle) or 50 μg/kgbw/day BPA for a period encompassing the first three reproductive cycles (12-15 days). BPA exposure did not alter any parameters related to ovulation. Moreover, BPA exposure reduced the percentage of fertilized oocytes after either in vitro fertilization or mating, but it did not alter the zygotic stages. The data indicate that exposure to the reference dose of BPA does not impact ovulation but that it does influence the oocyte quality in terms of its fertilization ability.

  19. Millimeter wave induced reversible externalization of phosphatidylserine molecules in cells exposed in vitro.

    PubMed

    Szabo, Imre; Kappelmayer, Janos; Alekseev, Stanislav I; Ziskin, Marvin C

    2006-04-01

    In vitro exposure of refrigerated samples (4 degrees C) of anti-coagulated blood with millimeter waves (MMWs) at incident power densities (IPDs) between 0.55 and 1.23 W/cm2 has been found to induce clot formation. We found a small but statistically significant change in clot size with increasing IPD value. MMW exposure of blood samples starting at room temperature (22 degrees C) did not induce blood coagulation; neither did conventional heating at temperatures up to 40 degrees C. Since cell-free plasma did not clot upon MMW exposure, the role of blood cells was particularly analyzed. Experiments on various mixtures of blood cells with plasma revealed an important role of red blood cells (RBC) in the coagulation process. Plasma coagulation also developed within the MMW beam above dense keratinocyte (HaCaT) monolayers suggesting it lacked cell-type specificity. We hypothesized that alteration of the membrane surface in exposed cells might be responsible for the circumscribed coagulation. The thrombogenic role of externalized phosphatidylserine (PS) molecules is well known. Therefore, we carried out experiments for immunolabeling PS molecules with fluorescein isothiocyanate (FITC)-conjugated Annexin V on exposed cells. Fluorescence microscopy of the adherent human keratinocytes (HaCaT) and murine melanoma cells (B16F10) showed that MMW exposure at an IPD of 1.23 W/cm2 is capable of inducing reversible externalization of PS molecules in cells within the beam area without detectable membrane damage. Nonadherent Jurkat cells exposed to MMW at an IPD of 34.5 mW/cm2 also showed reversible PS externalization with flow cytometry, whether the cell temperature was held constant or permitted to rise. These results suggest that certain biological effects induced by MMWs could be initiated by membrane changes in exposed cells.

  20. Alteration of catecholamine concentrations in rat testis after methamphetamine exposure.

    PubMed

    Janphet, S; Nudmamud-Thanoi, S; Thanoi, S

    2017-03-01

    Methamphetamine (METH) is an illicit drug that can lead to changes in catecholamines in the brain. It also has substantial effects on reproductive function. We investigated whether rat models of METH abuse could induce changes in the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), in testis. Four groups of rats received vehicle, acute dose (AB), escalating dose (ED) or ED with an acute high dose (ED-binge) METH. DOPAC, NE and DHPG were determined using HPLC. DOPAC was significantly increased in the AB while NE was significantly decreased in the ED-binge. DHPG was also significantly decreased in the ED and ED-binge. METH induces alterations of DOPAC, NE and DHPG testicular concentrations that may result in male reproductive dysfunction.

  1. Effect of prenatal haloperidol exposure on behavioral alterations in rats.

    PubMed

    Singh, K P; Singh, Mandavi

    2002-01-01

    Pregnant Charles-Foster rats were exposed to haloperidol (HAL), a neuroleptic drug that binds to and blocks dopamine (DA) receptor subtypes at a dose of 2.5 mg/kg body weight (intraperitoneally) from Gestation Day (GD) 12 to 20. The animals from both treated as well as vehicle control groups were allowed to deliver on GD 21. The offspring culled at birth on the basis of sex and weight were subjected to behavioral tests at the age of 8 weeks. The HAL-treated rat offspring showed a significant increase in anxiogenic behavior on the open field, elevated plus-maze and elevated zero-maze tests when compared with the vehicle-treated (control) rat offspring of the same age group. These findings suggest that prenatal exposure to HAL during a critical period of brain development leaves a lasting imprint on the brain, resulting in abnormal anxiety states, possibly through dopaminergic neurotransmission mechanisms.

  2. Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata.

    PubMed

    Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Jawna, Katarzyna; Pyrzanowska, Justyna; Piechal, Agnieszka; Wawer, Adriana; Widy-Tyszkiewicz, Ewa

    2015-09-01

    The effect and safety of prenatal and early life administration of paracetamol - routinely used over-the-counter antipyretic and analgesic medication on monoamines content and balance of amino acids in the medulla oblongata is still unknown. In this study we have determined the level of neurotransmitters in this structure in two-month old Wistar male rats exposed to paracetamol in the dose of 5 (P5, n=10) or 15mg/kg b.w. (P15, n=10) during prenatal period, lactation and till the end of the second month of life. Control group received drinking water (Con, n=10). Monoamines, their metabolites and amino acids concentration in medulla oblongata of rats were determined using high performance liquid chromatography (HPLC) in 60 postnatal day (PND60). This experiment shows that prenatal and early life paracetamol exposure modulates neurotransmission associated with serotonergic, noradrenergic and dopaminergic system in medulla oblongata. Reduction of alanine and taurine levels has also been established.

  3. Hurricane Sandy Exposure Alters the Development of Neural Reactivity to Negative Stimuli in Children.

    PubMed

    Kessel, Ellen M; Nelson, Brady D; Kujawa, Autumn; Hajcak, Greg; Kotov, Roman; Bromet, Evelyn J; Carlson, Gabrielle A; Klein, Daniel N

    2016-12-15

    This study examined whether exposure to Hurricane Sandy-related stressors altered children's brain response to emotional information. An average of 8 months (Mage  = 9.19) before and 9 months after (Mage  = 10.95) Hurricane Sandy, 77 children experiencing high (n = 37) and low (n = 40) levels of hurricane-related stress exposure completed a task in which the late positive potential, a neural index of emotional reactivity, was measured in response to pleasant and unpleasant, compared to neutral, images. From pre- to post-Hurricane Sandy, children with high stress exposure failed to show the same decrease in emotional reactivity to unpleasant versus neutral stimuli as those with low stress exposure. Results provide compelling evidence that exposure to natural disaster-related stressors alters neural emotional reactivity to negatively valenced information.

  4. Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations.

    PubMed

    Levin, Edward D; Addy, Nii; Baruah, Avanti; Elias, Alana; Christopher, N Channelle; Seidler, Frederic J; Slotkin, Theodore A

    2002-01-01

    Use of chlorpyrifos (CPF) has been curtailed due to its developmental neurotoxicity. In rats, postnatal CPF administration produces lasting changes in cognitive performance, but less information is available about the effects of prenatal exposure. We administered CPF to pregnant rats on gestational days (GD) 17-20, a peak period of neurogenesis, using doses (1 or 5 mg/kg/day) below the threshold for fetal growth impairment. We then evaluated performance in the T-maze, Figure-8 apparatus and 16-arm radial maze, beginning in adolescence and continuing into adulthood. CPF elicited initial locomotor hyperactivity in the T-maze. Females showed slower habituation in the Fig. 8 maze; no effects were seen in males. In the radial-arm maze, females showed impaired choice accuracy for both working and reference memory and again, males were unaffected. Despite the deficits, all animals eventually learned the maze with continued training. At that point, we challenged them with the muscarinic antagonist, scopolamine, to determine the dependence of behavioral performance on cholinergic function. Whereas control females showed impairment with scopolamine, CPF-exposed females did not, implying that the delayed acquisition of the task had been accomplished through alternative mechanisms. The differences were specific to muscarinic circuits, as control and CPF groups responded similarly to the nicotinic antagonist, mecamylamine. Surprisingly, adverse effects of CPF were greater in the group receiving 1 mg/kg as compared to 5 mg/kg. Promotional effects of acetylcholine (ACh) on cell differentiation may thus help to offset CPF-induced developmental damage that occurs through other noncholinergic mechanisms. Our results indicate that late prenatal exposure to CPF induces long-term changes in cognitive performance that are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus, uncovering the adaptive

  5. Phosphatidylserine in the brain: metabolism and function.

    PubMed

    Kim, Hee-Yong; Huang, Bill X; Spector, Arthur A

    2014-10-01

    Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear.

  6. Exposure to mercury alters early activation events in fish leukocytes.

    PubMed Central

    MacDougal, K C; Johnson, M D; Burnett, K G

    1996-01-01

    Although fish in natural populations may carry high body burdens of both organic and inorganic mercury, the effects of this divalent metal on such lower vertebrates is poorly understood. In this report, inorganic mercury in the form of mercuric chloride (HgCl2) is shown to produce both high-dose inhibition and low-dose activation of leukocytes in a marine teleost fish, Sciaenops ocellatus. Concentrations of inorganic mercury > or = 10 microM suppressed DNA synthesis and induced rapid influx of radiolabeled calcium, as well as tyrosine phosphorylation of numerous cellular proteins. Lower concentrations (0.1-1 microM) of HgCl2 that activated cell growth also induced a slow sustained rise in intracellular calcium in cells loaded with the calcium indicator dye fura-2, but did not produce detectable tyrosine phosphorylation of leukocyte proteins. These studies support the possibility that subtoxic doses of HgCl2 may inappropriately activate teleost leukocytes, potentially altering the processes that regulate the magnitude and specificity of the fish immune response to environmental pathogens. Images Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. PMID:8930553

  7. Exposure to high ambient temperatures alters embryology in rabbits

    NASA Astrophysics Data System (ADS)

    García, M. L.; Argente, M. J.

    2017-03-01

    High ambient temperatures are a determining factor in the deterioration of embryo quality and survival in mammals. The aim of this study was to evaluate the effect of heat stress on embryo development, embryonic size and size of the embryonic coats in rabbits. A total of 310 embryos from 33 females in thermal comfort zone and 264 embryos of 28 females in heat stress conditions were used in the experiment. The traits studied were ovulation rate, percentage of total embryos, percentage of normal embryos, embryo area, zona pellucida thickness and mucin coat thickness. Traits were measured at 24 and 48 h post-coitum (hpc); mucin coat thickness was only measured at 48 hpc. The embryos were classified as zygotes or two-cell embryos at 24 hpc, and 16-cells or early morulae at 48 hpc. The ovulation rate was one oocyte lower in heat stress conditions than in thermal comfort. Percentage of normal embryos was lower in heat stress conditions at 24 hpc (17.2%) and 48 hpc (13.2%). No differences in percentage of zygotes or two-cell embryos were found at 24 hpc. The embryo development and area was affected by heat stress at 48 hpc (10% higher percentage of 16-cells and 883 μm2 smaller, respectively). Zona pellucida was thicker under thermal stress at 24 hpc (1.2 μm) and 48 hpc (1.5 μm). No differences in mucin coat thickness were found. In conclusion, heat stress appears to alter embryology in rabbits.

  8. A new high-temperature transition of crystalline cholesterol in mixtures with phosphatidylserine.

    PubMed Central

    Epand, R M; Bach, D; Epand, R F; Borochov, N; Wachtel, E

    2001-01-01

    Phosphatidylserine and cholesterol are two major components of the cytoplasmic leaflet of the plasma membrane. The arrangement of cholesterol is markedly affected by the presence of phosphatidylserine in model membranes. At relatively low mol fractions of cholesterol in phosphatidylserine, compared with other phospholipids, cholesterol crystallites are formed that exhibit both thermotropic phase transitions as well as diffraction of x-rays. In the present study we have observed and characterized a novel thermotropic transition occurring in mixtures of phosphatidylserine and cholesterol. This new transition is observed at 96 degrees C by differential scanning calorimetry (DSC), using a heating scan rate of 2 degrees C/min. Observation of the transition requires that the hydrated lipid mixture be incubated for several days, depending on the temperature of incubation. The rate of formation of the material exhibiting a transition at 96 degrees C is more rapid at higher incubation temperatures. At 37 degrees C the half-time of conversion is approximately 7 days. Concomitant with the appearance of the 96 degrees C peak the previously known transitions of cholesterol, occurring at approximately 38 degrees C and 75 degrees C on heating scans of freshly prepared suspensions, disappear. These two transitions correspond to the polymorphic transition of anhydrous cholesterol and to the dehydration of cholesterol monohydrate, respectively. The loss of the 75 degrees C peak takes a longer time than that of the 38 degrees C peak, indicating that anhydrous cholesterol first gets hydrated to the monohydrate form exhibiting a transition at 75 degrees C and subsequently is converted by additional time of incubation to an altered form of the monohydrate, showing a phase transition at 96 degrees C. After several weeks of incubation at 37 degrees C, only the form with a phase transition at 96 degrees C remains. If such a sample undergoes several successive heating and cooling cycles

  9. Alteration of Rat Fetal Cerebral Cortex Development after Prenatal Exposure to Polychlorinated Biphenyls

    PubMed Central

    Naveau, Elise; Pinson, Anneline; Gérard, Arlette; Nguyen, Laurent; Charlier, Corinne; Thomé, Jean-Pierre; Zoeller, R. Thomas; Bourguignon, Jean-Pierre; Parent, Anne-Simone

    2014-01-01

    Polychlorinated biphenyls (PCBs) are environmental contaminants that persist in environment and human tissues. Perinatal exposure to these endocrine disruptors causes cognitive deficits and learning disabilities in children. These effects may involve their ability to interfere with thyroid hormone (TH) action. We tested the hypothesis that developmental exposure to PCBs can concomitantly alter TH levels and TH-regulated events during cerebral cortex development: progenitor proliferation, cell cycle exit and neuron migration. Pregnant rats exposed to the commercial PCB mixture Aroclor 1254 ended gestation with reduced total and free serum thyroxine levels. Exposure to Aroclor 1254 increased cell cycle exit of the neuronal progenitors and delayed radial neuronal migration in the fetal cortex. Progenitor cell proliferation, cell death and differentiation rate were not altered by prenatal exposure to PCBs. Given that PCBs remain ubiquitous, though diminishing, contaminants in human systems, it is important that we further understand their deleterious effects in the brain. PMID:24642964

  10. Alteration of rat fetal cerebral cortex development after prenatal exposure to polychlorinated biphenyls.

    PubMed

    Naveau, Elise; Pinson, Anneline; Gérard, Arlette; Nguyen, Laurent; Charlier, Corinne; Thomé, Jean-Pierre; Zoeller, R Thomas; Bourguignon, Jean-Pierre; Parent, Anne-Simone

    2014-01-01

    Polychlorinated biphenyls (PCBs) are environmental contaminants that persist in environment and human tissues. Perinatal exposure to these endocrine disruptors causes cognitive deficits and learning disabilities in children. These effects may involve their ability to interfere with thyroid hormone (TH) action. We tested the hypothesis that developmental exposure to PCBs can concomitantly alter TH levels and TH-regulated events during cerebral cortex development: progenitor proliferation, cell cycle exit and neuron migration. Pregnant rats exposed to the commercial PCB mixture Aroclor 1254 ended gestation with reduced total and free serum thyroxine levels. Exposure to Aroclor 1254 increased cell cycle exit of the neuronal progenitors and delayed radial neuronal migration in the fetal cortex. Progenitor cell proliferation, cell death and differentiation rate were not altered by prenatal exposure to PCBs. Given that PCBs remain ubiquitous, though diminishing, contaminants in human systems, it is important that we further understand their deleterious effects in the brain.

  11. PRENATAL EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE ALTERS GENE EXPRESSION IN THE DEVELOPING MURINE HIPPOCAMPUS

    PubMed Central

    Mukhopadhyay, Partha; Horn, Kristin H.; Greene, Robert M.; Pisano, M. Michele

    2010-01-01

    Background Little is known about the effects of passive smoke exposures on the developing brain. Objective The purpose of the current study was to identify changes in gene expression in the murine hippocampus as a consequence of in utero exposure to sidestream cigarette smoke (an experimental equivalent of environmental tobacco smoke (ETS)) at exposure levels that do not result in fetal growth inhibition. Methods A whole body smoke inhalation exposure system was utilized to deliver ETS to pregnant C57BL/6J mice for six hours/day from gestational days 6–17 (gd 6–17) [for microarray] or gd 6–18.5 [for fetal phenotyping]. Results There were no significant effects of ETS exposure on fetal phenotype. However, 61 “expressed” genes in the gd 18.5 fetal hippocampus were differentially regulated (up- or down-regulated by 1.5 fold or greater) by maternal exposure to ETS. Of these 61 genes, 25 genes were upregulated while 36 genes were downregulated. A systems biology approach, including computational methodologies, identified cellular response pathways, and biological themes, underlying altered fetal programming of the embryonic hippocampus by in utero cigarette smoke exposure. Conclusions Results from the present study suggest that even in the absence of effects on fetal growth, prenatal smoke exposure can alter gene expression during the “early” period of hippocampal growth and may result in abnormal hippocampal morphology, connectivity, and function. PMID:19969065

  12. Alterations in lung clearance mechanisms due to single and repeated nitrogen dioxide exposures in the rabbit

    SciTech Connect

    Vollmuth, T.A.

    1986-01-01

    Tracheobronchial mucociliary clearance was assessed following single, two-hour exposures to either 0.3, 1.0, 3.0, or 10.0 ppm NO/sub 2/, or 14 daily two hour exposures to 0.3, 1.0, 3.0 ppm NO/sub 2/. No significant changes in the mean residence time of tracer particles in the tracheobronchial region were produced under any exposure condition, indicating no effect upon mucociliary clearance. Macrophage functional properties were examined in vitro at select times following single, two hour in vivo exposures to 1.0 and 10.0 ppm NO/sub 2/. Macrophage number and viability were not affected; however, significant dose-related differences in phagocytosis and mobility were observed. These changes were associated with altered in vivo alveolar clearance patterns. Additional studies examined the effects of in vitro exposure to nitrite and hydrogen ion, two known NO/sub 2/ reaction products in the lung, on macrophage phagocytosis. While hydrogen ion had no effect at the levels used, nitrate was shown to enhance phagocytosis. These results demonstrate that alveolar clearance and macrophage function are altered by short-term NO/sub 2/ exposure at realistic, environmental levels. These data also provide insight into the mechanisms of NO/sub 2/-induced alteration in lung clearance pathways.

  13. FINE AMBIENT AIR PARTICULAR MATTER EXPOSURE INDUCES MOLECULAR ALTERATIONS INDICATIVE OF CARDIOVASCULAR DISEASE PROGRESSION IN ATHEROSCLEROTIC SUSCEPTIBLE MICE

    EPA Science Inventory

    Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...

  14. Low-dose, Chronic Exposure to Silver Nanoparticles Causes Mild Mitochondrial Alterations in the Liver of Sprague-Dawley Rat

    DTIC Science & Technology

    2014-05-10

    AFRL-AFOSR-UK-TR-2014-0032 Low-dose, chronic exposure to silver nanoparticles causes mild mitochondrial alterations in the liver ...TITLE AND SUBTITLE Low-dose, chronic exposure to silver nanoparticles causes mild mitochondrial alterations in the liver of Sprague-Dawley rat 5a...alterations were found in heart and kidney levels, and despite the fact that the alterations found in liver mitochondria did not appear to compromise ATP

  15. Human Ozone (O3) Exposure Alters Serum Profile of Lipid Metabolites

    EPA Science Inventory

    HUMAN OZONE (O3) EXPOSURE ALTERS SERUM PROFILE OF LIPID METABOLITES Miller, D B.1; Kodavanti, U P.2 Karoly, E D.3; Cascio W.E2, Ghio, A J. 21. UNC-Chapel Hill, Chapel Hill, N.C., United States. 2. NHEERL, U.S. EPA, RTP, N.C., United States. 3. METABOLON INC., Durham, N.C., United...

  16. ALTERATIONS IN BRAIN PROTEIN KINASE C ISOFORMS FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYL MIXTURE.

    EPA Science Inventory

    PCBs have been shown to alter several neurochemical end-points and are implicated in the etiology of some neurological diseases. Recent in vivo studies from our laboratory indicated that developmental exposure to a commercial PCB mixture, Aroclor 1254, caused perturbations in cal...

  17. Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors

    EPA Science Inventory

    Dose response and time-course (DRTC) are, along with exposure, the major determinants of health risk. Adaptive changes within exposed organisms in response to environmental stress are common, and alter DRTC behaviors to minimize the effects caused by stressors. In this project, ...

  18. PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS

    EPA Science Inventory

    PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS. R A Matulka1, AA Rooney3, W Williams2, CB Copeland2, and R J Smialowicz2. 1Curriculum in Toxicology, UNC, Chapel Hill, NC, USA; 2US EPA, ITB, ETD, NHEERL, RT...

  19. GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS) ALTERS DEVELOPMENT OF THE MOUSE TESTIS

    EPA Science Inventory

    GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS) ALTERS DEVELOPMENT OF THE MOUSE TESTIS. D.K. Tarka*1,2, J.D. Suarez*2, N.L. Roberts*2, J.M. Rogers*1,2, M.P. Hardy3, and G.R. Klinefelter1,2. 1University of North Carolina, Curriculum in Toxicology, Chapel Hill, NC; 2USEPA,...

  20. Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver

    EPA Science Inventory

    Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Cha...

  1. Caspofungin exposure alters the core septin AspB interactome of Aspergillus fumigatus.

    PubMed

    Vargas-Muñiz, José M; Renshaw, Hilary; Waitt, Greg; Soderblom, Erik J; Moseley, M Arthur; Palmer, Jonathan M; Juvvadi, Praveen R; Keller, Nancy P; Steinbach, William J

    2017-04-01

    Aspergillus fumigatus, the main etiological agent of invasive aspergillosis, is a leading cause of death in immunocompromised patients. Septins, a conserved family of GTP-binding proteins, serve as scaffolding proteins to recruit enzymes and key regulators to different cellular compartments. Deletion of the A. fumigatus septin aspB increases susceptibility to the echinocandin antifungal caspofungin. However, how AspB mediates this response to caspofungin is unknown. Here, we characterized the AspB interactome under basal conditions and after exposure to a clinically relevant concentration of caspofungin. While A. fumigatus AspB interacted with 334 proteins, including kinases, cell cycle regulators, and cell wall synthesis-related proteins under basal growth conditions, caspofungin exposure altered AspB interactions. A total of 69 of the basal interactants did not interact with AspB after exposure to caspofungin, and 54 new interactants were identified following caspofungin exposure. We generated A. fumigatus deletion strains for 3 proteins (ArpB, Cyp4, and PpoA) that only interacted with AspB following exposure to caspofungin that were previously annotated as induced after exposure to antifungal agents, yet only PpoA was implicated in the response to caspofungin. Taken together, we defined how the septin AspB interactome is altered in the presence of a clinically relevant antifungal.

  2. Adulthood stress responses in rats are variably altered as a factor of adolescent stress exposure.

    PubMed

    Moore, Nicole L T; Altman, Daniel E; Gauchan, Sangeeta; Genovese, Raymond F

    2016-05-01

    Stress exposure during development may influence adulthood stress response severity. The present study investigates persisting effects of two adolescent stressors upon adulthood response to predator exposure (PE). Rats were exposed to underwater trauma (UWT) or PE during adolescence, then to PE after reaching adulthood. Rats were then exposed to predator odor (PO) to test responses to predator cues alone. Behavioral and neuroendocrine assessments were conducted to determine acute effects of each stress experience. Adolescent stress altered behavioral response to adulthood PE. Acoustic startle response was blunted. Bidirectional changes in plus maze exploration were revealed as a factor of adolescent stress type. Neuroendocrine response magnitude did not predict severity of adolescent or adult stress response, suggesting that different adolescent stress events may differentially alter developmental outcomes regardless of acute behavioral or neuroendocrine response. We report that exposure to two different stressors in adolescence may differentially affect stress response outcomes in adulthood. Acute response to an adolescent stressor may not be consistent across all stressors or all dependent measures, and may not predict alterations in developmental outcomes pertaining to adulthood stress exposure. Further studies are needed to characterize factors underlying long-term effects of a developmental stressor.

  3. Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease.

    PubMed

    Ditzel, Eric J; Li, Hui; Foy, Caroline E; Perrera, Alec B; Parker, Patricia; Renquist, Benjamin J; Cherrington, Nathan J; Camenisch, Todd D

    2016-07-01

    Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease.

  4. Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention

    PubMed Central

    Han, Mingda

    2016-01-01

    Background Embryonic acute exposure to ethanol (EtOH), lithium, and homocysteine (HCy) induces cardiac defects at the time of exposure; folic acid (FA) supplementation protects normal cardiogenesis (Han et al., 2009, 2012; Serrano et al., 2010). Our hypothesis is that EtOH exposure and FA protection relate to lipid and FA metabolism during mouse cardiogenesis and placentation. Methods On the morning of conception, pregnant C57BL/6J mice were placed on either of two FA‐containing diets: a 3.3 mg health maintenance diet or a high FA diet of 10.5 mg/kg. Mice were injected a binge level of EtOH, HCy, or saline on embryonic day (E) 6.75, targeting gastrulation. On E15.5, cardiac and umbilical blood flow were examined by ultrasound. Embryonic cardiac tissues were processed for gene expression of lipid and FA metabolism; the placenta and heart tissues for neutral lipid droplets, or for medium chain acyl‐dehydrogenase (MCAD) protein. Results EtOH exposure altered lipid‐related gene expression on E7.5 in comparison to control or FA‐supplemented groups and remained altered on E15.5 similarly to changes with HCy, signifying FA deficiency. In comparison to control tissues, the lipid‐related acyl CoA dehydrogenase medium length chain gene and its protein MCAD were altered with EtOH exposure, as were neutral lipid droplet localization in the heart and placenta. Conclusion EtOH altered gene expression associated with lipid and folate metabolism, as well as neutral lipids, in the E15.5 abnormally functioning heart and placenta. In comparison to controls, the high FA diet protected the embryo and placenta from these effects allowing normal development. Birth Defects Research (Part A) 106:749–760, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. PMID:27296863

  5. Ozone Exposure Alters Serotonin and Serotonin Receptor Expression in the Developing Lung

    PubMed Central

    Van Winkle, Laura S.

    2013-01-01

    Ozone, a pervasive environmental pollutant, adversely affects functional lung growth in children. Animal studies demonstrate that altered lung development is associated with modified signaling within the airway epithelial mesenchymal trophic unit, including mediators that can change nerve growth. We hypothesized that ozone exposure alters the normal pattern of serotonin, its transporter (5-HTT), and two key receptors (5-HT2A and 5-HT4), a pathway involved in postnatal airway neural, epithelial, and immune processes. We exposed monkeys to acute or episodic ozone during the first 2 or 6 months of life. There were three exposure groups/age: (1) filtered air, (2) acute ozone challenge, and (3) episodic ozone + acute ozone challenge. Lungs were prepared for compartment-specific qRT-PCR, immunohistochemistry, and stereology. Airway epithelial serotonin immunopositive staining increased in all exposure groups with the most prominent in 2-month midlevel and 6-month distal airways. Gene expression of 5-HTT, 5-HT2AR, and 5-HT4R increased in an age-dependent manner. Overall expression was greater in distal compared with midlevel airways. Ozone exposure disrupted both 5-HT2AR and 5-HT4R protein expression in airways and enhanced immunopositive staining for 5-HT2AR (2 months) and 5-HT4R (6 months) on smooth muscle. Ozone exposure increases serotonin in airway epithelium regardless of airway level, age, and exposure history and changes the spatial pattern of serotonin receptor protein (5-HT2A and 5-HT4) and 5-HTT gene expression depending on compartment, age, and exposure history. Understanding how serotonin modulates components of reversible airway obstruction exacerbated by ozone exposure sets the foundation for developing clinically relevant therapies for airway disease. PMID:23570994

  6. Acrolein Inhalation Alters Myocardial Synchrony and Performance at and Below Exposure Concentrations that Cause Ventilatory Responses.

    PubMed

    Thompson, Leslie C; Ledbetter, Allen D; Haykal-Coates, Najwa; Cascio, Wayne E; Hazari, Mehdi S; Farraj, Aimen K

    2017-04-01

    Acrolein is an irritating aldehyde generated during combustion of organic compounds. Altered autonomic activity has been documented following acrolein inhalation, possibly impacting myocardial synchrony and function. Given the ubiquitous nature of acrolein in the environment, we sought to better define the immediate and delayed functional cardiac effects of acrolein inhalation in vivo. We hypothesized that acrolein inhalation would increase markers of cardiac mechanical dysfunction, i.e., myocardial dyssynchrony and performance index in mice. Male C57Bl/6J mice were exposed to filtered air (FA) or acrolein (0.3 or 3.0 ppm) for 3 h in whole-body plethysmography chambers (n = 6). Echocardiographic analyses were performed 1 day before exposure and at 1 and 24 h post-exposure. Speckle tracking echocardiography revealed that circumferential strain delay (i.e., dyssynchrony) was increased at 1 and 24 h following exposure to 3.0 ppm, but not 0.3 ppm, when compared to pre-exposure and/or FA exposure. Pulsed wave Doppler of transmitral blood flow revealed that acrolein exposure at 0.3 ppm, but not 3.0 ppm, increased the Tei index of myocardial performance (i.e., decreased global heart performance) at 1 and 24 h post-exposure compared to pre-exposure and/or FA exposure. We conclude that short-term inhalation of acrolein can acutely modify cardiac function in vivo and that echocardiographic evaluation of myocardial synchrony and performance following exposure to other inhaled pollutants could provide broader insight into the health effects of air pollution.

  7. Prenatal exposure to methylmercury alters development of adrenergic receptor binding sites in peripheral sympathetic target tissues

    SciTech Connect

    Slotkin, T.A.; Orband, L.; Cowdery, T.; Kavlock, R.J.; Bartolome, J.

    1987-01-01

    In order to assess the impact of prenatal exposure to methylmercury on sympathetic neurotransmission, effects on development of adrenergic receptor binding sites in peripheral tissues was evaluated. In the liver, methylmercury produced a dose-dependent increase in alpha/sub 1/, alpha/sub 2/, and beta-receptor binding of radioliganda throughout the first 5 weeks of postnatal life. Similarly, renal alpha-receptor subtypes showed increased binding capabilities, but binding to alpha-receptor sites was reduced. At least some of the changes in receptors appear to be of functional significance, as physiological reactivity to adrenergic stimulation is altered in the same directions in these two tissues. The actions of methylmercury displayed tissue specificity in that the same receptor populations were largely unaffected in other tissues (lung, heart). These results suggest that methylmercury exposure in utero alters adrenergic responses through targeted effects on postsynaptic receptor populations in specific tissues.

  8. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FALLS TO ALTER SOMATOSENSORY EVOKED POTENTIALS, COMPOUND NERVE ACTION POTENTIALS, OR NERVE CONDUCTION VELOCITY IN RATS.

    EPA Science Inventory

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in sensory modulation in the cortex and cerebellum, and therefore may be altered following chlorpyrifos (CPF) exposure...

  9. Waterborne manganese exposure alters plasma, brain, and liver metabolites accompanied by changes in stereotypic behaviors

    PubMed Central

    Fordahl, Steve; Cooney, Paula; Qiu, Yunping; Xie, Guoxiang; Jia, Wei; Erikson, Keith M.

    2011-01-01

    Overexposure to waterborne manganese (Mn) is linked with cognitive impairment in children and neurochemical abnormalities in other experimental models. In order to characterize the threshold between Mn-exposure and altered neurochemistry, it is important to identify biomarkers that positively correspond with brain Mn-accumulation. The objective of this study was to identify Mn-induced alterations in plasma, liver, and brain metabolites using liquid/gas chromatography-time of flight-mass spectrometry metabolomic analyses; and to monitor corresponding Mn-induced behavior changes. Weanling Sprague-Dawley rats had access to deionized drinking water either Mn-free or containing 1g Mn/L for six weeks. Behaviors were monitored during the sixth week for a continuous 24h period while in a home cage environment using video surveillance. Mn-exposure significantly increased liver, plasma, and brain Mn concentrations compared to control, specifically targeting the globus pallidus (GP). Mn significantly altered 98 metabolites in the brain, liver, and plasma; notably shifting cholesterol and fatty acid metabolism in the brain (increased oleic and palmitic acid; 12.57 and 15.48 fold change (FC), respectively), and liver (increased oleic acid, 14.51 FC; decreased hydroxybutyric acid, −14.29 FC). Additionally, Mn-altered plasma metabolites homogentisic acid, chenodeoxycholic acid, and aspartic acid correlated significantly with GP and striatal Mn. Total distance traveled was significantly increased and positively correlated with Mn-exposure, while nocturnal stereotypic and exploratory behaviors were reduced with Mn-exposure and performed largely during the light cycle compared to unexposed rats. These data provide putative biomarkers for Mn-neurotoxicity and suggest that Mn disrupts the circadian cycle in rats. PMID:22056924

  10. Waterborne manganese exposure alters plasma, brain, and liver metabolites accompanied by changes in stereotypic behaviors.

    PubMed

    Fordahl, Steve; Cooney, Paula; Qiu, Yunping; Xie, Guoxiang; Jia, Wei; Erikson, Keith M

    2012-01-01

    Overexposure to waterborne manganese (Mn) is linked with cognitive impairment in children and neurochemical abnormalities in other experimental models. In order to characterize the threshold between Mn-exposure and altered neurochemistry, it is important to identify biomarkers that positively correspond with brain Mn-accumulation. The objective of this study was to identify Mn-induced alterations in plasma, liver, and brain metabolites using liquid/gas chromatography-time of flight-mass spectrometry metabolomic analyses; and to monitor corresponding Mn-induced behavior changes. Weanling Sprague-Dawley rats had access to deionized drinking water either Mn-free or containing 1g Mn/L for 6 weeks. Behaviors were monitored during the sixth week for a continuous 24h period while in a home cage environment using video surveillance. Mn-exposure significantly increased liver, plasma, and brain Mn concentrations compared to control, specifically targeting the globus pallidus (GP). Mn significantly altered 98 metabolites in the brain, liver, and plasma; notably shifting cholesterol and fatty acid metabolism in the brain (increased oleic and palmitic acid; 12.57 and 15.48 fold change (FC), respectively), and liver (increased oleic acid, 14.51 FC; decreased hydroxybutyric acid, -14.29 FC). Additionally, Mn-altered plasma metabolites homogentisic acid, chenodeoxycholic acid, and aspartic acid correlated significantly with GP and striatal Mn. Total distance traveled was significantly increased and positively correlated with Mn-exposure, while nocturnal stereotypic and exploratory behaviors were reduced with Mn-exposure and performed largely during the light cycle compared to unexposed rats. These data provide putative biomarkers for Mn-neurotoxicity and suggest that Mn disrupts the circadian cycle in rats.

  11. Formaldehyde exposure alters miRNA expression profiles in the olfactory bulb.

    PubMed

    Li, Guifa; Yang, Jing; Ling, Shucai

    2015-01-01

    It has been reported that inhaling formaldehyde (FA) causes damage to the central nervous system. However, it is unclear whether FA can disturb the function of the olfactory bulb. Using a microarray, we found that FA inhalation altered the miRNA expression profile. Functional enrichment analysis of the predicted targets of the changed miRNA showed that the enrichment canonical pathways and networks associated with cancer and transcriptional regulation. FA exposure disrupts miRNA expression profiles within the olfactory bulb.

  12. Regulation of phosphatidylserine synthase from Saccharomyces cerevisiae by phospholipid precursors.

    PubMed Central

    Poole, M A; Homann, M J; Bae-Lee, M S; Carman, G M

    1986-01-01

    The addition of ethanolamine or choline to inositol-containing growth medium of Saccharomyces cerevisiae wild-type cells resulted in a reduction of membrane-associated phosphatidylserine synthase (CDPdiacylglycerol:L-serine O-phosphatidyltransferase, EC 2.7.8.8) activity in cell extracts. The reduction of activity did not occur when inositol was absent from the growth medium. Under the growth conditions where a reduction of enzyme activity occurred, there was a corresponding qualitative reduction of enzyme subunit as determined by immunoblotting with antiserum raised against purified phosphatidylserine synthase. Water-soluble phospholipid precursors did not effect purified phosphatidylserine synthase activity. Phosphatidylserine synthase (activity and enzyme subunit) was not regulated by the availability of water-soluble phospholipid precursors in S. cerevisiae VAL2C(YEp CHO1) and the opi1 mutant. VAL2C(YEp CHO1) is a plasmid-bearing strain that over produces phosphatidylserine synthase activity, and the opi1 mutant is an inositol biosynthesis regulatory mutant. The results of this study suggest that the regulation of phosphatidylserine synthase by the availability of phospholipid precursors occurs at the level of enzyme formation and not at the enzyme activity level. Furthermore, the regulation of phosphatidylserine synthase is coupled to inositol synthesis. Images PMID:3023284

  13. Transport of phosphatidylserine from the endoplasmic reticulum to the site of phosphatidylserine decarboxylase2 in yeast.

    PubMed

    Kannan, Muthukumar; Riekhof, Wayne R; Voelker, Dennis R

    2015-02-01

    Over the past two decades, most of the genes specifying lipid synthesis and metabolism in yeast have been identified and characterized. Several of these biosynthetic genes and their encoded enzymes have provided valuable tools for the genetic and biochemical dissection of interorganelle lipid transport processes in yeast. One such pathway involves the synthesis of phosphatidylserine (PtdSer) in the endoplasmic reticulum (ER), and its non-vesicular transport to the site of phosphatidylserine decarboxylase2 (Psd2p) in membranes of the Golgi and endosomal sorting system. In this review, we summarize the identification and characterization of the yeast phosphatidylserine decarboxylases, and examine their role in studies of the transport-dependent pathways of de novo synthesis of phosphatidylethanolamine (PtdEtn). The emerging picture of the Psd2p-specific transport pathway is one in which the enzyme and its non-catalytic N-terminal domains act as a hub to nucleate the assembly of a multiprotein complex, which facilitates PtdSer transport at membrane contact sites between the ER and Golgi/endosome membranes. After transport to the catalytic site of Psd2p, PtdSer is decarboxylated to form PtdEtn, which is disseminated throughout the cell to support the structural and functional needs of multiple membranes.

  14. Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure.

    PubMed

    Klaren, W D; Gadupudi, G S; Wels, B; Simmons, D L; Olivier, A K; Robertson, L W

    2015-12-02

    Polychlorinated Biphenyls (PCBs) are industrial chemicals that have become a persistent threat to human health due to ongoing exposure. A subset of PCBs, known as dioxin-like PCBs, pose a special threat given their potent hepatic effects. Micronutrients, especially Cu, Zn and Se, homeostatic dysfunction is commonly seen after exposure to dioxin-like PCBs. This study investigates whether micronutrient alteration is the byproduct of the ongoing hepatotoxicity, marked by lipid accumulation, or a concurrent, yet independent event of hepatic damage. A time course study was carried out using male Sprague-Dawley rats with treatments of PCB126, the prototypical dioxin-like PCB, resulting in 6 different time points. Animals were fed a purified diet, based on AIN-93G, for three weeks to ensure micronutrient equilibration. A single IP injection of either tocopherol-stripped soy oil vehicle (5 mL/kg) or 5 μmol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9h, 18 h, 36 h, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 h with drastic changes at the later time points, 6 and 12 days. Micronutrient alterations, specifically Cu, Zn, and Se, were not seen until after day 3 and only observed in the liver. No alterations were seen in the duodenum, suggesting that absorption and excretion may not be involved. Micronutrient alterations occur with ROS formation, lipid accumulation, and hepatomegaly. To probe the mechanistic underpinnings, alteration of gene expression of several copper chaperones was investigated; only metallothionein appeared elevated. These data suggest that the disruption in micronutrient status is a result of the hepatic injury elicited by PCB126 and is mediated in part by metallothionein.

  15. Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs.

    PubMed

    Herring, M J; Putney, L F; St George, J A; Avdalovic, M V; Schelegle, E S; Miller, L A; Hyde, D M

    2015-02-15

    In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6 months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in the lung parenchyma would be permanent following a long-term recovery in filtered air (FA) housing. Forty-eight infant rhesus macaques (30 days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O3) or HDMA/ozone (HDMA+O3) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes, interalveolar capillary density. After 30 months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. These alveoli also had higher capillary densities as compared with FA controls. These results indicate that early life exposure to HDMA alone or HDMA+O3 alters the development process in the lung alveoli.

  16. Fetal alcohol exposure alters neurosteroid levels in the developing rat brain.

    PubMed

    Caldeira, Jerri C; Wu, Yan; Mameli, Manuel; Purdy, Robert H; Li, Pui-Kai; Akwa, Yvette; Savage, Daniel D; Engen, John R; Valenzuela, C Fernando

    2004-09-01

    Neurosteroids are modulators of neuronal function that may play important roles in brain maturation. We determined whether chronic prenatal ethanol exposure altered neurosteroid levels in the developing brain. Rat dams were exposed to: (i) a 5% ethanol-containing liquid diet that produces peak maternal blood alcohol levels near the legal intoxication limit (approximately 0.08 g/dL); (ii) an isocaloric liquid diet containing maltose-dextrin instead of ethanol with pair-feeding; (iii) rat chow ad libitum. Neurosteroid levels were assessed in offspring brains using radioimmunoassay or gas chromatography-mass spectrometry techniques. A prenatal ethanol exposure-induced increase in pregnenolone sulfate levels, but not dehydroepiandrosterone sulfate levels, was evident at the earliest time point studied (embryonic day 14). This effect lasted until post-natal day 5. Levels of other neurosteroids were assessed at embryonic day 20; pregnenolone levels, but not allopregnanolone levels, were elevated. Pregnenolone sulfate levels were not altered in the maternal brain. Neither pregnenolone nor pregnenolone sulfate levels were significantly altered in the fetal liver, placenta and maternal blood, indicating that the effect of ethanol is not secondary to accumulation of peripherally-produced steroids. Fetal ethanol exposure has been shown to decrease both cellular and behavioral responsiveness to neurosteroids, and our findings provide a plausible explanation for this effect.

  17. Altered myelination and axonal integrity in adults with childhood lead exposure: a diffusion tensor imaging study.

    PubMed

    Brubaker, Christopher J; Schmithorst, Vincent J; Haynes, Erin N; Dietrich, Kim N; Egelhoff, John C; Lindquist, Diana M; Lanphear, Bruce P; Cecil, Kim M

    2009-11-01

    Childhood lead exposure is associated with adverse cognitive, neurobehavioral and motor outcomes, suggesting altered brain structure and function. The purpose of this work was to assess the long-term impact of childhood lead exposure on white matter integrity in young adults. We hypothesized that childhood lead exposure would alter adult white matter architecture via deficits in axonal integrity and myelin organization. Adults (22.9+/-1.5 years, range 20.0-26.1 years) from the Cincinnati Lead Study were recruited to undergo a study employing diffusion tensor imaging (DTI). The anatomic regions of association between water diffusion characteristics in white matter and mean childhood blood lead level were determined for 91 participants (52 female). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured on an exploratory voxel-wise basis. In adjusted analyses, mean childhood blood lead levels were associated with decreased FA throughout white matter. Regions of the corona radiata demonstrated highly significant lead-associated decreases in FA and AD and increases in MD and RD. The genu, body, and splenium of the corpus callosum demonstrated highly significant lead-associated decreases in RD, smaller and less significant decreases in MD, and small areas with increases in AD. The results of this analysis suggest multiple insults appear as distinct patterns of white matter diffusion abnormalities in the adult brain. Neurotoxic insults from the significant lead burden the participants experienced throughout childhood affect neural elements differently and may be related to the developmental stage of myelination at periods of exposure. This study indicates that childhood lead exposure is associated with a significant and persistent impact on white matter microstructure as quantified with diffusivity changes suggestive of altered myelination and axonal integrity.

  18. The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

    PubMed Central

    Buczynski, Matthew W; Polis, Ilham Y; Parsons, Loren H

    2013-01-01

    Cannabinoid-1 receptors (CB1) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compared the effects of volitional nicotine self-administration (SA) and forced nicotine exposure (yoked administration (YA)) on levels of eCBs and related neuroactive lipids in the ventral tegmental area (VTA) and other brain regions. Brain lipid levels were indexed both by in vivo microdialysis in the VTA and lipid extractions from brain tissues. Nicotine SA, but not YA, reduced baseline VTA dialysate oleoylethanolamide (OEA) levels relative to nicotine-naïve controls, and increased anandamide (AEA) release during nicotine intake. In contrast, all nicotine exposure paradigms increased VTA dialysate 2-arachidonoyl glycerol (2-AG) levels. Thus, nicotine differentially modulates brain lipid (2-AG, AEA, and OEA) signaling, and these modulations are influenced by the volitional nature of the drug exposure. Corresponding bulk tissue analysis failed to identify these lipid changes. Nicotine exposure had no effect on fatty acid amide hydrolase activity in the VTA, suggesting that changes in AEA and OEA signaling result from alterations in their nicotine-induced biosynthesis. Both CB1 (by AEA and 2-AG) and non-CB1 (by OEA) targets can alter the excitability and activity of the dopaminergic neurons in the VTA. Collectively, these findings implicate disrupted lipid signaling in the motivational effects of nicotine. PMID:23169348

  19. The volitional nature of nicotine exposure alters anandamide and oleoylethanolamide levels in the ventral tegmental area.

    PubMed

    Buczynski, Matthew W; Polis, Ilham Y; Parsons, Loren H

    2013-03-01

    Cannabinoid-1 receptors (CB(1)) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compared the effects of volitional nicotine self-administration (SA) and forced nicotine exposure (yoked administration (YA)) on levels of eCBs and related neuroactive lipids in the ventral tegmental area (VTA) and other brain regions. Brain lipid levels were indexed both by in vivo microdialysis in the VTA and lipid extractions from brain tissues. Nicotine SA, but not YA, reduced baseline VTA dialysate oleoylethanolamide (OEA) levels relative to nicotine-naïve controls, and increased anandamide (AEA) release during nicotine intake. In contrast, all nicotine exposure paradigms increased VTA dialysate 2-arachidonoyl glycerol (2-AG) levels. Thus, nicotine differentially modulates brain lipid (2-AG, AEA, and OEA) signaling, and these modulations are influenced by the volitional nature of the drug exposure. Corresponding bulk tissue analysis failed to identify these lipid changes. Nicotine exposure had no effect on fatty acid amide hydrolase activity in the VTA, suggesting that changes in AEA and OEA signaling result from alterations in their nicotine-induced biosynthesis. Both CB(1) (by AEA and 2-AG) and non-CB(1) (by OEA) targets can alter the excitability and activity of the dopaminergic neurons in the VTA. Collectively, these findings implicate disrupted lipid signaling in the motivational effects of nicotine.

  20. Selective peroxidation and externalization of phosphatidylserine in normal human epidermal keratinocytes during oxidative stress induced by cumene hydroperoxide.

    PubMed

    Shvedova, Anna A; Tyurina, Julia Y; Kawai, Kazuaki; Tyurin, Vladimir A; Kommineni, Choudari; Castranova, Vincent; Fabisiak, James P; Kagan, Valerian E

    2002-06-01

    Reactive oxygen species not only modulate important signal transduction pathways, but also induce DNA damage and cytotoxicity in keratinocytes. Hydrogen peroxide and organic peroxides are particularly important as these chemicals are widely used in dermally applied cosmetics and pharmaceuticals, and also represent endogenous metabolic intermediates. Lipid peroxidation is of fundamental interest in the cellular response to peroxides, as lipids are extremely sensitive to oxidation and lipid-based signaling systems have been implicated in a number of cellular processes, including apoptosis. Oxidation of specific phospholipid classes was measured in normal human epidermal keratinocytes exposed to cumene hydroperoxide after metabolic incorporation of the fluorescent oxidation-sensitive fatty acid, cis-parinaric acid, using a fluorescence high-performance liquid chromatography assay. In addition, lipid oxidation was correlated with changes in membrane phospholipid asymmetry and other markers of apoptosis. Although cumene hydroperoxide produced significant oxidation of cis-parinaric acid in all phospholipid classes, one phospholipid, phosphatidylserine, appeared to be preferentially oxidized above all other species. Using fluorescamine derivatization and annexin V binding it was observed that specific oxidation of phosphatidylserine was accompanied by phosphatidylserine translocation from the inner to the outer plasma membrane surface where it may serve as a recognition signal for interaction with phagocytic macrophages. These effects occurred much earlier than any detectable changes in other apoptotic markers such as caspase-3 activation, DNA fragmentation, or changes in nuclear morphology. Thus, normal human epidermal keratinocytes undergo profound lipid oxidation with preference for phosphatidylserine followed by phosphatidylserine externalization upon exposure to cumene hydroperoxide. It is therefore likely that normal human epidermal keratinocytes exposed to similar

  1. Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.

    PubMed

    Zhang, Chong; Xu, Dan; Luo, Hanwen; Lu, Juan; Liu, Lian; Ping, Jie; Wang, Hui

    2014-11-05

    The hypothalamic-pituitary-adrenal (HPA) axis is one of the most important neuroendocrine axes and plays an important role in stress defense responses before and after birth. Prenatal exposure to xenobiotics, including environmental toxins (such as smoke, sulfur dioxide and carbon monoxide), drugs (such as synthetic glucocorticoids), and foods and beverage categories (such as ethanol and caffeine), affects fetal development indirectly by changing the maternal status or damaging the placenta. Certain xenobiotics (such as caffeine, ethanol and dexamethasone) may also affect the fetus directly by crossing the placenta into the fetus due to their lipophilic properties and lower molecular weights. All of these factors probably result in intrauterine programming alteration of the HPA axis, which showed a low basal activity but hypersensitivity to chronic stress. These alterations will, therefore, increase the susceptibility to adult neuropsychiatric (such as depression and schizophrenia) and metabolic diseases (such as hypertension, diabetes and non-alcoholic fatty liver disease). The "over-exposure of fetuses to maternal glucocorticoids" may be the main initiation factor by which the fetal HPA axis programming is altered. Meantime, xenobiotics can directly induce abnormal epigenetic modifications and expression on the important fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein, et al) or damage by in situ oxidative metabolism of fetal adrenals, which may also be contributed to the programming alteration of fetal HPA axis.

  2. Investigation into the role of phosphatidylserine in modifying the susceptibility of human lymphocytes to secretory phospholipase A(2) using cells deficient in the expression of scramblase.

    PubMed

    Nelson, Jennifer; Francom, Lyndee L; Anderson, Lynn; Damm, Kelly; Baker, Ryan; Chen, Joseph; Franklin, Sarah; Hamaker, Amy; Izidoro, Izadora; Moss, Eric; Orton, Mikayla; Stevens, Evan; Yeung, Celestine; Judd, Allan M; Bell, John D

    2012-05-01

    Normal human lymphocytes resisted the hydrolytic action of secretory phospholipase A(2) but became susceptible to the enzyme following treatment with a calcium ionophore, ionomycin. To test the hypothesis that this susceptibility requires exposure of the anionic lipid phosphatidylserine on the external face of the cell membrane, experiments were repeated with a human Burkitt's lymphoma cell line (Raji cells). In contrast to normal lymphocytes or S49 mouse lymphoma cells, most of the Raji cells (83%) did not translocate phosphatidylserine to the cell surface upon treatment with ionomycin. Those few that did display exposed phosphatidylserine were hydrolyzed immediately upon addition of phospholipase A(2). Interestingly, the remaining cells were also completely susceptible to the enzyme but were hydrolyzed at a slower rate and after a latency of about 100s. In contradistinction to the defect in phosphatidylserine translocation, Raji cells did display other physical membrane changes upon ionomycin treatment that may be relevant to hydrolysis by phospholipase A(2). These changes were detected by merocyanine 540 and trimethylammonium diphenylhexatriene fluorescence and were common among normal lymphocytes, S49 cells, and Raji cells. The levels of these latter effects corresponded well with the relative rates of hydrolysis among the three cell lines. These results suggested that while phosphatidylserine enhances the rate of cell membrane hydrolysis by secretory phospholipase A(2), it is not an absolute requirement. Other physical properties such as membrane order contribute to the level of membrane susceptibility to the enzyme independent of phosphatidylserine.

  3. Environmentally Realistic Exposure to the Herbicide Atrazine Alters Some Sexually Selected Traits in Male Guppies

    PubMed Central

    Shenoy, Kausalya

    2012-01-01

    Male mating signals, including ornaments and courtship displays, and other sexually selected traits, like male-male aggression, are largely controlled by sex hormones. Environmental pollutants, notably endocrine disrupting compounds, can interfere with the proper functioning of hormones, thereby impacting the expression of hormonally regulated traits. Atrazine, one of the most widely used herbicides, can alter sex hormone levels in exposed animals. I tested the effects of environmentally relevant atrazine exposures on mating signals and behaviors in male guppies, a sexually dimorphic freshwater fish. Prolonged atrazine exposure reduced the expression of two honest signals: the area of orange spots (ornaments) and the number of courtship displays performed. Atrazine exposure also reduced aggression towards competing males in the context of mate competition. In the wild, exposure levels vary among individuals because of differential distribution of the pollutants across habitats; hence, differently impacted males often compete for the same mates. Disrupted mating signals can reduce reproductive success as females avoid mating with perceptibly suboptimal males. Less aggressive males are at a competitive disadvantage and lose access to females. This study highlights the effects of atrazine on ecologically relevant mating signals and behaviors in exposed wildlife. Altered reproductive traits have important implications for population dynamics, evolutionary patterns, and conservation of wildlife species. PMID:22312428

  4. Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring.

    PubMed

    Razavinasab, Moazamehosadat; Moazzami, Kasra; Shabani, Mohammad

    2016-06-01

    Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques.

  5. Neonatal exposure to monosodium glutamate induces morphological alterations in suprachiasmatic nucleus of adult rat.

    PubMed

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Chávez-Saldaña, Margarita; Rojas, Patricia; Gutiérrez-Pérez, Oscar; Rojas, Carolina; Arteaga-Silva, Marcela

    2016-02-01

    Neonatal exposure to monosodium glutamate (MSG) induces circadian disorders in several physiological and behavioural processes regulated by the suprachiasmatic nucleus (SCN). The objective of this study was to evaluate the effects of neonatal exposure to MSG on locomotor activity, and on morphology, cellular density and expression of proteins, as evaluated by optical density (OD), of vasopressin (VP)-, vasoactive intestinal polypeptide (VIP)- and glial fibrillary acidic protein (GFAP)-immunoreactive cells in the SCN. Male Wistar rats were used: the MSG group was subcutaneously treated from 3 to 10 days of age with 3.5 mg/g/day. Locomotor activity was evaluated at 90 days of age using 'open-field' test, and the brains were processed for immunohistochemical studies. MSG exposure induced a significant decrease in locomotor activity. VP- and VIP-immunoreactive neuronal densities showed a significant decrease, while the somatic OD showed an increase. Major axes and somatic area were significantly increased in VIP neurons. The cellular and optical densities of GFAP-immunoreactive sections of SCN were significantly increased. These results demonstrated that newborn exposure to MSG induced morphological alterations in SCN cells, an alteration that could be the basis for behavioural disorders observed in the animals.

  6. Embryo-larval exposure to atrazine reduces viability and alters oxidative stress parameters in Drosophila melanogaster.

    PubMed

    Figueira, Fernanda Hernandes; Aguiar, Lais Mattos de; Rosa, Carlos Eduardo da

    2017-01-01

    The herbicide atrazine has been used worldwide with subsequent residual contamination of water and food, which may cause adverse effects on non-target organisms. Animal exposure to this herbicide may affect development, reproduction and energy metabolism. Here, the effects of atrazine regarding survival and redox metabolism were assessed in the fruit fly D. melanogaster exposed during embryonic and larval development. The embryos (newly fertilized eggs) were exposed to different atrazine concentrations (10μM and 100μM) in the diet until the adult fly emerged. Pupation and emergence rates, developmental time and sex ratio were determined as well as oxidative stress parameters and gene expression of the antioxidant defence system were evaluated in newly emerged male and female flies. Atrazine exposure reduced pupation and emergence rates in fruit flies without alterations to developmental time and sex ratio. Different redox imbalance patterns were observed between males and females exposed to atrazine. Atrazine caused an increase in oxidative damage, reactive oxygen species generation and antioxidant capacity and decreased thiol-containing molecules. Further, atrazine exposure altered the mRNA expression of antioxidant genes (keap1, sod, sod2, cat, irc, gss, gclm, gclc, trxt, trxr-1 and trxr-2). Reductions in fruit fly larval and pupal viability observed here are likely consequences of the oxidative stress induced by atrazine exposure.

  7. Rat hippocampal alterations could underlie behavioral abnormalities induced by exposure to moderate noise levels.

    PubMed

    Uran, S L; Aon-Bertolino, M L; Caceres, L G; Capani, F; Guelman, L R

    2012-08-30

    Noise exposure is known to affect auditory structures in living organisms. However, it should not be ignored that many of the effects of noise are extra-auditory. Previous findings of our laboratory demonstrated that noise was able to induce behavioral alterations that are mainly related to the cerebellum (CE) and the hippocampus (HC). Therefore, the aim of this work was to reveal new data about the vulnerability of developing rat HC to moderate noise levels through the assessment of potential histological changes and hippocampal-related behavioral alterations. Male Wistar rats were exposed to noise (95-97 dB SPL, 2h daily) either for 1 day (acute noise exposure, ANE) or between postnatal days 15 and 30 (sub-acute noise exposure, SANE). Hippocampal histological evaluation as well as short (ST) and long term (LT) habituation and recognition memory assessments were performed. Results showed a mild disruption in the different hippocampal regions after ANE and SANE schemes, along with significant behavioral abnormalities. These data suggest that exposure of developing rats to noise levels of moderate intensity is able to trigger changes in the HC, an extra-auditory structure of the Central Nervous System (CNS), that could underlie the observed behavioral effects.

  8. Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Rats

    PubMed Central

    Smith, Catherine A.; Farmer, Kyle; Lee, Hyunmin; Holahan, Matthew R.; Smith, Jeffrey C.

    2015-01-01

    Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. Previous findings have demonstrated that postnatal exposure to di (2-ethylhexyl) phthalate (DEHP) disrupts normal axonal and neural development in the hippocampus. The goal of the current study was to determine whether postnatal exposure to DEHP alters the lipid profile in the hippocampus during postnatal development. Systemic treatment with 10 mg/kg DEHP during postnatal development led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female rats. There was no effect of DEHP exposure on the overall abundance of phosphatidylcholine or sphingomyelin in male rats or of lysophosphatidylcholine in male or female rats. Individual analyses of each identified lipid species revealed 10 phosphatidylcholine and six sphingomyelin lipids in DEHP-treated females and a single lysophosphatidylcholine in DEHP-treated males with a two-fold or higher increase in relative abundance. Our results are congruent with previous work that found that postnatal exposure to DEHP had a near-selective detrimental effect on hippocampal development in males but not females. Together, results suggest a neuroprotective effect of these elevated lipid species in females. PMID:26516880

  9. Arsenic Exposure and Epigenetic Alterations: Recent Findings Based on the Illumina 450K DNA Methylation Array.

    PubMed

    Argos, Maria

    2015-06-01

    Arsenic is a major public health concern worldwide. While it is an established carcinogen and associated with a number of other adverse health outcomes, the molecular mechanisms underlying arsenic toxicity are not completely clarified. There is mounting evidence from human studies suggesting that arsenic exposure is associated with epigenetic alterations, including DNA methylation. In this review, we summarize several recent human studies that have evaluated arsenic exposure using the Illumina HumanMethylation 450K BeadChip, which interrogates more than 485,000 methylation sites across the genome. Many of these studies have observed novel regions of the genome associated with arsenic exposure. However, few studies have evaluated the biological and functional relevance of these DNA methylation changes, which are still needed. We emphasize the need for future studies to replicate the identified DNA methylation signals as well as assess whether these markers are associated with risk of arsenic-related diseases.

  10. Proteolytic activity is altered in brain tissue of rats upon chronic exposure to ozone

    SciTech Connect

    Benuck, M.; Banay-Schwartz, M.; Lajtha, A. )

    1993-01-01

    Tissue from pons medulla of rats exposed in vivo to various levels of ozone was assayed for calpain and cathepsin D activity. Chronic exposure to ozone increased calpain activity, which was 35% to 46% higher in the homogenates of animals exposed to 1.0 ppm ozone than in those of animals exposed to 0.5 ppm ozone or of controls. An increase in activity of 26% was also observed in the soluble supernatant. The increase in activity did not seem to be caused by ozone effects on calpastatin. Addition of 32 mM carnitine to the incubation mixture increased total activity 3-4 fold, making the differences in activity proportionately smaller. Cathepsin D activity was little altered. Changes in calpain activity and in the generation of free oxygen radicals have been implicated in the aging process, long-term exposure to ozone may magnify changes. Ozone exposure may cause changes in brain protein metabolism. 15 refs., 2 tabs.

  11. Cigarette smoke exposure-associated alterations to non-coding RNA.

    PubMed

    Maccani, Matthew A; Knopik, Valerie S

    2012-01-01

    Environmental exposures vary by timing, severity, and frequency and may have a number of deleterious effects throughout the life course. The period of in utero development, for example, is one of the most crucial stages of development during which adverse environmental exposures can both alter the growth and development of the fetus as well as lead to aberrant fetal programming, increasing disease risk. During fetal development and beyond, the plethora of exposures, including nutrients, drugs, stress, and trauma, influence health, development, and survival. Recent research in environmental epigenetics has investigated the roles of environmental exposures in influencing epigenetic modes of gene regulation during pregnancy and at various stages of life. Many relatively common environmental exposures, such as cigarette smoking, alcohol consumption, and drug use, may have consequences for the expression and function of non-coding RNA (ncRNA), important post-transcriptional regulators of gene expression. A number of ncRNA have been discovered, including microRNA (miRNA), Piwi-interacting RNA (piRNA), and long non-coding RNA (long ncRNA). The best-characterized species of ncRNA are miRNA, the mature forms of which are ∼22 nucleotides in length and capable of post-transcriptionally regulating target mRNA utilizing mechanisms based largely on the degree of complementarity between miRNA and target mRNA. Because miRNA can still negatively regulate gene expression when imperfectly base-paired with a target mRNA, a single miRNA can have a large number of potential mRNA targets and can regulate many different biological processes critical for health and development. The following review analyzes the current literature detailing links between cigarette smoke exposure and aberrant expression and function of ncRNA, assesses how such alterations may have consequences throughout the life course, and proposes future directions for this intriguing field of research.

  12. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.

    PubMed

    Caldwell, Katharine E; Labrecque, Matthew T; Solomon, Benjamin R; Ali, Abdulmehdi; Allan, Andrea M

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  13. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development

    PubMed Central

    Caldwell, Katharine E.; Labrecque, Matthew T.; Solomon, Benjamin R.; Ali, Abdulmehdi; Allan, Andrea M.

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50 ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  14. Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors.

    PubMed

    Blanco, Víctor M; Chu, Zhengtao; Vallabhapurapu, Subrahmanya D; Sulaiman, Mahaboob K; Kendler, Ady; Rixe, Olivier; Warnick, Ronald E; Franco, Robert S; Qi, Xiaoyang

    2014-08-30

    Brain tumors, either primary (e.g., glioblastoma multiforme) or secondary (metastatic), remain among the most intractable and fatal of all cancers. We have shown that nanovesicles consisting of Saposin C (SapC) and dioleylphosphatidylserine (DOPS) are able to effectively target and kill cancer cells both in vitro and in vivo. These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature. In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity. Second, we demonstrate that SapC-DOPS selectively targets brain metastases-forming cancer cells both in vitro, in co-cultures with human astrocytes, and in vivo, in mouse models of brain metastases derived from human breast or lung cancer cells. Third, we demonstrate that SapC-DOPS have cytotoxic activity against metastatic breast cancer cells in vitro, and prolong the survival of mice harboring brain metastases. Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

  15. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults

    PubMed Central

    Cheung, Ivy N.; Zee, Phyllis C.; Shalman, Dov; Malkani, Roneil G.; Kang, Joseph; Reid, Kathryn J.

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. PMID:27191727

  16. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults.

    PubMed

    Cheung, Ivy N; Zee, Phyllis C; Shalman, Dov; Malkani, Roneil G; Kang, Joseph; Reid, Kathryn J

    2016-01-01

    Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism.

  17. Altered Proteome of Burkholderia pseudomallei Colony Variants Induced by Exposure to Human Lung Epithelial Cells

    PubMed Central

    Al-Maleki, Anis Rageh; Mariappan, Vanitha; Vellasamy, Kumutha Malar; Tay, Sun Tee; Vadivelu, Jamuna

    2015-01-01

    Burkholderia pseudomallei primary diagnostic cultures demonstrate colony morphology variation associated with expression of virulence and adaptation proteins. This study aims to examine the ability of B. pseudomallei colony variants (wild type [WT] and small colony variant [SCV]) to survive and replicate intracellularly in A549 cells and to identify the alterations in the protein expression of these variants, post-exposure to the A549 cells. Intracellular survival and cytotoxicity assays were performed followed by proteomics analysis using two-dimensional gel electrophoresis. B. pseudomallei SCV survive longer than the WT. During post-exposure, among 259 and 260 protein spots of SCV and WT, respectively, 19 were differentially expressed. Among SCV post-exposure up-regulated proteins, glyceraldehyde 3-phosphate dehydrogenase, fructose-bisphosphate aldolase (CbbA) and betaine aldehyde dehydrogenase were associated with adhesion and virulence. Among the down-regulated proteins, enolase (Eno) is implicated in adhesion and virulence. Additionally, post-exposure expression profiles of both variants were compared with pre-exposure. In WT pre- vs post-exposure, 36 proteins were differentially expressed. Of the up-regulated proteins, translocator protein, Eno, nucleoside diphosphate kinase (Ndk), ferritin Dps-family DNA binding protein and peptidyl-prolyl cis-trans isomerase B were implicated in invasion and virulence. In SCV pre- vs post-exposure, 27 proteins were differentially expressed. Among the up-regulated proteins, flagellin, Eno, CbbA, Ndk and phenylacetate-coenzyme A ligase have similarly been implicated in adhesion, invasion. Protein profiles differences post-exposure provide insights into association between morphotypic and phenotypic characteristics of colony variants, strengthening the role of B. pseudomallei morphotypes in pathogenesis of melioidosis. PMID:25996927

  18. Genistein Exposure Inhibits Growth and Alters Steroidogenesis in Adult Mouse Antral Follicles

    PubMed Central

    Patel, Shreya; Peretz, Jackye; Pan, Yuan-Xiang; Helferich, William G.; Flaws, Jodi A.

    2016-01-01

    Genistein is a naturally occurring isoflavone phytoestrogen commonly found in plant products such as soybeans, lentils, and chickpeas. Genistein, like other phytoestrogens, has the potential to mimic, enhance, or impair the estradiol biosynthesis pathway, thereby potentially altering ovarian follicle growth. Previous studies have inconsistently indicated that genistein exposure may alter granulosa cell proliferation and hormone production, but no studies have examined the effects of genistein on intact antral follicles. Thus, this study was designed to test the hypothesis that genistein exposure inhibits follicle growth and steroidogenesis in intact antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice were cultured with vehicle (dimethyl sulfoxide; DMSO) or genistein (6.0 and 36 μM) for 18 – 96 hours (h). Every 24 h, follicle diameters were measured to assess growth. At the end of each culture period, the media were pooled to measure hormone levels, and the cultured follicles were collected to measure expression of cell cycle regulators and steroidogenic enzymes. The results indicate that genistein (36 μM) inhibits growth of mouse antral follicles. Additionally, genistein (6.0 and 36 μM) increases progesterone, testosterone, and dehydroepiandrosterone (DHEA) levels, but decreases estrone and estradiol levels. The results also indicate that genistein alters the expression of steroidogenic enzymes at 24, 72 and 96 h, and the expression of cell cycle regulators at 18 h. These data indicate that genistein exposure inhibits antral follicle growth by inhibiting the cell cycle, alters sex steroid hormone levels, and dysregulates steroidogenic enzymes in cultured mouse antral follicles. PMID:26792615

  19. Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs

    SciTech Connect

    Herring, M.J.; Putney, L.F.; St George, J.A.; Avdalovic, M.V.; Schelegle, E.S.; Miller, L.A.; Hyde, D.M.

    2015-02-15

    In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6 months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in the lung parenchyma would be permanent following a long-term recovery in filtered air (FA) housing. Forty-eight infant rhesus macaques (30 days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O{sub 3}) or HDMA/ozone (HDMA + O{sub 3}) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes, interalveolar capillary density. After 30 months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. These alveoli also had higher capillary densities as compared with FA controls. These results indicate that early life exposure to HDMA alone or HDMA + O{sub 3} alters the development process in the lung alveoli. - Highlights: • Abnormal lung development after postnatal exposure to ozone and allergen • This remodeling is shown as smaller, more numerous alveoli and narrower airways. • Allergen appears to have more of an effect than ozone during recovery. • These animals also have continued airway hyperresponsiveness (Moore et al. 2014)

  20. Subchronic arsenic exposure through drinking water alters vascular redox homeostasis and affects physical health in rats.

    PubMed

    Waghe, Prashantkumar; Sarath, Thengumpallil Sasindran; Gupta, Priyanka; Kutty, Harikumar Sankaran; Kandasamy, Kannan; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

    2014-12-01

    We evaluated whether arsenic can alter vascular redox homeostasis and modulate antioxidant status, taking rat thoracic aorta as a model vascular tissue. In addition, we evaluated whether the altered vascular biochemical homeostasis could be associated with alterations in the physical indicators of toxicity development. Rats were exposed to arsenic as 25, 50, and 100 ppm of sodium arsenite through drinking water for 90 consecutive days. Body weight, food intake, and water consumption were recorded weekly. On the 91st day, rats were sacrificed; vital organs and thoracic aorta were collected. Lipid peroxidation, reactive oxygen species generation, and antioxidants were assessed in the thoracic aorta. Arsenic increased aortic lipid peroxidation and hydrogen peroxide generation while decreased reduced glutathione content in a dose-dependent manner. The activities of the enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were decreased. Further, arsenic at 100 ppm decreased feed intake, water consumption, and body weight from the 11th week onward. At this concentration, arsenic increased the relative weights of the liver and kidney. The results suggest that arsenic causes dose-dependent oxidative stress, reduction in antioxidative defense systems, and body weight loss with alteration in hepato-renal organosomatic indices. Overall, subchronic arsenic exposure through drinking water causes alteration in vascular redox homeostasis and at high concentration affects physical health.

  1. Prenatal Exposure to Lipopolysaccharide Alters Renal DNA Methyltransferase Expression in Rat Offspring

    PubMed Central

    Chen, Rui; Deng, Youcai; Liao, Xi; Wei, Yanling; Li, Xiaohui; Su, Min; Yu, Jianhua; Yi, Ping

    2017-01-01

    Prenatal exposure to inflammation results in hypertension during adulthood but the mechanisms are not well understood. Maternal exposure to lipopolysaccharide (LPS) alters interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in the fetal environment. As reported in many recent studies, IL-6 regulates DNA methyltransferases (DNMTs) through the transcription factor friend leukemia virus integration 1 (Fli-1). The present study explores the role of intrarenal DNMTs during development of hypertension induced by prenatal exposure to LPS. Pregnant rats were randomly divided into four treatment groups: control, LPS, pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor), and the combination of LPS and PDTC. Expression of IL-6, Fli-1, TNF-α, DNMT1 and DNMT3B was significantly increased in the offspring of LPS-treated rats. Global DNA methylation level of renal cortex also increased dramatically in rat offspring of the LPS group. Prenatal PDTC administration reversed the increases in gene expression and global DNA methylation level. These findings suggest that prenatal exposure to LPS may result in changes of intrarenal DNMTs through the IL-6/Fli-1 pathway and TNF-α, which probably involves hypertension in offspring due to maternal exposure to inflammation. PMID:28103274

  2. Methamphetamine exposure during brain development alters the brain acetylcholine system in adolescent mice.

    PubMed

    Siegel, Jessica A; Park, Byung S; Raber, Jacob

    2011-10-01

    Children exposed to methamphetamine during brain development as a result of maternal drug use have long-term hippocampus-dependent cognitive impairments, but the mechanisms underlying these impairments are not understood. The acetylcholine system plays an important role in cognitive function and potential methamphetamine-induced acetylcholine alterations may be related to methamphetamine-induced cognitive impairments. In this study, we investigated the potential long-term effects of methamphetamine exposure during hippocampal development on the acetylcholine system in adolescence mice on postnatal day 30 and in adult mice on postnatal day 90. Methamphetamine exposure increased the density of acetylcholine neurons in regions of the basal forebrain and the area occupied by acetylcholine axons in the hippocampus in adolescent female mice. In contrast, methamphetamine exposure did not affect the density of GABA cells or total neurons in the basal forebrain. Methamphetamine exposure also increased the number of muscarinic acetylcholine receptors in the hippocampus of adolescent male and female mice. Our results demonstrate for the first time that methamphetamine exposure during hippocampal development affects the acetylcholine system in adolescent mice and that these changes are more profound in females than males.

  3. A Complex Interaction Between Reduced Reelin Expression and Prenatal Organophosphate Exposure Alters Neuronal Cell Morphology

    PubMed Central

    Mullen, Brian R.; Ross, Brennan; Chou, Joan Wang; Khankan, Rana; Khialeeva, Elvira; Bui, Kimberly

    2016-01-01

    Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders including schizophrenia, autism spectrum disorders, and major depressive disorders. Prior studies from our laboratory and others have demonstrated that the combinatorial effect of two factors—reduced expression of reelin protein and prenatal exposure to the organophosphate pesticide chlorpyrifos oxon—gives rise to acute biochemical effects and to morphological and behavioral phenotypes in adolescent and young adult mice. In the current study, we examine the consequences of these factors on reelin protein expression and neuronal cell morphology in adult mice. While the cell populations that express reelin in the adult brain appear unchanged in location and distribution, the levels of full length and cleaved reelin protein show persistent reductions following prenatal exposure to chlorpyrifos oxon. Cell positioning and organization in the hippocampus and cerebellum are largely normal in animals with either reduced reelin expression or prenatal exposure to chlorpyrifos oxon, but cellular complexity and dendritic spine organization is altered, with a skewed distribution of immature dendritic spines in adult animals. Paradoxically, combinatorial exposure to both factors appears to generate a rescue of the dendritic spine phenotypes, similar to the mitigation of behavioral and morphological changes observed in our prior study. Together, our observations support an interaction between reelin expression and chlorpyrifos oxon exposure that is not simply additive, suggesting a complex interplay between genetic and environmental factors in regulating brain morphology. PMID:27364165

  4. Acute exposure to 2,4-dinitrophenol alters zebrafish swimming performance and whole body triglyceride levels.

    PubMed

    Marit, Jordan S; Weber, Lynn P

    2011-06-01

    While swimming endurance (critical swimming speed or U(crit)) and lipid stores have both been reported to acutely decrease after exposure to a variety of toxicants, the relationship between these endpoints has not been clearly established. In order to examine these relationships, adult zebrafish (Danio rerio) were aqueously exposed to solvent control (ethanol) or two nominal concentrations of 2,4-dinitrophenol (DNP), a mitochondrial electron transport chain uncoupler, for a 24-h period. Following exposure, fish were placed in a swim tunnel in clean water for swimming testing or euthanized immediately without testing, followed by analysis of whole body triglyceride levels. U(crit) decreased in both the 6 mg/L and 12 mg/L DNP groups, with 12 mg/L approaching the LC₅₀. A decrease in tail beat frequency was observed without a significant change in tail beat amplitude. In contrast, triglyceride levels were elevated in a concentration-dependent manner in the DNP exposure groups, but only in fish subjected to swimming tests. This increase in triglyceride stores may be due to a direct interference of DNP on lipid catabolism as well as increased triglyceride production when zebrafish were subjected to the co-stressors of swimming and toxicant exposure. Future studies should be directed at determining how acute DNP exposure combines with swimming to cause alterations in triglyceride accumulation.

  5. Parental Exposure to Dim Light at Night Prior to Mating Alters Offspring Adaptive Immunity

    PubMed Central

    Cissé, Yasmine M.; Russart, Kathryn L.G.; Nelson, Randy J.

    2017-01-01

    Exposure to dim light at night (dLAN) disrupts natural light/dark cycles and impairs endogenous circadian rhythms necessary to maintain optimal biological function, including the endocrine and immune systems. We have previously demonstrated that white dLAN compromises innate and cell mediated immune responses in adult Siberian hamsters (Phodopus sungorus). We hypothesized that dLAN has transgenerational influences on immune function. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 9 weeks, then paired in full factorial design, mated, and thereafter housed under dark nights. Offspring were gestated and reared in dark nights, then tested as adults for cell-mediated and humoral immunity. Maternal exposure to dLAN dampened delayed type hypersensitivity (DTH) responses in male offspring. Maternal and paternal exposure to dLAN reduced DTH responses in female offspring. IgG antibodies to a novel antigen were elevated in offspring of dams exposed to dLAN. Paternal exposure to dLAN decreased splenic endocrine receptor expression and global methylation in a parental sex-specific manner. Together, these data suggest that exposure to dLAN has transgenerational effects on endocrine-immune function that may be mediated by global alterations in the epigenetic landscape of immune tissues. PMID:28361901

  6. Phosphatidylserine receptors: enhancers of enveloped virus entry and infection

    PubMed Central

    Moller-Tank, Sven; Maury, Wendy

    2014-01-01

    A variety of both RNA and DNA viruses envelop their capsids in a lipid bilayer. One of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (PtdSer). Surface exposure of PtdSer disguises viruses as apoptotic bodies; tricking cells into engulfing virions. This mechanism is termed apoptotic mimicry. Several PtdSer receptors have been identified to enhance virus entry and we have termed this group of proteins PtdSer-mediated virus entry enhancing receptors or PVEERs. These receptors enhance entry of a broad range of enveloped viruses. Internalization of virions by PVEERs provides a broad mechanism of entry with little investment by the virus itself and may allow some viruses to attach to cells, thereby making viral glycoprotein/cellular receptor interactions more probable. Alternatively, other viruses may rely entirely on PVEERs for internalization into endosomes. This review provides an overview of PtdSer receptors that serve as PVEERs and the biology behind virion/PVEER interaction. PMID:25277499

  7. In Vitro Exposure of Harbor Seal Immune Cells to Aroclor 1260 Alters Phocine Distemper Virus Replication.

    PubMed

    Bogomolni, Andrea; Frasca, Salvatore; Levin, Milton; Matassa, Keith; Nielsen, Ole; Waring, Gordon; De Guise, Sylvain

    2016-01-01

    In the last 30 years, several large-scale marine mammal mortality events have occurred, often in close association with highly polluted regions, leading to suspicions that contaminant-induced immunosuppression contributed to these epizootics. Some of these recent events also identified morbillivirus as a cause of or contributor to death. The role of contaminant exposures regarding morbillivirus mortality is still unclear. The results of this study aimed to address the potential for a mixture of polychlorinated biphenyls (PCBs), specifically Aroclor 1260, to alter harbor seal T-lymphocyte proliferation and to assess if exposure resulted in increased likelihood of phocine distemper virus (PDV USA 2006) to infect susceptible seals in an in vitro system. Exposure of peripheral blood mononuclear cells to Aroclor 1260 did not significantly alter lymphocyte proliferation (1, 5, 10, and 20 ppm). However, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), lymphocytes exposed to 20 ppm Aroclor 1260 exhibited a significant decrease in PDV replication at day 7 and a significant increase at day 11 compared with unexposed control cells. Similar and significant differences were apparent on exposure to Aroclor 1260 in monocytes and supernatant. The results here indicate that in harbor seals, Aroclor 1260 exposure results in a decrease in virus early during infection and an increase during late infection. The consequences of this contaminant-induced infection pattern in a highly susceptible host could result in a greater potential for systemic infection with greater viral load, which could explain the correlative findings seen in wild populations exposed to a range of persistent contaminants that suffer from morbillivirus epizootics.

  8. Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception

    PubMed Central

    Weikum, Whitney M.; Oberlander, Tim F.; Hensch, Takao K.; Werker, Janet F.

    2012-01-01

    Language acquisition reflects a complex interplay between biology and early experience. Psychotropic medication exposure has been shown to alter neural plasticity and shift sensitive periods in perceptual development. Notably, serotonin reuptake inhibitors (SRIs) are antidepressant agents increasingly prescribed to manage antenatal mood disorders, and depressed maternal mood per se during pregnancy impacts infant behavior, also raising concerns about long-term consequences following such developmental exposure. We studied whether infants’ language development is altered by prenatal exposure to SRIs and whether such effects differ from exposure to maternal mood disturbances. Infants from non–SRI-treated mothers with little or no depression (control), depressed but non–SRI-treated (depressed-only), and depressed and treated with an SRI (SRI-exposed) were studied at 36 wk gestation (while still in utero) on a consonant and vowel discrimination task and at 6 and 10 mo of age on a nonnative speech and visual language discrimination task. Whereas the control infants responded as expected (success at 6 mo and failure at 10 mo) the SRI-exposed infants failed to discriminate the language differences at either age and the depressed-only infants succeeded at 10 mo instead of 6 mo. Fetuses at 36 wk gestation in the control condition performed as expected, with a response on vowel but not consonant discrimination, whereas the SRI-exposed fetuses showed accelerated perceptual development by discriminating both vowels and consonants. Thus, prenatal depressed maternal mood and SRI exposure were found to shift developmental milestones bidirectionally on infant speech perception tasks. PMID:23045665

  9. Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration.

    PubMed

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P

    2013-08-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a "humanized" plasma METH half life or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7 and 1.5 µM. Animals were sacrificed during their last METH administration for autoradiography assessment using [³H]ligands and D2 agonist-induced [³⁵S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15-20%) and [³⁵S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal's total intake was similar within and across three 24-h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans.

  10. Alterations in the Striatal Dopamine System During Intravenous Methamphetamine Exposure: Effects of Contingent and Noncontingent Administration

    PubMed Central

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P.

    2014-01-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a ‘humanized’ plasma METH half life, or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7–1.5 μM. Animals were sacrificed during their last METH administration for autoradiography assessment using [3H]ligands and D2 agonist-induced [35S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15–20%) and [35S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal’s total intake was similar within and across three 24 h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  11. Perinatal exposure to diethylstilbestrol alters the functional differentiation of the adult rat uterus.

    PubMed

    Bosquiazzo, Verónica L; Vigezzi, Lucía; Muñoz-de-Toro, Mónica; Luque, Enrique H

    2013-11-01

    The exposure to endocrine disrupters and female reproductive tract disorders has not been totally clarified. The present study assessed the long-term effect of perinatal (gestation+lactation) exposure to diethylstilbestrol (DES) on the rat uterus and the effect of estrogen replacement therapy. DES (5μg/kg bw/day) was administered in the drinking water from gestational day 9 until weaning and we studied the uterus of young adult (PND90) and adult (PND360) females. To investigate whether perinatal exposure to DES modified the uterine response to a long-lasting estrogen treatment, 12-month-old rats exposed to DES were ovariectomized and treated with 17β-estradiol for 3 months (PND460). In young adult rats (PND90), the DES treatment decreased both the proliferation of glandular epithelial cells and the percentage of glandular perimeter occupied by α-smooth muscle actin-positive cells. The other tissue compartments remained unchanged. Cell apoptosis was not altered in DES-exposed females. In control adult rats (PND360), there were some morphologically abnormal uterine glands. In adult rats exposed to DES, the incidence of glands with cellular anomalies increased. In response to estrogens (PND460), the incidence of cystic glands increased in the DES group. We observed glands with daughter glands and conglomerates of glands only on PND460 and in response to estrogen replacement therapy, independently of DES exposure. The p63 isoforms were expressed without changes on PND460. Estrogen receptors α and β showed no changes, while the progesterone receptor decreased in the subepithelial stroma of DES-exposed animals with estrogen treatment. The long-lasting effects of perinatal exposure to DES included the induction of abnormalities in uterine tissues of aged female rats and an altered response of the adult uterus to estradiol.

  12. Chronic exposure to pentachlorophenol alters thyroid hormones and thyroid hormone pathway mRNAs in zebrafish.

    PubMed

    Yu, Li-Qin; Zhao, Gao-Feng; Feng, Min; Wen, Wu; Li, Kun; Zhang, Pan-Wei; Peng, Xi; Huo, Wei-Jie; Zhou, Huai-Dong

    2014-01-01

    Pentachlorophenol (PCP) is frequently detected in the aquatic environment and has been implicated as an endocrine disruptor in fish. In the present study, 4-month-old zebrafish (Danio rerio) were exposed to 1 of 4 concentrations of PCP (0.1, 1, 9, and 27 µg/L) for 70 d. The effects of PCP exposure on plasma thyroid hormone levels, and the expression levels of selected genes, were measured in the brain and liver. The PCP exposure at 27 µg/L resulted in elevated plasma thyroxine concentrations in male and female zebrafish and depressed 3, 5, 3'-triiodothyronine concentrations in males only. In both sexes, PCP exposure resulted in decreased messenger RNA (mRNA) expression levels of thyroid-stimulating hormone β-subunit (tshβ) and thyroid hormone receptor β (trβ) in the brain, as well as increased liver levels of uridine diphosphoglucuronosyl transferase (ugt1ab) and decreased deiodinase 1 (dio1). The authors also identified several sex-specific effects of PCP exposure, including changes in mRNA levels for deiodinase 2 (dio2), cytosolic sulfotransferase (sult1 st5), and transthyretin (ttr) genes in the liver. Environmental PCP exposure also caused an increased malformation rate in offspring that received maternal exposure to PCP. The present study demonstrates that chronic exposure to environmental levels of PCP alters plasma thyroid hormone levels, as well as the expression of genes associated with thyroid hormone signaling and metabolism in the hypothalamic-pituitary-thyroid (HPT) axis and liver, resulting in abnormal zebrafish development.

  13. Alterations in the Rat Serum Proteome Induced by Prepubertal Exposure to Bisphenol A and Genistein

    PubMed Central

    2015-01-01

    Humans are exposed to an array of chemicals via the food, drink and air, including a significant number that can mimic endogenous hormones. One such chemical is Bisphenol A (BPA), a synthetic chemical that has been shown to cause developmental alterations and to predispose for mammary cancer in rodent models. In contrast, the phytochemical genistein has been reported to suppress chemically induced mammary cancer in rodents, and Asians ingesting a diet high in soy containing genistein have lower incidence of breast and prostate cancers. In this study, we sought to: (1) identify protein biomarkers of susceptibility from blood sera of rats exposed prepubertally to BPA or genistein using Isobaric Tandem Mass Tags quantitative mass spectrometry (TMT-MS) combined with MudPIT technology and, (2) explore the relevance of these proteins to carcinogenesis. Prepubertal exposures to BPA and genistein resulted in altered expression of 63 and 28 proteins in rat sera at postnatal day (PND) 21, and of 9 and 18 proteins in sera at PND35, respectively. This study demonstrates the value of using quantitative proteomic techniques to explore the effect of chemical exposure on the rat serum proteome and its potential for unraveling cellular targets altered by BPA and genistein involved in carcinogenesis. PMID:24552547

  14. Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats

    PubMed Central

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Rojas, Patricia; Chávez-Saldaña, Margarita; Pérez, Oscar Gutiérrez; Montes, Sergio; Ríos, Camilo

    2011-01-01

    Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals. PMID:21324006

  15. Prenatal exposure to low levels of carbon monoxide alters sciatic nerve myelination in rat offspring.

    PubMed

    Carratù, M R; Cagiano, R; Desantis, S; Labate, M; Tattoli, M; Trabace, L; Cuomo, V

    2000-08-25

    Prenatal exposure to low concentrations of carbon monoxide (CO, 75 and 150 ppm from day 0 to day 20 of gestation), resulting in maternal blood HbCO concentrations equivalent to those maintained by human cigarette smokers, leads to subtle myelin alterations in the sciatic nerve of male rat offspring. The rapid growth spurt in pup body weight was related to the period of maximal increase in myelin sheath thickness in both control and CO-exposed animals. A significant reduction in myelin sheath thickness of sciatic nerve fibers, paralleled by changes in the frequency distribution, occurred in both 40- and 90-day-old rats exposed in utero to CO (75 and 150 ppm). Myelin deficit observed in 75 and 150 ppm CO-exposed animals showed up only after the major spurt in myelination but not early during development. The subtle myelin alterations observed in CO-exposed offspring were not accompanied by changes in developmental pattern of axon diameters and did not result in a gross impairment of motor activity. These results suggest that the myelination process is selectively targeted by a prenatal exposure model simulating the CO exposure observed in human cigarette smokers.

  16. Alterations in Cell Signaling Pathways in Breast Cancer Cells after Environmental Exposure

    SciTech Connect

    Kulp, K; McCutcheon-Maloney, S M; Bennett, L M

    2003-02-01

    Recent human epidemiological studies suggest that up to 75% of human cancers can be attributed to environmental exposures. Understanding the biologic impact of being exposed to a lifetime of complex environmental mixtures that may not be fully characterized is currently a major challenge. Functional endpoints may be used to assess the gross health consequences of complex mixture exposures from groundwater contamination, superfund sites, biologic releases, or nutritional sources. Such endpoints include the stimulation of cell growth or the induction of a response in an animal model. An environmental exposure that upsets normal cell growth regulation may have important ramifications for cancer development. Stimulating cell growth may alter an individual's cancer risk by changing the expression of genes and proteins that have a role in growth regulatory pathways within cells. Modulating the regulation of these genes and their products may contribute to the initiation, promotion or progression of disease in response to environmental exposure. We are investigating diet-related compounds that induce cell proliferation in breast cancer cell lines. These compounds, PhIP, Flor-Essence{reg_sign} and Essiac{reg_sign}, may be part of an everyday diet. PhIP is a naturally occurring mutagen that is formed in well-cooked muscle meats. PhIP consistently causes dose-dependent breast tumor formation in rats and consumption of well-done meat has been linked to increased risk of breast cancer in women. Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics are complementary and alternative medicines used by women who have been diagnosed with breast cancer as an alternative therapy for disease treatment and prevention. The long-term goal of this work is to identify those cellular pathways that are altered by a chemical or biologic environmental exposure and understand how those changes correlate with and or predict changes in human health risk. This project addressed this goal by

  17. Secretion of interferon gamma from human immune cells is altered by exposure to tributyltin and dibutyltin.

    PubMed

    Lawrence, Shanieek; Reid, Jacqueline; Whalen, Margaret

    2015-05-01

    Tributyltin (TBT) and dibutyltin (DBT) are widespread environmental contaminants found in food, beverages, and human blood samples. Both of these butyltins (BTs) interfere with the ability of human natural killer (NK) cells to lyse target cells and alter secretion of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells in vitro. The capacity of BTs to interfere with secretion of other pro-inflammatory cytokines has not been examined. Interferon gamma (IFNγ) is a modulator of adaptive and innate immune responses, playing an important role in overall immune competence. This study shows that both TBT and DBT alter secretion of IFNγ from human immune cells. Peripheral blood cell preparations that were increasingly reconstituted were used to determine if exposures to either TBT or DBT affected IFNγ secretion and how the makeup of the cell preparation influenced that effect. IFNγ secretion was examined after 24 h, 48 h, and 6 day exposures to TBT (200 - 2.5 nM) and DBT (5 - 0.05 µM) in highly enriched human NK cells, a monocyte-depleted preparation of PBMCs, and monocyte-containing PBMCs. Both BTs altered IFNγ secretion from immune cells at most of the conditions tested (either increasing or decreasing secretion). However, there was significant variability among donors as to the concentrations and time points that showed changes as well as the baseline secretion of IFNγ. The majority of donors showed an increase in IFNγ secretion in response to at least one concentration of TBT or DBT at a minimum of one length of exposure.

  18. Epigenetic Alterations May Regulate Temporary Reversal of CD4+ T Cell Activation Caused by Trichloroethylene Exposure

    PubMed Central

    Gilbert, Kathleen M.; Nelson, Ashley R.; Cooney, Craig A.; Reisfeld, Brad; Blossom, Sarah J.

    2012-01-01

    Previous studies have shown that short-term (4 weeks) or chronic (32 weeks) exposure to trichloroethylene (TCE) in drinking water of female MRL+/+ mice generated CD4+ T cells that secreted increased levels of interferon (IFN)-γ and expressed an activated (CD44hiCD62Llo) phenotype. In contrast, the current study of subchronic TCE exposure showed that midway in the disease process both of these parameters of CD4+ T cell activation were reversed. This phase of the disease process may represent an attempt by the body to counteract the inflammatory effects of TCE. The decrease in CD4+ T cell production of IFN-γ following subchronic TCE exposure could not be attributed to skewing toward a Th2 or Th17 phenotype or to an increase in Treg cells. Instead, the suppression corresponded to alterations in markers used to assess DNA methylation, namely increased expression of retrotransposons Iap (intracisternal A particle) and Muerv (murine endogenous retrovirus). Also observed was an increase in the expression of Dnmt1 (DNA methyltransferase-1) and decreased expression of several genes known to be downregulated by DNA methylation, namely Ifng, Il2, and Cdkn1a. CD4+ T cells from a second study in which MRL+/+ mice were treated for 17 weeks with TCE showed a similar increase in Iap and decrease in Cdkn1a. In addition, DNA collected from the CD4+ T cells in the second study showed TCE-decreased global DNA methylation. Thus, these results described the biphasic nature of TCE-induced alterations in CD4+ T cell function and suggested that these changes represented potentially reversible alterations in epigenetic processes. PMID:22407948

  19. In vitro exposure of Ulva lactuca Linnaeus (Chlorophyta) to gasoline - Biochemical and morphological alterations.

    PubMed

    Pilatti, Fernanda Kokowicz; Ramlov, Fernanda; Schmidt, Eder Carlos; Kreusch, Marianne; Pereira, Débora Tomazi; Costa, Christopher; de Oliveira, Eva Regina; Bauer, Cláudia M; Rocha, Miguel; Bouzon, Zenilda Laurita; Maraschin, Marcelo

    2016-08-01

    Refined fuels have considerable share of pollution of marine ecosystems. Gasoline is one of the most consumed fuel worldwide, but its effects on marine benthic primary producers are poorly investigated. In this study, Ulva lactuca was chosen as a biological model due to its cosmopolitan nature and tolerance to high levels and wide range of xenobiotics and our goal was to evaluate the effects of gasoline on ultrastructure and metabolism of that seaweed. The experimental design consisted of in vitro exposure of U. lactuca to four concentrations of gasoline (0.001%, 0.01%, 0.1%, and 1.0%, v/v) over 30 min, 1 h, 12 h, and 24 h, followed by cytochemical, SEM, and biochemical analysis. Increase in the number of cytoplasmic granules, loss of cell turgor, cytoplasmic shrinkage, and alterations in the mucilage were some of the ultrastructural alterations observed in thalli exposed to gasoline. Decrease in carotenoid and polyphenol contents, as well as increase of soluble sugars and starch contents were associated with the time of exposure to the xenobiotic. In combination, the results revealed important morphological and biochemical alterations in the phenotype of U. lactuca upon acute exposure to gasoline. This seaweed contain certain metabolites assigned as candidates to biomarkers of the environmental stress investigated and it is thought to be a promise species for usage in coastal ecosystems perturbation monitoring system. In addition, the findings suggest that U. lactuca is able to metabolize gasoline hydrocarbons and use them as energy source, acting as bioremediator of marine waters contaminated by petroleum derivatives.

  20. Acetylcholinesterase activity and antioxidant capacity of zebrafish brain is altered by heavy metal exposure.

    PubMed

    Richetti, S K; Rosemberg, D B; Ventura-Lima, J; Monserrat, J M; Bogo, M R; Bonan, C D

    2011-01-01

    Pollution is a world problem with immeasurable consequences. Heavy metal compounds are frequently found as components of anthropogenic pollution. Here we evaluated the effects of the treatment with cadmium acetate, lead acetate, mercury chloride, and zinc chloride in acetylcholinesterase activity and gene expression pattern, as well as the effects of these treatments in antioxidant competence in the brain of an aquatic and well-established organism for toxicological analysis, zebrafish (Danio rerio, Cyprinidae). Mercury chloride and lead acetate promoted a significant decrease in acetylcholinesterase activity whereas they did not alter the gene expression pattern. In addition, the antioxidant competence was decreased after exposure to mercury chloride. The data presented here allowed us to hypothesize a signal transmission impairment, through alterations in cholinergic transmission, and also in the antioxidant competence of zebrafish brain tissue as some of the several effects elicited by these pollutants.

  1. Adolescent Alcohol Exposure Alters GABAA Receptor Subunit Expression in Adult Hippocampus

    PubMed Central

    Centanni, Samuel W.; Teppen, Tara; Risher, Mary-Louise; Fleming, Rebekah L.; Moss, Julia L.; Acheson, Shawn K.; Mulholland, Patrick J.; Pandey, Subhash C.; Chandler, L. Judson; Swartzwelder, H. Scott

    2014-01-01

    Background The long-term consequences of adolescent alcohol abuse that persist into adulthood are poorly understood and have not been widely investigated. We have shown that intermittent exposure to alcohol during adolescence decreased the amplitude of GABAA receptor-mediated tonic currents in hippocampal dentate granule cells in adulthood. The aim of the present study was to investigate the enduring effects of chronic intermittent alcohol exposure during adolescence or adulthood on the expression of hippocampal GABAA receptors (GABAARs). Methods We used a previously characterized tissue fractionation method to isolate detergent resistant membranes and soluble fractions, followed by western blots to measure GABAAR protein expression. We also measured mRNA levels of GABAAR subunits using quantitative real-time PCR. Results Although the protein levels of α1-, α4- and δ-GABAAR subunits remained stable between postnatal day (PD) 30 (early adolescence) and PD71 (adulthood), the α5-GABAAR subunit was reduced across that period. In rats that were subjected to adolescent intermittent ethanol (AIE) exposure between PD30–46, there was a significant reduction in the protein levels of the δ-GABAAR, in the absence of any changes in mRNA levels, at 48 hours and 26 days after the last ethanol exposure. Protein levels of the α4-GABAAR subunit were significantly reduced, but mRNA levels were increased, 26 days (but not 48 hours) after the last AIE exposure. Protein levels of α5-GABAAR were not changed by AIE, but mRNA levels were reduced at 48hrs but normalized 26 days after AIE. In contrast to the effects of AIE, chronic intermittent exposure to ethanol during adulthood (CIE) had no effect on expression of any of the GABAAR subunits examined. Conclusions AIE produced both short- and long-term alterations of GABAAR subunits mRNA and protein expression in the hippocampus, whereas CIE produced no long lasting effects on those measures. The observed reduction of protein

  2. Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs.

    PubMed

    Schuster, Andrew; Skinner, Michael K; Yan, Wei

    Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5' halves of mature tRNAs (5' halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5' halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon.

  3. Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs

    PubMed Central

    Schuster, Andrew; Skinner, Michael K.; Yan, Wei

    2016-01-01

    Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5′ halves of mature tRNAs (5′ halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5′ halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon. PMID:27390623

  4. Thymosin α1 Interacts with Exposed Phosphatidylserine in Membrane Models and in Cells and Uses Serum Albumin as a Carrier.

    PubMed

    Mandaliti, Walter; Nepravishta, Ridvan; Sinibaldi Vallebona, Paola; Pica, Francesca; Garaci, Enrico; Paci, Maurizio

    2016-03-15

    Thymosin α1 is a peptidic hormone with pleiotropic activity and is used in the therapy of several diseases. It is unstructured in water solution and interacts with negative regions of vesicles by assuming two tracts of helical conformation with a structural break between them. This study reports on Thymosin α1's interaction with mixed phospholipids phosphatidylcholine and phosphatidylserine, the negative component of the membranes, by ¹H and natural abundance ¹⁵N nuclear magnetic resonance (NMR). The results indicate that interaction occurs when the membrane is negatively charged by exposing phosphatidylserine. Moreover, the direct interaction of Thymosin α1 with K562 cells with an overexposure of phosphatidylserine as a consequence of resveratrol-induced apoptosis was conducted. Thymosin α1's interaction with human serum albumin was also investigated by NMR spectroscopy. Steady-state saturation transfer, transfer nuclear Overhauser effect spectroscopy, and diffusion-ordered spectroscopy methodologies all reveal that the C-terminal region of Thymosin α1 is involved in the interaction with serum albumin. These results may shed more light on Thymosin α1's mechanism of action by its insertion in negative regions of membranes due to the exposure of phosphatidylserine. Once Thymosin α1's N-terminus has been inserted into the membrane, the rest may interact with nearby proteins and/or receptors acting as effectors and causing a biological signaling cascade, thus exerting thymosin α1's pleiotropy.

  5. Early postnatal diazepam exposure alters sex differences in the rat brain.

    PubMed

    Segovia, S; Pérez-Laso, C; Rodríguez-Zafra, M; Calés, J M; Del Abril, A; De Blas, M R; Collado, P; Valencia, A; Guillamón, A

    1991-06-01

    The volume and neuron number of the sexually dimorphic accessory olfactory bulb and locus coeruleus are altered by early postnatal exposure (from the day of birth to postnatal day 16) to diazepam. After diazepam treatment, both volume and neuron number were decreased in the male accessory olfactory bulb and in the female locus coeruleus. These results indicate that early postnatal diazepam administration can bear gender-dependent teratogenic effects upon sexually dimorphic nuclei and suggest that endogenous benzodiazepines may be involved in the sexual differentiation of the brain.

  6. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    SciTech Connect

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-06-27

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C {r_arrow} A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C {r_arrow} T, two C {r_arrow} A, one C {r_arrow} G, and one A {r_arrow} T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab.

  7. Common behaviors alterations after extremely low-frequency electromagnetic field exposure in rat animal model.

    PubMed

    Mahdavi, Seyed Mohammad; Sahraei, Hedayat; Rezaei-Tavirani, Mostafa; Najafi Abedi, Akram

    2016-01-01

    Naturally, the presence of electromagnetic waves in our living environment affects all components of organisms, particularly humans and animals, as the large part of their body consists of water. In the present study, we tried to investigate the relation between exposure to the extremely low-frequency electromagnetic field (ELF-EMF) and common behaviors such as body weight, food and water intake, anorexia (poor appetite), plasma glucose concentration, movement, rearing and sniffing in rats. For this purpose, rats were exposed to 40  Hz ELF-EMF once a day for 21 days, then at days 1, 3, 7, 14 and 21 after exposure, any changes in the above-mentioned items were assessed in the exposed rats and compared to the non-exposed group as control. Body weight of irradiated rats significantly increased only a week after exposure and decreased after that. No significant change was observed in food and water intake of irradiated rats compared to the control, and the anorexia parameter in the group exposed to ELF-EMF was significantly decreased at one and two weeks after irradiation. A week after exposure, the level of glucose was significantly increased but at other days these changes were not significant. Movements, rearing and sniffing of rats at day 1 after exposure were significantly decreased and other days these changes did not follow any particular pattern. However, the result of this study demonstrated that exposure to ELF-EMF can alter the normal condition of animals and may represent a harmful impact on behavior.

  8. Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos

    SciTech Connect

    Meyer, Armando; Seidler, Frederic J.; Aldridge, Justin E.; Slotkin, Theodore A. . E-mail: t.slotkin@duke.edu

    2005-03-01

    Exposure to apparently unrelated neurotoxicants can nevertheless converge on common neurodevelopmental events. We examined the long-term effects of developmental exposure of rats to terbutaline, a {beta}-adrenoceptor agonist used to arrest preterm labor, and the organophosphorus insecticide chlorpyrifos (CPF) separately and together. Treatments mimicked the appropriate neurodevelopmental stages for human exposures: terbutaline on postnatal days (PN) 2-5 and CPF on PN11-14, with assessments conducted on PN45. Although neither treatment affected growth or viability, each elicited alterations in CNS cell signaling mediated by adenylyl cyclase (AC), a transduction pathway shared by numerous neuronal and hormonal signals. Terbutaline altered signaling in the brainstem and cerebellum, with gender differences particularly notable in the cerebellum (enhanced AC in males, suppressed in females). By itself, CPF exposure elicited deficits in AC signaling in the midbrain, brainstem, and striatum. However, sequential exposure to terbutaline followed by CPF produced larger alterations and involved a wider spectrum of brain regions than were obtained with either agent alone. In the cerebral cortex, adverse effects of the combined treatment intensified between PN45 and PN60, suggesting that exposures alter the long-term program for development of synaptic communication, leading to alterations in AC signaling that emerge even after adolescence. These findings indicate that terbutaline, like CPF, is a developmental neurotoxicant, and reinforce the idea that its use in preterm labor may create a subpopulation that is sensitized to long-term CNS effects of organophosphorus insecticides.

  9. Detection of intracellular phosphatidylserine in living cells.

    PubMed

    Calderon, Frances; Kim, Hee-Yong

    2008-03-01

    To demonstrate the intracellular phosphatidylserine (PS) distribution in neuronal cells, neuroblastoma cells and hippocampal neurons expressing green fluorescence protein (GFP)-AnnexinV were stimulated with a calcium ionophore and localization of GFP-AnnexinV was monitored by fluorescence microscopy. Initially, GFP-AnnexinV distributed evenly in the cytosol and nucleus. Raising the intracellular calcium level with ionomycin-induced translocation of cytoplasmic GFP-AnnexinV to the plasma membrane but not to the nuclear membrane, indicating that PS distributes in the cytoplasmic side of the plasma membrane. Nuclear GFP-AnnexinV subsequently translocated to the nuclear membrane, indicating PS localization in the nuclear envelope. GFP-AnnexinV also localized in a juxtanuclear organelle that was identified as the recycling endosome. However, minimal fluorescence was detected in any other subcellular organelles including mitochondria, endoplasmic reticulum, Golgi complex, and lysosomes, strongly suggesting that PS distribution in the cytoplasmic face in these organelles is negligible. Similarly, in hippocampal primary neurons PS distributed in the inner leaflet of plasma membranes of cell body and dendrites, and in the nuclear envelope. To our knowledge, this is the first demonstration of intracellular PS localization in living cells, providing an insight for specific sites of PS interaction with soluble proteins involved in signaling processes.

  10. MicroRNA expression profiling altered by variant dosage of radiation exposure.

    PubMed

    Lee, Kuei-Fang; Chen, Yi-Cheng; Hsu, Paul Wei-Che; Liu, Ingrid Y; Wu, Lawrence Shih-Hsin

    2014-01-01

    Various biological effects are associated with radiation exposure. Irradiated cells may elevate the risk for genetic instability, mutation, and cancer under low levels of radiation exposure, in addition to being able to extend the postradiation side effects in normal tissues. Radiation-induced bystander effect (RIBE) is the focus of rigorous research as it may promote the development of cancer even at low radiation doses. Alterations in the DNA sequence could not explain these biological effects of radiation and it is thought that epigenetics factors may be involved. Indeed, some microRNAs (or miRNAs) have been found to correlate radiation-induced damages and may be potential biomarkers for the various biological effects caused by different levels of radiation exposure. However, the regulatory role that miRNA plays in this aspect remains elusive. In this study, we profiled the expression changes in miRNA under fractionated radiation exposure in human peripheral blood mononuclear cells. By utilizing publicly available microRNA knowledge bases and performing cross validations with our previous gene expression profiling under the same radiation condition, we identified various miRNA-gene interactions specific to different doses of radiation treatment, providing new insights for the molecular underpinnings of radiation injury.

  11. MicroRNA Expression Profiling Altered by Variant Dosage of Radiation Exposure

    PubMed Central

    Lee, Kuei-Fang; Hsu, Paul Wei-Che; Liu, Ingrid Y.; Wu, Lawrence Shih-Hsin

    2014-01-01

    Various biological effects are associated with radiation exposure. Irradiated cells may elevate the risk for genetic instability, mutation, and cancer under low levels of radiation exposure, in addition to being able to extend the postradiation side effects in normal tissues. Radiation-induced bystander effect (RIBE) is the focus of rigorous research as it may promote the development of cancer even at low radiation doses. Alterations in the DNA sequence could not explain these biological effects of radiation and it is thought that epigenetics factors may be involved. Indeed, some microRNAs (or miRNAs) have been found to correlate radiation-induced damages and may be potential biomarkers for the various biological effects caused by different levels of radiation exposure. However, the regulatory role that miRNA plays in this aspect remains elusive. In this study, we profiled the expression changes in miRNA under fractionated radiation exposure in human peripheral blood mononuclear cells. By utilizing publicly available microRNA knowledge bases and performing cross validations with our previous gene expression profiling under the same radiation condition, we identified various miRNA-gene interactions specific to different doses of radiation treatment, providing new insights for the molecular underpinnings of radiation injury. PMID:25313363

  12. Biochemical alterations induced by oral subchronic exposure to fipronil, fluoride and their combination in buffalo calves.

    PubMed

    Gill, Kamalpreet Kaur; Dumka, Vinod Kumar

    2013-11-01

    The effects of various pesticides and minerals on biochemical parameters have been explored in different species, but hardly any data exist regarding the combined toxicological effect of pesticides and minerals on these parameters in animals. The present study investigated the effects of fipronil and fluoride co-exposure on biochemical parameters in buffalo calves. Twenty-four healthy male buffalo calves divided into four groups were treated for 98 consecutive days. Group I, receiving no treatment served as the control. Animals of groups II and III were orally administered with fipronil @ 0.5mg/kg/day and sodium fluoride (NaF) @ 6.67 mg/kg/day, respectively, for 98 days. An additional group IV was co-administered fipronil and NaF at the same dosages as groups II and III. Administration of fipronil alone produced mild toxic signs, significant elevation in plasma proteins, blood glucose, blood urea nitrogen (BUN) and significant decline in the plasma cholesterol levels. NaF exposure produced toxic signs specifically of muscle weakness and brown and black discoloration of teeth. Significant elevation was seen in whole blood cholinesterase, BUN and creatinine levels. However, it produced significant decline in blood glucose, cholesterol and plasma protein levels. Combined exposure to fipronil and sodium fluoride produced toxic signs with greater intensity while biochemical alterations produced were similar to those that were produced by their individual exposures.

  13. Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour

    PubMed Central

    Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C.; Hughes, Ieuan A.; Acerini, Carlo L.

    2016-01-01

    Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development. PMID:26833843

  14. Nicotine exposure in adolescence alters the response of serotonin systems to nicotine administered subsequently in adulthood.

    PubMed

    Slotkin, Theodore A; Seidler, Frederic J

    2009-01-01

    Developmental nicotine exposure produces lasting changes in serotonin (5-HT) function. We gave nicotine to adolescent rats (postnatal days, PD, 30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in young adulthood (PD 90-107), focusing on 5-HT(1A) and 5-HT(2) receptors and the 5-HT transporter during nicotine treatment (PD 105) and withdrawal (PD 110, 120, 130), and long-term changes (PD 180). Adolescent nicotine exposure by itself evoked long-term elevations in cerebrocortical binding parameters in males that emerged in young adulthood. Nicotine given in adulthood produced transient elevations in 5-HT receptor expression in both males and females during withdrawal, and persistent upregulation in the male cerebral cortex. In contrast, females showed decrements in cerebrocortical 5-HT receptors by PD 180. Adolescent nicotine exposure altered the responses to nicotine given in adulthood, sensitizing the initial effects and changing both the withdrawal response and long-term actions. Our results thus provide mechanistic evidence that nicotine exposure, during the period in which nearly all smokers begin to use tobacco, reprograms the future response of 5-HT systems to nicotine.

  15. Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells.

    PubMed

    Agarwal, Amit R; Yin, Fei; Cadenas, Enrique

    2014-08-01

    Cigarette smoke (CS)-induced alveolar destruction and energy metabolism changes are known contributors to the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examines the effect of CS exposure on metabolism in alveolar type II cells. Male A/J mice (8 wk old) were exposed to CS generated from a smoking machine for 4 or 8 weeks, and a recovery group was exposed to CS for 8 weeks and allowed to recover for 2 weeks. Alveolar type II cells were isolated from air- or CS- exposed mice. Acute CS exposure led to a reversible airspace enlargement in A/J mice as measured by the increase in mean linear intercept, indicative of alveolar destruction. The effect of CS exposure on cellular respiration was studied using the XF Extracellular Flux Analyzer. A decrease in respiration while metabolizing glucose was observed in the CS-exposed group, indicating altered glycolysis that was compensated by an increase in palmitate utilization; palmitate utilization was accompanied by an increase in the expression of CD36 and carnitine-palmitoyl transferase 1 in type II alveolar cells for the transport of palmitate into the cells and into mitochondria, respectively. The increase in palmitate use for energy production likely affects the surfactant biosynthesis pathway, as evidenced by the decrease in phosphatidylcholine levels and the increase in phospholipase A2 activity after CS exposure. These findings help our understanding of the mechanism underlying the surfactant deficiency observed in smokers and provide a target to delay the onset of COPD.

  16. Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour.

    PubMed

    Hines, Melissa; Pasterski, Vickie; Spencer, Debra; Neufeld, Sharon; Patalay, Praveetha; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L

    2016-02-19

    Individual variability in human gender-related behaviour is influenced by many factors, including androgen exposure prenatally, as well as self-socialization and socialization by others postnatally. Many studies have looked at these types of influences in isolation, but little is known about how they work together. Here, we report that girls exposed to high concentrations of androgens prenatally, because they have the genetic condition congenital adrenal hyperplasia, show changes in processes related to self-socialization of gender-related behaviour. Specifically, they are less responsive than other girls to information that particular objects are for girls and they show reduced imitation of female models choosing particular objects. These findings suggest that prenatal androgen exposure may influence subsequent gender-related behaviours, including object (toy) choices, in part by changing processes involved in the self-socialization of gendered behaviour, rather than only by inducing permanent changes in the brain during early development. In addition, the findings suggest that some of the behavioural effects of prenatal androgen exposure might be subject to alteration by postnatal socialization processes. The findings also suggest a previously unknown influence of early androgen exposure on later processes involved in self-socialization of gender-related behaviour, and thus expand understanding of the developmental systems regulating human gender development.

  17. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L. L.

    2003-10-01

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

  18. Bisphenol A Exposure Alters Developmental Gene Expression in the Fetal Rhesus Macaque Uterus

    PubMed Central

    Calhoun, Kathryn C.; Padilla-Banks, Elizabeth; Jefferson, Wendy N.; Liu, Liwen; Gerrish, Kevin E.; Young, Steven L.; Wood, Charles E.; Hunt, Patricia A.; VandeVoort, Catherine A.; Williams, Carmen J.

    2014-01-01

    Bisphenol A (BPA) exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 µg/kg BPA or vehicle control daily from gestation day (GD) 50–100 or GD100–165. Fetal uteri were collected at the completion of treatment (GD100 or GD165); tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERα) and progesterone receptor (PR) were compared to that of controls. Gene expression analysis was conducted using rhesus macaque microarrays. There were no significant differences in histology or in the percentage of cells expressing the proliferation marker Ki-67, ERα, or PR in BPA-exposed uteri compared to controls at GD100 or GD165. Minimal differences in gene expression were observed between BPA-exposed and control GD100 uteri. However, at GD165, BPA-exposed uteri had significant differences in gene expression compared to controls. Several of the altered genes, including HOXA13, WNT4, and WNT5A, are critical for reproductive organ development and/or adult function. We conclude that second or third trimester BPA exposure does not significantly affect fetal uterus development based on morphological, proliferation, and steroid hormone receptor assessments. However, differences in expression of key developmental genes after third trimester exposure suggest that BPA could alter transcriptional signals influencing uterine function later in life. PMID:24465770

  19. Exposure to nicotine during periadolescence or early adulthood alters aversive and physiological effects induced by ethanol.

    PubMed

    Rinker, Jennifer A; Hutchison, Mary Anne; Chen, Scott A; Thorsell, Annika; Heilig, Markus; Riley, Anthony L

    2011-07-01

    The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4mg/kg, IP) from postnatal days 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0g/kg) and the hypothermic effects of alcohol (1.0g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8g/kg) and hypothermic (1.8g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine may alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed.

  20. Moderate prenatal alcohol exposure alters behavior and neuroglial parameters in adolescent rats.

    PubMed

    Brolese, Giovana; Lunardi, Paula; Broetto, Núbia; Engelke, Douglas S; Lírio, Franciane; Batassini, Cristiane; Tramontina, Ana Carolina; Gonçalves, Carlos-Alberto

    2014-08-01

    Alcohol consumption by women during gestation has become increasingly common. Although it is widely accepted that exposure to high doses of ethanol has long-lasting detrimental effects on brain development, the case for moderate doses is underappreciated, and benchmark studies have demonstrated structural and behavioral defects associated with moderate prenatal alcohol exposure in humans and animal models. This study aimed to investigate the influence of in utero exposure to moderate levels of ethanol throughout pregnancy on learning/memory, anxiety parameters and neuroglial parameters in adolescent offspring. Female rats were exposed to an experimental protocol throughout gestation up to weaning. After mating, the dams were divided into three groups and treated with only water (control), non-alcoholic beer (vehicle) or 10% (vv) beer solution (moderate prenatal alcohol exposure - MPAE). Adolescent male offspring were subjected to the plus-maze discriminative avoidance task to evaluate learning/memory and anxiety-like behavior. Hippocampi were dissected and slices were obtained for immunoquantification of GFAP, NeuN, S100B and the NMDA receptor. The MPAE group clearly presented anxiolytic-like behavior, even though they had learned how to avoid the aversive arm. S100B protein was increased in the cerebrospinal fluid (CSF) in the group treated with alcohol, and alterations in GFAP expression were also shown. This study indicates that moderate ethanol doses administered during pregnancy could induce anxiolytic-like effects, suggesting an increase in risk-taking behavior in adolescent male offspring. Furthermore, the data show the possibility that glial cells are involved in the altered behavior present after prenatal ethanol treatment.

  1. Growth of human bronchial epithelial cells at an air-liquid interface alters the response to particle exposure

    EPA Science Inventory

    Abstract: We tested the hypothesis that relative to submerged cells, airway epithelial cells grown at an air-liquid interface would have an altered response to particle exposure. RNA for IL-8, IL-6, heme oxygenase 1 and cyclooxygenase 2 increased following exposure of submer...

  2. Developmental exposure to endocrine disrupting chemicals alters the epigenome: Identification of reprogrammed targets

    PubMed Central

    Prusinski, Lauren; Al-Hendy, Ayman; Yang, Qiwei

    2016-01-01

    Endocrine disruptions induced by environmental toxicants have placed an immense burden on society to properly diagnose, treat and attempt to alleviate symptoms and disease. Environmental exposures during critical periods of development can permanently reprogram normal physiological responses, thereby increasing susceptibility to disease later in life - a process known as developmental reprogramming. During development, organogenesis and tissue differentiation occur through a continuous series of tightly-regulated and precisely-timed molecular, biochemical and cellular events. Humans may encounter endocrine disrupting chemicals (EDCs) daily and during all stages of life, from conception and fetal development through adulthood and senescence. Though puberty and perimenopausal periods may be affected by endocrine disruption due to hormonal effects, prenatal and early postnatal windows are most critical for proper development due to rapid changes in system growth. Developmental reprogramming is shown to be caused by alterations in the epigenome. Development is the time when epigenetic programs are ‘installed’ on the genome by ‘writers’, such as histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), which add methyl groups to lysine and arginine residues on histone tails and to CpG sites in DNA, respectively. A number of environmental compounds, referred to as estrogenic endocrine disruptors (EEDs), are able to bind to estrogen receptors (ERs) and interfere with the normal cellular development in target tissues including the prostate and uterus. These EEDs, including diethylstilbestrol (DES), bisphenol A (BPA), and genistein (a phytoestrogen derived from soybeans), have been implicated in the malformation of reproductive organs and later development of disease. Due to the lack of fully understanding the underlying mechanisms of how environmental toxicants and their level of exposure affect the human genome, it can be challenging to create clear

  3. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    PubMed

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia.

  4. Prenatal exposure to pesticides disrupts testicular histoarchitecture and alters testosterone levels in male Caiman latirostris.

    PubMed

    Rey, Florencia; González, Marianela; Zayas, Marcelo A; Stoker, Cora; Durando, Milena; Luque, Enrique H; Muñoz-de-Toro, Mónica

    2009-07-01

    The increased use of agrochemical pesticides, such as atrazine (ATZ) and endosulfan (END), may have a significant impact on ecosystem health and biodiversity. The aim of this study was to investigate the consequences of in ovum exposure to ATZ and END on Caiman latirostris gonadal histo-functional features. Caiman eggs were collected from environmentally pristine areas and incubated in controlled conditions at male producing temperature (33 degrees C). At stage 20 of embryonic development, the sensitive stage for gonadal sex determination, eggs were exposed to one dose of either END or ATZ. Gonadal histo-morphology was examined in caiman hatchlings and serum levels of testosterone were measured. Regardless of treatment condition, all eggs incubated at 33 degrees C resulted in male hatchlings. Tortuous seminiferous tubules with increased perimeter, disrupted distribution of peritubular myoid cells (desmin positive), and emptied tubular lumens characterized the testes of pesticide-exposed caiman. An imbalance between proliferative activity and cell death was observed in the testes of caiman exposed to the higher doses of END, mainly due to a high frequency of apoptosis in intratubular cells. This altered cell turnover was associated with decreased testosterone levels. Prenatal exposure to only one dose of END and ATZ disrupted neonatal male gonadal histo-functional features. Alterations described here could have detrimental effects on the sexual maturation of the caiman and, ultimately, on the success of male caiman reproduction.

  5. Histopathological findings on Carassius auratus hepatopancreas upon exposure to acrylamide: correlation with genotoxicity and metabolic alterations.

    PubMed

    Larguinho, Miguel; Costa, Pedro M; Sousa, Gonçalo; Costa, Maria H; Diniz, Mário S; Baptista, Pedro V

    2014-12-01

    Acrylamide is an amide used in several industrial applications making it easily discharged to aquatic ecosystems. The toxicity of acrylamide to aquatic organisms is scarcely known, although previous studies with murine models provided evidence for deleterious effects. To assess the effects of acrylamide to freshwater fish, goldfish (Carassius auratus L.) were exposed to several concentrations of waterborne acrylamide and analysed for genotoxic damage, alterations to detoxifying enzymes and histopathology. Results revealed a dose-dependent increase in total DNA strand breakage, the formation of erythrocytic nuclear abnormalities and in the levels of hepatic cytochrome P4501A (CYP1A) and glutathione S-transferase (GST) activity. In addition, acrylamide induced more histopathological changes to pancreatic acini than to the hepatic parenchyma, regardless of exposure concentration, whereas hepatic tissue only endured significant alterations at higher concentrations of exposure. Thus, results confirm the genotoxic potential of acrylamide to fish and its ability to induce CYP1A, probably as a direct primary defence mechanism. This strongly suggests the substance's pro-mutagenic potential in fish, similarly to what is known for rodents. However, the deleterious effects observed in the pancreatic acini, more severe than in the liver, could indicate a specific, albeit unknown toxic mechanism of acrylamide to fish that overran the organism's metabolic defences against a chemical agent rather than causing a general systemic failure.

  6. Acute high-intensity sound exposure alters responses of place cells in hippocampus.

    PubMed

    Goble, T J; Møller, A R; Thompson, L T

    2009-07-01

    Overstimulation is known to activate neural plasticity in the auditory nervous system causing changes in function and re-organization. It has been shown earlier that overstimulation using high-intensity noise or tones can induce signs of tinnitus. Here we show in studies in rats that overstimulation causes changes in the way place cells of the hippocampus respond as rats search for rewards in a spatial maze. In familiar environments, a subset of hippocampal pyramidal neurons, known as place cells, respond when the animal moves through specific locations but are relatively silent in others. This place-field activity (i.e. location-specific firing) is stable in a fixed environment. The present study shows that activation of neural plasticity through overstimulation by sound can alter the response of these place cells. Rats implanted with chronic drivable dorsal hippocampal tetrodes (four microelectrodes) were assessed for stable single-unit place-field responses that were extracted from multiunit responses using NeuroExplorer computer spike-sorting software. Rats then underwent either 30 min exposure to a 4 kHz tone at 104 dB SPL or a control period in the same sound chamber. The place-field activity was significantly altered after sound exposure showing that plastic changes induced by overstimulation are not limited to the auditory nervous system but extend to other parts of the CNS, in this case to the hippocampus, a brain region often studied in the context of plasticity.

  7. Low lead environmental exposure alters semen quality and sperm chromatin condensation in northern Mexico.

    PubMed

    Hernández-Ochoa, Isabel; García-Vargas, Gonzalo; López-Carrillo, Lizbeth; Rubio-Andrade, Marisela; Morán-Martínez, Javier; Cebrián, Mariano E; Quintanilla-Vega, Betzabet

    2005-01-01

    We evaluated environmental-lead (Pb) effects on semen quality and sperm chromatin, considering Pb in seminal fluid (PbSF), spermatozoa (PbSpz), and blood (PbB) as exposure biomarkers in urban men (9.3 microg/dL PbB). Several individuals (44%) showed decreases in sperm quality; sperm concentration, motility, morphology and viability associated negatively with PbSpz, whereas semen volume associated negatively with PbSF. Multiple linear regression estimated PbSF and PbSpz thresholds for alterations in semen quality. Forty-eight percent of samples showed high values of nuclear chromatin condensation (NCD) positively associated with PbSF and zinc in spermatozoa (ZnSpz). ZnSpz values were higher than in fertile men. These results suggest that Pb may affect sperm chromatin by altering sperm Zn availability. PbB was not associated with semen quality or NCD, suggesting that Pb in semen compartments assesses better the amount of Pb in the reproductive tract; therefore, these are better biomarkers to evaluate toxicity at low Pb-exposure levels.

  8. Adolescent binge alcohol exposure alters hippocampal progenitor cell proliferation in rats: effects on cell cycle kinetics.

    PubMed

    McClain, Justin A; Hayes, Dayna M; Morris, Stephanie A; Nixon, Kimberly

    2011-09-01

    Binge alcohol exposure in adolescent rats potently inhibits adult hippocampal neurogenesis by altering neural progenitor cell (NPC) proliferation and survival; however, it is not clear whether alcohol results in an increase or decrease in net proliferation. Thus, the effects of alcohol on hippocampal NPC cell cycle phase distribution and kinetics were assessed in an adolescent rat model of an alcohol use disorder. Cell cycle distribution was measured using a combination of markers (Ki-67, bromodeoxyuridine incorporation, and phosphohistone H3) to determine the proportion of NPCs within G1, S, and G2/M phases of the cell cycle. Cell cycle kinetics were calculated using a cumulative bromodeoxyuridine injection protocol to determine the effect of alcohol on cell cycle length and S-phase duration. Binge alcohol exposure reduced the proportion of NPCs in S-phase, but had no effect on G1 or G2/M phases, indicating that alcohol specifically targets S-phase of the cell cycle. Cell cycle kinetics studies revealed that alcohol reduced NPC cell cycle duration by 36% and shortened S-phase by 62%, suggesting that binge alcohol exposure accelerates progression through the cell cycle. This effect would be expected to increase NPC proliferation, which was supported by a slight, but significant increase in the number of Sox-2+ NPCs residing in the hippocampal subgranular zone following binge alcohol exposure. These studies suggest the mechanism of alcohol inhibition of neurogenesis and also reveal the earliest evidence of the compensatory neurogenesis reaction that has been observed a week after binge alcohol exposure.

  9. Hypertension Does Not Alter the Increase in Cardiac Baroreflex Sensitivity Caused by Moderate Cold Exposure.

    PubMed

    Hintsala, Heidi E; Kiviniemi, Antti M; Tulppo, Mikko P; Helakari, Heta; Rintamäki, Hannu; Mäntysaari, Matti; Herzig, Karl-Heinz; Keinänen-Kiukaanniemi, Sirkka; Jaakkola, Jouni J K; Ikäheimo, Tiina M

    2016-01-01

    Exposure to cold increases blood pressure and may contribute to higher wintertime cardiovascular morbidity and mortality in hypertensive people, but the mechanisms are not well-established. While hypertension does not alter responses of vagally-mediated heart rate variability to cold, it is not known how hypertension modifies baroreflex sensitivity (BRS) and blood pressure variability during cold exposure. Our study assessed this among untreated hypertensive men during short-term exposure comparable to habitual winter time circumstances in subarctic areas. We conducted a population-based recruitment of 24 untreated hypertensive and 17 men without hypertension (age 55-65 years) who underwent a whole-body cold exposure (-10°C, wind 3 m/s, winter clothes, 15 min, standing). Electrocardiogram and continuous blood pressure were measured to compute spectral powers of systolic blood pressure and heart rate variability at low (0.04-0.15 Hz) and high frequency (0.15-0.4 Hz) and spontaneous BRS at low frequency (LF). Comparable increases in BRS were detected in hypertensive men, from 2.6 (2.0, 4.2) to 3.8 (2.5, 5.1) ms/mmHg [median (interquartile range)], and in control group, from 4.3 (2.7, 5.0) to 4.4 (3.1, 7.1) ms/mmHg. Instead, larger increase (p < 0.05) in LF blood pressure variability was observed in control group; response as median (interquartile range): 8 (2, 14) mmHg(2), compared with hypertensive group [0 (-13, 20) mmHg(2)]. Untreated hypertension does not disturb cardiovascular protective mechanisms during moderate cold exposure commonly occurring in everyday life. Blunted response of the estimate of peripheral sympathetic modulation may indicate higher tonic sympathetic activity and decreased sympathetic responsiveness to cold in hypertension.

  10. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts

    PubMed Central

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird’s-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant’s developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  11. Perinatal Exposure to Bisphenol-A Alters Peripubertal Mammary Gland Development in Mice

    PubMed Central

    Muñoz-de-Toro, Monica; Markey, Caroline M.; Wadia, Perinaaz R.; Luque, Enrique H.; Rubin, Beverly S.; Sonnenschein, Carlos; Soto, Ana M.

    2010-01-01

    Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of perinatal exposure to low, environmentally relevant doses of BPA [25 and 250 ng BPA/kg body weight (bw)·d] on the peripubertal development of the mammary gland. BPA exposure enhanced the mammary glands' sensitivity to estradiol in ovariectomized CD-1 mice. In their intact 30-d-old littermates, the area and numbers of terminal end buds relative to the gland ductal area increased whereas their apoptotic activity decreased. There was a positive correlation between ductal length and the age at first proestrus; that was reduced as the BPA dose increased, suggesting that BPA exposure slows down ductal invasion of the stroma. There was also a significant increase of progesterone receptor-positive ductal epithelial cells that were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in mice exposed to 25 ng BPA /kg bw·d. In conclusion, perinatal exposure to environmentally relevant BPA doses results in persistent alterations in mammary gland morphogenesis. Of special concern is the increased terminal end bud density at puberty as well as the increased number of terminal ends reported previously in adult animals, as these two structures are the sites at which cancer arises in humans and rodents. PMID:15919749

  12. Chronic 835-MHz radiofrequency exposure to mice hippocampus alters the distribution of calbindin and GFAP immunoreactivity.

    PubMed

    Maskey, Dhiraj; Pradhan, Jonu; Aryal, Bijay; Lee, Chang-Min; Choi, In-Young; Park, Ki-Sup; Kim, Seok Bae; Kim, Hyung Gun; Kim, Myeung Ju

    2010-07-30

    Exponential interindividual handling in wireless communication system has raised possible doubts in the biological aspects of radiofrequency (RF) exposure on human brain owing to its close proximity to the mobile phone. In the nervous system, calcium (Ca(2+)) plays a critical role in releasing neurotransmitters, generating action potential and membrane integrity. Alterations in intracellular Ca(2+) concentration trigger aberrant synaptic action or cause neuronal apoptosis, which may exert an influence on the cellular pathology for learning and memory in the hippocampus. Calcium binding proteins like calbindin D28-K (CB) is responsible for the maintaining and controlling Ca(2+) homeostasis. Therefore, in the present study, we investigated the effect of RF exposure on rat hippocampus at 835 MHz with low energy (specific absorption rate: SAR=1.6 W/kg) for 3 months by using both CB and glial fibrillary acidic protein (GFAP) specific antibodies by immunohistochemical method. Decrease in CB immunoreactivity (IR) was noted in exposed (E1.6) group with loss of interneurons and pyramidal cells in CA1 area and loss of granule cells. Also, an overall increase in GFAP IR was observed in the hippocampus of E1.6. By TUNEL assay, apoptotic cells were detected in the CA1, CA3 areas and dentate gyrus of hippocampus, which reflects that chronic RF exposure may affect the cell viability. In addition, the increase of GFAP IR due to RF exposure could be well suited with the feature of reactive astrocytosis, which is an abnormal increase in the number of astrocytes due to the loss of nearby neurons. Chronic RF exposure to the rat brain suggested that the decrease of CB IR accompanying apoptosis and increase of GFAP IR might be morphological parameters in the hippocampus damages.

  13. Opt2 mediates the exposure of phospholipids during cellular adaptation to altered lipid asymmetry.

    PubMed

    Yamauchi, Saori; Obara, Keisuke; Uchibori, Kenya; Kamimura, Akiko; Azumi, Kaoru; Kihara, Akio

    2015-01-01

    Plasma membrane lipid asymmetry is important for various membrane-associated functions and is regulated by membrane proteins termed flippases and floppases. The Rim101 pathway senses altered lipid asymmetry in the yeast plasma membrane. The mutant lem3Δ cells, in which lipid asymmetry is disturbed owing to the inactivation of the plasma membrane flippases, showed a severe growth defect when the Rim101 pathway was impaired. To identify factors involved in the Rim101-pathway-dependent adaptation to altered lipid asymmetry, we performed DNA microarray analysis and found that Opt2 induced by the Rim101 pathway plays an important role in the adaptation to altered lipid asymmetry. Biochemical investigation of Opt2 revealed its localization to the plasma membrane and the Golgi, and provided several lines of evidence for the Opt2-mediated exposure of phospholipids. In addition, Opt2 was found to be required for the maintenance of vacuolar morphology and polarized cell growth. These results suggest that Opt2 is a novel factor involved in cell homeostasis by regulating lipid asymmetry.

  14. Neonatal exposure to amphetamine alters social affiliation and central dopamine activity in adult male prairie voles.

    PubMed

    Fukushiro, D F; Olivera, A; Liu, Y; Wang, Z

    2015-10-29

    The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms pair bonds after mating. Recent data have shown that amphetamine (AMPH) is rewarding to prairie voles as it induces conditioned place preferences. Further, repeated treatment with AMPH impairs social bonding in adult prairie voles through a central dopamine (DA)-dependent mechanism. The present study examined the effects of neonatal exposure to AMPH on behavior and central DA activity in adult male prairie voles. Our data show that neonatal exposure to AMPH makes voles less social in an affiliation test during adulthood, but does not affect animals' locomotor activity and anxiety-like behavior. Neonatal exposure to AMPH also increases the levels of tyrosine hydroxylase (TH) and DA transporter (DAT) mRNA expression in the ventral tegmental area (VTA) in the brain, indicating an increase in central DA activity. As DA has been implicated in AMPH effects on behavioral and cognitive functions, altered DA activity in the vole brain may contribute to the observed changes in social behavior.

  15. Alteration of the behavioral effects of nicotine by chronic caffeine exposure.

    PubMed

    Tanda, G; Goldberg, S R

    2000-05-01

    The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Some epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the effects of nicotine. This paper reviews various aspects of the pharmacology of caffeine and nicotine, in humans and experimental animals, important for the understanding of the interactions between these drugs. In particular, recent experiments are reviewed in which chronic exposure to caffeine in the drinking water of rats facilitated acquisition of self-adminstration behavior, enhanced nicotine-induced increases in dopamine levels in the shell of the nucleus accumbens and altered the dopaminergic component of a nicotine discrimination. These studies provide evidence that the rewarding and subjective properties of nicotine can be changed by chronic caffeine exposure and indicate that caffeine exposure may be an important environmental factor in shaping and maintaining tobacco smoking.

  16. Metabolic and histopathological alterations in the marine bivalve Mytilus galloprovincialis induced by chronic exposure to acrylamide.

    PubMed

    Larguinho, Miguel; Cordeiro, Ana; Diniz, Mário S; Costa, Pedro M; Baptista, Pedro V

    2014-11-01

    Although the neurotoxic and genotoxic potential of acrylamide has been established in freshwater fish, the full breadth of the toxicological consequences induced by this xenobiotic has not yet been disclosed, particularly in aquatic invertebrates. To assess the effects of acrylamide on a bivalve model, the Mediterranean mussel (Mytilus galloprovincialis), two different setups were accomplished: 1) acute exposure to several concentrations of waterborne acrylamide to determine lethality thresholds of the substance and 2) chronic exposure to more reduced acrylamide concentrations to survey phases I and II metabolic endpoints and to perform a whole-body screening for histopathological alterations. Acute toxicity was low (LC50≈400mg/L). However, mussels were responsive to prolonged exposure to chronic concentrations of waterborne acrylamide (1-10mg/L), yielding a significant increase in lipid peroxidation plus EROD and GST activities. Still, total anti-oxidant capacity was not exceeded. In addition, no neurotoxic effects could be determined through acetylcholine esterase (AChE) activity. The findings suggest aryl-hydrocarbon receptor (Ahr)-dependent responses in mussels exposed to acrylamide, although reduced comparatively to vertebrates. No significant histological damage was found in digestive gland or gills but female gonads endured severe necrosis and oocyte atresia. Altogether, the results indicate that acrylamide may induce gonadotoxicity in mussels, although the subject should benefit from further research. Altogether, the findings suggest that the risk of acrylamide to aquatic animals, especially molluscs, may be underestimated.

  17. Dietary selenomethionine exposure alters swimming performance, metabolic capacity and energy homeostasis in juvenile fathead minnow.

    PubMed

    McPhee, D Landon; Janz, David M

    2014-10-01

    Selenium (Se) is known to cause chronic toxicity in aquatic species. In particular, dietary exposure of fish to selenomethionine (SeMet), the primary form of Se in the diet, is of concern. Recent studies suggest that chronic exposure to elevated dietary SeMet alters energy and endocrine homeostasis in adult fish. However, little is known about the direct effects of dietary SeMet exposure in juvenile fish. The objective of the present study was to investigate sublethal physiological effects of dietary SeMet exposure in juvenile fathead minnow (Pimephales promelas). Twenty days-post-hatch fathead minnow were exposed for 60 days to different measured concentrations (2.8, 5.4, 9.9, 26.5 μg Se/g dry mass [dm]) of Se in food in the form of SeMet. After exposure, samples were collected for Se analysis and fish were subjected to a swimming performance challenge to assess critical swim speed (Ucrit), tail beat frequency and tail beat amplitude, oxygen consumption (MO2), cost of transport (COT), standard metabolic rate (SMR), active metabolic rate (AMR), and factorial aerobic scope (F-AS). Ucrit was decreased in the 26.5 μg Se/g dm exposure group compared to the control group. Tail beat frequency and tail beat amplitude were significantly reduced in fish fed 9.9 and 26.5 μg Se/g. An increase in MO2 and COT was observed in the 9.9 and 26.5 μg Se/g exposure groups compared to the control group. While the AMR of the high dose group was increased relative to control, there were no significant differences in SMR and F-AS. Energy storage capacity was measured via whole body triglyceride and glycogen concentrations. Triglyceride concentrations in non-swam fish were elevated in the 5.4 μg Se/g group relative to controls. Fatigued (swam) fish had significantly lower whole body triglycerides than non-swam fish. All non-swam SeMet exposure groups had significantly decreased whole body glycogen concentrations compared to controls, while the 5.4 and 26.5 μg Se/g exposure groups had

  18. Exposure to mixtures of solvents among paint workers and biochemical alterations of liver function.

    PubMed Central

    Chen, J D; Wang, J D; Jang, J P; Chen, Y Y

    1991-01-01

    The objective of this study was to determine biochemical alterations of liver function among paint manufacturers and sprayers associated with exposure to organic solvents. Two paint manufacturing factories and 22 various kinds of spray painting factories (16 car painting, two aircraft painting, three video terminal painting; and one trailer painting) were included. Air concentrations of organic solvents were collected by personal samplers and analysed by gas chromatography. A total of 180 workers were given a comprehensive physical examination, a questionnaire, a liver function test, and a test for hepatitis B surface antigen. The questionnaire contained questions regarding detailed personal medical history, intake of alcohol, and use of medicine. Mixtures of solvents were used throughout the factories, and xylene and toluene were the major components found in almost all air samples with average contents of 46% and 29% on a weight basis of 67 air samples. No strong hepatotoxic solvents were detected. Workers were classified according to the different exposure patterns and different air concentrations of breathing zones as: high (eight hour time weighted average (8 h TWA) hygienic effects of solvents 0.25-9.83, median 1.66), short term high (8 h TWA hygienic effects of solvents 0-3.38, median 0.12), and low (8 h TWA hygienic effects of solvents all below 0.38). After applying a multivariate model to control the non-occupational factors (alcohol, medication, age, and hepatitis B viral infection), increase in gamma-glutamyl transferase (GGT) activity was found to be associated with severity of exposure to the mixture of solvents. Because the possible effects on GGT activity of non-occupational factors were controlled for, it is concluded that increased GGT activity among exposed workers may be due to a higher exposure to the mixture of solvents. PMID:1931729

  19. Does Switching to Reduced Ignition Propensity Cigarettes Alter Smoking Behavior or Exposure to Tobacco Smoke Constituents?

    PubMed Central

    Rees, Vaughan W.; Norton, Kaila J.; Cummings, K. Michael; Connolly, Gregory N.; Alpert, Hillel R.; Sjödin, Andreas; Romanoff, Lovisa; Li, Zheng; June, Kristie M.; Giovino, Gary A.

    2010-01-01

    Introduction: Since 2004, several jurisdictions have mandated that cigarettes show reduced ignition propensity (RIP) in laboratory testing. RIP cigarettes may limit fires caused by smoldering cigarettes, reducing fire-related deaths and injury. However, some evidence suggests that RIP cigarettes emit more carbon monoxide and polycyclic aromatic hydrocarbons, and smokers may alter their smoking patterns in response to RIP cigarettes. Both of these could increase smokers’ exposures to harmful constituents in cigarettes. Methods: An 18-day switching study with a comparison group was conducted in Boston, MA (N = 77), and Buffalo, NY (N = 83), in 2006–2007. Current daily smokers completed 4 laboratory visits and two 48-hr field data collections. After a 4-day baseline, Boston participants switched to RIP cigarettes for 14 days, whereas Buffalo participants smoked RIP cigarettes throughout. Outcome measures included cigarettes smoked per day; smoking topography; salivary cotinine; breath CO; and hydroxylated metabolites of pyrene, naphthalene, phenanthrene, and fluorene. Because the groups differed demographically, analyses adjusted for race, age, and sex. Results: We observed no significant changes in smoking topography or CO exposure among participants who switched to RIP cigarettes. Cigarette use decreased significantly in the switched group (37.7 cigarettes/48 hr vs. 32.6 cigarettes/48 hr, p = .031), while hydroxyphenanthrenes increased significantly (555 ng/g creatinine vs. 669 ng/g creatinine, p = .007). No other biomarkers were significantly affected. Discussion: Small increases in exposure to phenanthrene among smokers who switched to RIP versions were observed, while other exposures and smoking topography were not significantly affected. Toxicological implications of these findings are unclear. These findings should be weighed against the potential public health benefits of adopting RIP design standards for cigarette products. PMID:20805292

  20. Early Phthalates Exposure in Pregnant Women Is Associated with Alteration of Thyroid Hormones

    PubMed Central

    Tsai, Chih-Hsin; Liang, Wei-Yen; Li, Sih-Syuan; Huang, Han-Bin

    2016-01-01

    Introduction Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy. Method We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG). Results Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 μg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (β = –5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction. Conclusion We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations. PMID:27455052

  1. Acute and chronic ethanol exposure differentially alters alcohol dehydrogenase and aldehyde dehydrogenase activity in the zebrafish liver.

    PubMed

    Tran, Steven; Nowicki, Magda; Chatterjee, Diptendu; Gerlai, Robert

    2015-01-02

    Chronic ethanol exposure paradigms have been successfully used in the past to induce behavioral and central nervous system related changes in zebrafish. However, it is currently unknown whether chronic ethanol exposure alters ethanol metabolism in adult zebrafish. In the current study we examine the effect of acute ethanol exposure on adult zebrafish behavioral responses, as well as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activity in the liver. We then examine how two different chronic ethanol exposure paradigms (continuous and repeated ethanol exposure) alter behavioral responses and liver enzyme activity during a subsequent acute ethanol challenge. Acute ethanol exposure increased locomotor activity in a dose-dependent manner. ADH activity was shown to exhibit an inverted U-shaped curve and ALDH activity was decreased by ethanol exposure at all doses. During the acute ethanol challenge, animals that were continuously housed in ethanol exhibited a significantly reduced locomotor response and increased ADH activity, however, ALDH activity did not change. Zebrafish that were repeatedly exposed to ethanol demonstrated a small but significant attenuation of the locomotor response during the acute ethanol challenge but ADH and ALDH activity was similar to controls. Overall, we identified two different chronic ethanol exposure paradigms that differentially alter behavioral and physiological responses in zebrafish. We speculate that these two paradigms may allow dissociation of central nervous system-related and liver enzyme-dependent ethanol induced changes in zebrafish.

  2. Phosphatidylserine directly and positively regulates fusion of myoblasts into myotubes

    SciTech Connect

    Jeong, Jaemin; Conboy, Irina M.

    2011-10-14

    Highlights: {yields} PS broadly and persistently trans-locates to the outer leaflet of plasma membrane during myoblast fusion into myotubes. {yields} Robust myotubes are formed when PS liposomes are added exogenously. {yields} PS increases the width of de novo myotubes and the numbers of myonuclei, but not the myotube length. {yields} Annexin V or PS antibody inhibits myotube formation by masking exposed PS. -- Abstract: Cell membrane consists of various lipids such as phosphatidylserine (PS), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). Among them, PS is a molecular marker of apoptosis, because it is located to the inner leaflet of plasma membrane generally but it is moved to the outer leaflet during programmed cell death. The process of apoptosis has been implicated in the fusion of muscle progenitor cells, myoblasts, into myotubes. However, it remained unclear whether PS regulates muscle cell differentiation directly. In this paper, localization of PS to the outer leaflet of plasma membrane in proliferating primary myoblasts and during fusion of these myoblasts into myotubes is validated using Annexin V. Moreover, we show the presence of PS clusters at the cell-cell contact points, suggesting the importance of membrane ruffling and PS exposure for the myogenic cell fusion. Confirming this conclusion, experimentally constructed PS, but not PC liposomes dramatically enhance the formation of myotubes from myoblasts, thus demonstrating a direct positive effect of PS on the muscle cell fusion. In contrast, myoblasts exposed to PC liposomes produce long myotubes with low numbers of myonuclei. Moreover, pharmacological masking of PS on the myoblast surface inhibits fusion of these cells into myotubes in a dose-dependent manner.

  3. Neonatal exposure to a glyphosate based herbicide alters the development of the rat uterus.

    PubMed

    Guerrero Schimpf, Marlise; Milesi, María M; Ingaramo, Paola I; Luque, Enrique H; Varayoud, Jorgelina

    2017-02-01

    Glyphosate-based herbicides (GBHs) are extensively used to control weeds on both cropland and non-cropland areas. No reports are available regarding the effects of GBHs exposure on uterine development. We evaluated if neonatal exposure to a GBH affects uterine morphology, proliferation and expression of proteins that regulate uterine organogenetic differentiation in rats. Female Wistar pups received saline solution (control, C) or a commercial formulation of glyphosate (GBH, 2mg/kg) by sc injection every 48h from postnatal day (PND) 1 to PND7. Rats were sacrificed on PND8 (neonatal period) and PND21 (prepubertal period) to evaluate acute and short-term effects, respectively. The uterine morphology was evaluated in hematoxylin and eosin stained sections. The epithelial and stromal immunophenotypes were established by assessing the expression of luminal epithelial protein (cytokeratin 8; CK8), basal epithelial proteins (p63 and pan cytokeratin CK1, 5, 10 and 14); and vimentin by immunohistochemistry (IHC). To investigate changes on proteins that regulate uterine organogenetic differentiation we evaluated the expression of estrogen receptor alpha (ERα), progesterone receptor (PR), Hoxa10 and Wnt7a by IHC. The GBH-exposed uteri showed morphological changes, characterized by an increase in the incidence of luminal epithelial hyperplasia (LEH) and an increase in the stromal and myometrial thickness. The epithelial cells showed a positive immunostaining for CK8, while the stromal cells for vimentin. GBH treatment increased cell proliferation in the luminal and stromal compartment on PND8, without changes on PND21. GBH treatment also altered the expression of proteins involved in uterine organogenetic differentiation. PR and Hoxa10 were deregulated both immediately and two weeks after the exposure. ERα was induced in the stromal compartment on PND8, and was downregulated in the luminal epithelial cells of gyphosate-exposed animals on PND21. GBH treatment also increased

  4. Subchronic Arsenic Exposure Through Drinking Water Alters Lipid Profile and Electrolyte Status in Rats.

    PubMed

    Waghe, Prashantkumar; Sarkar, Souvendra Nath; Sarath, Thengumpallil Sasindran; Kandasamy, Kannan; Choudhury, Soumen; Gupta, Priyanka; Harikumar, Sankarankutty; Mishra, Santosh Kumar

    2017-04-01

    Arsenic is a groundwater pollutant and can cause various cardiovascular disorders in the exposed population. The aim of the present study was to assess whether subchronic arsenic exposure through drinking water can induce vascular dysfunction associated with alteration in plasma electrolytes and lipid profile. Rats were exposed to arsenic as 25, 50, and 100 ppm of sodium arsenite through drinking water for 90 consecutive days. On the 91st day, rats were sacrificed and blood was collected. Lipid profile and the levels of electrolytes (sodium, potassium, and chloride) were assessed in plasma. Arsenic reduced high-density lipoprotein cholesterol (HDL-C) and HDL-C/LDL-C ratio, but increased the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and electrolytes. The results suggest that the arsenic-mediated dyslipidemia and electrolyte retention could be important mechanisms in the arsenic-induced vascular disorder.

  5. Perinatal Nicotine Exposure Increases Obesity Susceptibility in Adult Male Rat Offspring by Altering Early Adipogenesis.

    PubMed

    Fan, Jie; Zhang, Wan-Xia; Rao, Yi-Song; Xue, Jing-Ling; Wang, Fei-Fei; Zhang, Li; Yan, You-E

    2016-11-01

    The present study aims to evaluate whether perinatal nicotine (NIC) exposure increases obesity susceptibility in adult male rat offspring by altering early adipogenesis. NIC was sc administered (2.0 mg/kg per day) to pregnant rats from gestational day 9 to the time of weaning (postnatal day 28). At weaning, NIC-exposed male pups had an increased body weight and inguinal sc fat mass and a decreased average cell area of adipocyte, which was accompanied by an overexpression of adipogenic and lipogenic genes in the epididymal white adipose tissue. Additionally, the hepatic lipogenic gene levels from NIC-exposed male pups were also affected. At 12 and 26 weeks of age, body weight and fat mass were increased, whereas there was no change in food intake in NIC-exposed male offspring. Adipogenic and lipogenic genes, glucose transporter 4, and leptin mRNA levels were increased, whereas adiponectin mRNA levels were decreased in the epididymal white adipose tissue of NIC-exposed males. The hepatic lipogenic gene expression of NIC-exposed males was increased. NIC-exposed male offspring showed normal glycemia and a higher serum insulin level, homeostasis model assessment of insulin resistance, and homeostasis model assessment of β-cell function. Furthermore, the NIC-exposed male offspring showed higher serum lipids and Castelli index I and lower nonesterified fatty acid. At 26 weeks, in the ip glucose and insulin tolerance tests, the glucose clearance was delayed, and the area under the curve was higher in the NIC-exposed male offspring. In conclusion, perinatal NIC exposure increased obesity susceptibility in adult male rat offspring by altering early adipogenesis.

  6. Functional and inflammatory alterations in the lung following exposure of rats to nitrogen mustard

    SciTech Connect

    Sunil, Vasanthi R.; Patel, Kinal J.; Shen, Jianliang; Reimer, David; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-01-01

    Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (male Wistar, 200-225 g) with nitrogen mustard (mechlorethamine hydrochloride, i.t., 0.25 mg/kg) resulted in marked histological changes in the respiratory tract, including necrotizing bronchiolitis, thickening of alveolar septa, and inflammation which was evident within 24 h. This was associated with increases in bronchoalveolar lavage protein and cells, confirming injury to alveolar epithelial regions of the lung. Nitrogen mustard administration also resulted in increased expression of inducible nitric oxide synthase and cyclooxygenase-2, pro-inflammatory proteins implicated in lung injury, in alveolar macrophages and alveolar and bronchial epithelial cells. Expression of connective tissue growth factor and matrix metalloproteinase-9, mediators regulating extracellular matrix turnover was also increased, suggesting that pathways leading to chronic lung disease are initiated early in the pathogenic process. Following nitrogen mustard exposure, alterations in lung mechanics and function were also observed. These included decreases in baseline static compliance, end-tidal volume and airway resistance, and a pronounced loss of methacholine responsiveness in resistance, tissue damping and elastance. Taken together, these data demonstrate that nitrogen mustard induces rapid structural and inflammatory changes in the lung which are associated with altered lung functioning. Understanding the nature of the injury induced by nitrogen mustard and related analogs may aid in the development of efficacious therapies for treatment of pulmonary injury resulting from exposure to vesicants.

  7. Steroid levels in crinoid echinoderms are altered by exposure to model endocrine disruptors.

    PubMed

    Lavado, Ramón; Barbaglio, Alice; Carnevali, M Daniela Candia; Porte, Cinta

    2006-06-01

    Sexual steroids (testosterone and estradiol) were measured in the whole body of wild specimens of the crinoid Antedon mediterranea collected from the Tyrrhenian Sea (Italy). Testosterone levels (274-1,488 pg/g wet weight (w.w.)) were higher than those of estradiol (60-442 pg/g w.w.) and no significant differences between males and females were observed. No clear seasonal trend was either detected - individuals from February, June and October 2004 analyzed - apart from a peak of estradiol in males in autumn. Nonetheless, dramatic changes on tissue steroid levels were observed when individuals were exposed to model androgenic and anti-androgenic compounds for 2 and 4 weeks. The selected compounds were 17 alpha-methyltestosterone (17 alpha-MT), triphenyltin (TPT), fenarimol (FEN), cyproterone acetate (CPA), and p,p'-DDE. Endogenous testosterone levels were significantly increased after exposure to 17 alpha-MT, TPT and FEN, while different responses were observed for estradiol; 17 alpha-MT and FEN increased endogenous estradiol (up to seven-fold), and TPT lead to a significant decrease. Concerning the anti-androgenic compounds, CPA significantly reduced testosterone in a dose-dependent manner without altering estradiol levels, whereas specimens exposed to p,p'-DDE at a low dose (24 ng/L) for 4 weeks showed a four-fold increase in T levels. Overall, the data show the ability of the selected compounds to alter endogenous steroid concentrations in A. mediterranea, and suggest the existence in this echinoderm species of vertebrate-like mechanisms that can be affected by exposure to androgenic and anti-androgenic chemicals.

  8. Prenatal exposure to urban air nanoparticles in mice causes altered neuronal differentiation and depression-like responses.

    PubMed

    Davis, David A; Bortolato, Marco; Godar, Sean C; Sander, Thomas K; Iwata, Nahoko; Pakbin, Payam; Shih, Jean C; Berhane, Kiros; McConnell, Rob; Sioutas, Constantinos; Finch, Caleb E; Morgan, Todd E

    2013-01-01

    Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m(3)) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols.

  9. In utero exposure to chloroquine alters sexual development in the male fetal rat

    SciTech Connect

    Clewell, Rebecca A. Pluta, Linda; Thomas, Russell S.; Andersen, Melvin E.

    2009-06-15

    Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenance doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.

  10. Adolescent exposure to nicotine alters the aversive effects of cocaine in adult rats.

    PubMed

    Hutchison, Mary Anne; Riley, Anthony L

    2008-01-01

    Nicotine is one of the most commonly used drugs in adolescence and has been shown to alter the rewarding effects of cocaine when administered in adulthood. Although the abuse potential of a drug has been suggested to be a balance between its rewarding and aversive effects, the long-term effects of nicotine on the aversive properties of other drugs had not been studied. To that end, in the present study rats exposed to nicotine (0.4 mg/kg) during adolescence (postnatal days 35-44) were tested for the acquisition and extinction of a cocaine-induced conditioned taste aversion (10, 18 or 32 mg/kg) in adulthood. Conditioning consisted of four saccharin-drug pairings followed by six extinction trials. Although cocaine-induced aversions at all doses, no effect of nicotine preexposure was seen during acquisition. During extinction, the nicotine-preexposed groups conditioned with 10 and 18 mg/kg cocaine displayed a decreased rate of extinction compared to their respective controls. These results suggest that while adolescent nicotine exposure does not appear to directly alter the aversive properties of cocaine it may affect other processes related to the response to drugs given in adulthood.

  11. Maternal caffeine exposure alters neuromotor development and hippocampus acetylcholinesterase activity in rat offspring.

    PubMed

    Souza, Ana Claudia; Souza, Andressa; Medeiros, Liciane Fernandes; De Oliveira, Carla; Scarabelot, Vanessa Leal; Da Silva, Rosane Souza; Bogo, Mauricio Reis; Capiotti, Katiucia Marques; Kist, Luiza Wilges; Bonan, Carla D; Caumo, Wolnei; Torres, Iraci L S

    2015-01-21

    The objective of this study was to evaluate the effects of maternal caffeine intake on the neuromotor development of rat offspring and on acetylcholine degradation and acetylcholinesterase (AChE) expression in the hippocampus of 14-day-old infant rats. Rat dams were treated with caffeine (0.3g/L) throughout gestation and lactation until the pups were 14 days old. The pups were divided into three groups: (1) control, (2) caffeine, and (3) washout caffeine. The washout group received a caffeine solution until the seventh postnatal day (P7). Righting reflex (RR) and negative geotaxis (NG) were assessed to evaluate postural parameters as an index of neuromotor reflexes. An open-field (OF) test was conducted to assess locomotor and exploratory activities as well as anxiety-like behaviors. Caffeine treatment increased both RR and NG latency times. In the OF test, the caffeine group had fewer outer crossings and reduced locomotion compared to control, while the washout group showed increased inner crossings in relation to the other groups and fewer rearings only in comparison to the control group. We found decreased AChE activity in the caffeine group compared to the other groups, with no alteration in AChE transcriptional regulation. Chronic maternal exposure to caffeine promotes important alterations in neuromotor development. These results highlight the ability of maternal caffeine intake to interfere with cholinergic neurotransmission during brain development.

  12. Alterations of oxidative stress biomarkers due to in utero and neonatal exposures of airborne manganese.

    PubMed

    Erikson, Keith M; Dorman, David C; Fitsanakis, Vanessa; Lash, Lawrence H; Aschner, Michael

    2006-01-01

    Neonatal rats were exposed to airborne manganese sulfate (MnSO4) (0, 0.05, 0.5, or 1.0 mg Mn/m3) during gestation (d 0-19) and postnatal days (PNDs) 1-18. On PND 19, rats were killed, and we assessed biochemical end points indicative of oxidative stress in five brain regions: cerebellum, hippocampus, hypothalamus, olfactory bulb, and striatum. Glutamine synthetase (GS) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), TH and GS mRNA levels, and reduced and oxidized glutathione (GSH and GSSG, respectively) levels were determined for all five regions. Mn exposure (all three doses) significantly (p = 0.0021) decreased GS protein levels in the cerebellum, and GS mRNA levels were significantly (p = 0.0008) decreased in the striatum. Both the median and high dose of Mn significantly (p = 0.0114) decreased MT mRNA in the striatum. Mn exposure had no effect on TH protein levels, but it significantly lowered TH mRNA levels in the olfactory bulb (p = 0.0402) and in the striatum (p = 0.0493). Mn exposure significantly lowered GSH levels at the median dose in the olfactory bulb (p = 0.0032) and at the median and high dose in the striatum (p = 0.0346). Significantly elevated (p = 0.0247) GSSG, which can be indicative of oxidative stress, was observed in the cerebellum of pups exposed to the high dose of Mn. These data reveal that alterations of oxidative stress biomarkers resulting from in utero and neonatal exposures of airborne Mn exist. Coupled with our previous study in which similarly exposed rats were allowed to recover from Mn exposure for 3 wk, it appears that many of these changes are reversible. It is important to note that the doses of Mn utilized represent levels that are a hundred- to a thousand-fold higher than the inhalation reference concentration set by the United States Environmental Protection Agency.

  13. Exposure to sorbitol during lactation causes metabolic alterations and genotoxic effects in rat offspring.

    PubMed

    Cardoso, Felipe S; Araujo-Lima, Carlos F; Aiub, Claudia A F; Felzenszwalb, Israel

    2016-10-17

    Sorbitol is a polyol used by the food industry as a sweetener. Women are consuming diet and light products containing sorbitol during pregnancy and in the postnatal period to prevent themselves from excessive weight gain and maintain a slim body. Although there is no evidence for the genotoxicity of sorbitol in the perinatal period, this study focused on evaluating the effects of the maternal intake of sorbitol on the biochemical and toxicological parameters of lactating Wistar rat offspring after 14days of mother-to-offspring exposure. A dose-dependent reduction of offspring length was observed. An increase in sorbitol levels determined in the milk was also observed. However, we detected an inverse relationship between the exposition dose in milk fructose and triacylglycerols concentrations. There was an increase in the plasmatic levels of ALT, AST and LDLc and a decrease in proteins, cholesterol and glucose levels in the offspring. Sorbitol exposure caused hepatocyte genotoxicity, including micronuclei induction. Maternal sorbitol intake induced myelotoxicity and myelosuppression in their offspring. The Comet assay of the blood cells detected a dose-dependent genotoxic response within the sorbitol-exposed offspring. According to our results, sorbitol is able to induce important metabolic alterations and genotoxic responses in the exposed offspring.

  14. Maternal nicotine exposure during lactation alters hypothalamic neuropeptides expression in the adult rat progeny.

    PubMed

    Younes-Rapozo, Viviane; Moura, Egberto G; Manhães, Alex C; Pinheiro, Cintia R; Santos-Silva, Ana Paula; de Oliveira, Elaine; Lisboa, Patricia C

    2013-08-01

    Maternal exposure to nicotine during lactation causes hyperleptinemia in the pups and, at adulthood, these animals are overweight and hyperleptinemic, while, in their hypothalamus, the leptin signaling pathway is reduced, evidencing a central leptin resistance. Then, we evaluated the expression of pro-opiomelanocortin (POMC), alpha-melanocyte stimulating hormone (α-MSH), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY), agouti-related peptide (AgRP) and others in different hypothalamic nuclei in order to better understand the mechanisms underlying the obese phenotype observed in these animals at adulthood. On the 2nd postnatal day (P2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6 mg/kg/day) or saline for 14 days. Offspring were killed in P180 and immunohistochemistry and Western blot analysis were carried out. Significance data had p<0.05. Adult NIC offspring showed more intense NPY staining in the paraventricular nucleus (PVN) (+21%) and increased number of POMC-positive cells in the: arcuate nucleus (+33%), as an increase in fiber density of α-MSH in PVN (+85%). However, the number of CART-positive cells was reduced in the PVN (-25%). CRH staining was more intense in NIC offspring (+136%). Orexins and AgRP were not altered. Thus, maternal nicotine exposure changes hypothalamic neuropeptides in the adult progeny that is partially compatible with leptin resistance.

  15. Alteration of transcriptional networks in the entorhinal cortex after maternal immune activation and adolescent cannabinoid exposure.

    PubMed

    Hollins, Sharon L; Zavitsanou, Katerina; Walker, Frederick Rohan; Cairns, Murray J

    2016-08-01

    Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders.

  16. Prenatal cocaine exposure alters emotional arousal regulation and its effects on working memory.

    PubMed

    Li, Zhihao; Coles, Claire D; Lynch, Mary Ellen; Hamann, Stephan; Peltier, Scott; LaConte, Stephen; Hu, Xiaoping

    2009-01-01

    While prenatal cocaine exposure (PCE) has been associated with arousal dysregulation and attentional impairments in both human and animal studies, the neurobiological bases of these teratogenic effects have not been well characterized. In the current study, we report functional neuroimaging observations of these effects in exposed youth. Using functional magnetic resonance imaging (fMRI), we embedded task-irrelevant emotional distracters in a working memory task to examine the interaction of emotional arousal and memory in 33 PCE and 23 non-exposed adolescents. Though with similar behavioral performance, the two groups exhibited different activation patterns associated with emotion-memory interactions. On the one hand, higher memory load attenuated emotion-related amygdala activation in controls but not in the exposed adolescents; on the other hand, prefrontal activation associated with memory load decreased in the presence of emotional distraction in the controls but increased in the exposed group. These group interaction differences suggest neurobiological substrates for arousal-associated neuronal alterations related to prenatal cocaine exposure. Consistent with previous findings in behavioral and physiological studies, the present neuroimaging data provided more in-depth evidence supporting the view that PCE has significant long-term teratogenic effect on arousal regulation system.

  17. Developmental exposure to methylmercury alters learning and induces depression-like behavior in male mice.

    PubMed

    Onishchenko, Natalia; Tamm, Christoffer; Vahter, Marie; Hökfelt, Tomas; Johnson, Jeffrey A; Johnson, Delinda A; Ceccatelli, Sandra

    2007-06-01

    To investigate the long-term effects of developmental exposure to methylmercury (MeHg), pregnant mice were exposed to at 0.5 mg MeHg/kg/day via drinking water from gestational day 7 until day 7 after delivery. The behavior of offspring was monitored at 5-15 and 26-36 weeks of age using an automated system (IntelliCage) designed for continuous long-term recording of the home cage behavior in social groups and complex analysis of basic activities and learning. In addition, spontaneous locomotion, motor coordination on the accelerating rotarod, spatial learning in Morris water maze, and depression-like behavior in forced swimming test were also studied. The analysis of behavior performed in the IntelliCage without social deprivation occurred to be more sensitive in detecting alterations in activity and learning paradigms. We found normal motor function but decreased exploratory activity in MeHg-exposed male mice, especially at young age. Learning disturbances observed in MeHg-exposed male animals suggest reference memory impairment. Interestingly, the forced swimming test revealed a predisposition to depressive-like behavior in the MeHg-exposed male offspring. This study provides novel evidence that the developmental exposure to MeHg can affect not only cognitive functions but also motivation-driven behaviors.

  18. Ethanol exposure during gastrulation alters neuronal morphology and behavior in zebrafish.

    PubMed

    Shan, Shubham D; Boutin, Savanna; Ferdous, Jannatul; Ali, Declan W

    2015-01-01

    Ethanol (EtOH) exposure during development has been shown to lead to deficits in fine and gross motor control. In this study we used zebrafish embryos to determine the effects of EtOH treatment during gastrulation. We treated embryos in the gastrulation stage (5.25 hours post fertilization (hpf) to 10.75 hpf) with 10 mM, 50 mM or 100 mM EtOH and examined the effects on general animal morphology, the c-start reflex behavior, Mauthner cell (M-cell) morphology and motor neuron morphology. EtOH treated fish exhibited a minor but significant increase in gross morphological deformities compared with untreated fish. Behavioral studies showed that EtOH treatment resulted in an increase in the peak speed of the tail during the escape response. Furthermore, there was a marked increase in abnormally directed c-starts, with treated fish showing greater incidences of c-starts in inappropriate directions. Immunolabeling of the M-cells, which are born during gastrulation, revealed that they were significantly smaller in fish treated with 100 mM EtOH compared with controls. Immunolabeling of primary motor neurons using anti-znp1, showed no significant effect on axonal branching, whereas secondary motor axons had a greater number of branches in ethanol treated fish compared with controls. Together these findings indicate that ethanol exposure during gastrulation can lead to alterations in behavior, neuronal morphology and possibly function.

  19. RNA-Seq Identifies Key Reproductive Gene Expression Alterations in Response to Cadmium Exposure

    PubMed Central

    Hu, Hanyang; Lu, Xing; Cen, Xiang; Chen, Xiaohua; Li, Feng; Zhong, Shan

    2014-01-01

    Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice. PMID:24982889

  20. Prenatal cocaine exposure alters emotional arousal regulation and its effects on working memory

    PubMed Central

    Li, Zhihao; Coles, Claire D.; Lynch, Mary Ellen; Hamann, Stephan; Peltier, Scott; LaConte, Stephen; Hu, Xiaoping

    2009-01-01

    While prenatal cocaine exposure (PCE) has been associated with arousal dysregulation and attentional impairments in both human and animal studies, the neurobiological bases of these teratogenic effects have not been well characterized. In the current study, we report functional neuroimaging observations of these effects in exposed youth. Using functional magnetic resonance imaging (fMRI), we embedded task-irrelevant emotional distracters in a working memory task to examine the interaction of emotional arousal and memory in 33 PCE and 23 non-exposed adolescents. Though with similar behavioral performance, the two groups exhibited different activation patterns associated with emotion-memory interactions. On the one hand, higher memory load attenuated emotion-related amygdala activation in controls but not in the exposed adolescents; on the other hand, prefrontal activation associated with memory load decreased in the presence of emotional distraction in the controls but increased in the exposed group. These group interaction differences suggest neurobiological substrates for arousal-associated neuronal alterations related to prenatal cocaine exposure. Consistent with previous findings in behavioral and physiological studies, the present neuroimaging data provided more in-depth evidence supporting the view that PCE has significant long-term teratogenic effect on arousal regulation system. PMID:19699795

  1. Exposure of soil microbial communities to chromium and arsenic alters their diversity and structure.

    PubMed

    Sheik, Cody S; Mitchell, Tyler W; Rizvi, Fariha Z; Rehman, Yasir; Faisal, Muhammad; Hasnain, Shahida; McInerney, Michael J; Krumholz, Lee R

    2012-01-01

    Extensive use of chromium (Cr) and arsenic (As) based preservatives from the leather tanning industry in Pakistan has had a deleterious effect on the soils surrounding production facilities. Bacteria have been shown to be an active component in the geochemical cycling of both Cr and As, but it is unknown how these compounds affect microbial community composition or the prevalence and form of metal resistance. Therefore, we sought to understand the effects that long-term exposure to As and Cr had on the diversity and structure of soil microbial communities. Soils from three spatially isolated tanning facilities in the Punjab province of Pakistan were analyzed. The structure, diversity and abundance of microbial 16S rRNA genes were highly influenced by the concentration and presence of hexavalent chromium (Cr (VI)) and arsenic. When compared to control soils, contaminated soils were dominated by Proteobacteria while Actinobacteria and Acidobacteria (which are generally abundant in pristine soils) were minor components of the bacterial community. Shifts in community composition were significant and revealed that Cr (VI)-containing soils were more similar to each other than to As contaminated soils lacking Cr (VI). Diversity of the arsenic resistance genes, arsB and ACR3 were also determined. Results showed that ACR3 becomes less diverse as arsenic concentrations increase with a single OTU dominating at the highest concentration. Chronic exposure to either Cr or As not only alters the composition of the soil bacterial community in general, but affects the arsenic resistant individuals in different ways.

  2. Histological and morphological alterations induced by copper exposure in Laeonereis acuta (Polychaeta, Nereididae).

    PubMed

    Geracitano, L A; Luquet, C; Monserrat, J M; Bianchini, A

    2004-01-01

    Laeonereis acuta (Polychaeta, Nereididae) was collected in an unpolluted (UP) and an polluted (P) site at the Patos Lagoon estuary (Southern Brazil) and maintained under control conditions (UPC and PC, respectively) or exposed to waterborne copper (UPCu and PCu; 500 microg Cu/l), for 48 h. Four groups (aaUPC, aaPC, aaUPCu, and aaPCu) were also pre-exposed for 48 h to ascorbic acid (aa; 0.1 mM) before copper exposure. Histological and morphological alterations, as well as oxygen consumption changes were evaluated. Independently of the sampling site and the pre-exposure to the ascorbic acid, morphological abnormalities were evident in more than 80% of worms exposed to copper. Conspicuous histological changes (coeloma obliteration, cuticle separation from the epidermis, and absence of dorsal vessel) were also observed. In addition, PCu worms showed loss of the digestive epithelium and coiling behavior. Similar oxygen consumption values were observed in control and copper exposed worms.

  3. Prenatal neuroleptic exposure alters postnatal striatal cholinergic activity in the rat.

    PubMed

    Miller, J C; Friedhoff, A J

    1986-01-01

    Previous studies in our laboratory have shown that prenatal exposure to a neuroleptic during a critical period of gestation in the rat results in a marked deficit in the number of striatal dopamine-binding sites and in a diminution of dopamine agonist-induced stereotyped behavior. In the present studies, we examined the effect of prenatal neuroleptic exposure on biochemical parameters of cholinergic activity to determine whether the balance between striatal dopaminergic and cholinergic activity might be altered. The number of muscarinic cholinergic-binding sites and the specific activity of choline acetyltransferase were found to be significantly increased by prenatal treatment with the neuroleptics haloperidol or (+)-butaclamol. From the present studies and previous observations made in our laboratory, it is concluded that the ability of a neuroleptic to affect the number of muscarinic cholinergic receptors in postnatal life may be a result of the phenotypically undifferentiated state of the developing dopamine-binding site. Our findings of increased striatal cholinergic activity accompanied by a marked decrease in dopaminergic activity may have implications for an increased vulnerability to extrapyramidal motor disturbances during postnatal development.

  4. Cellular alterations upon IR-laser (890 nm) exposures, in vivo.

    PubMed

    Kolesnikova, A I; Kubasova, T; Konoplyannikov, A G; Köteles, G J

    1998-01-01

    Exposure of cultured cells and small animals to ionizing radiation as well as irradiation of cultured cells with He-Ne laser can cause changes in the functional condition of plasma membranes. The ionizing radiation-induced cell membrane alterations have been determined after either partial or local exposures. The aim of the present study was to reveal whether the local laser treatments cause a general, distant, so called abscopal" effect measured at cellular level, when the laser treatment is intended as a stimulatory procedure. The biological effect of infrared laser (mean power of 5 Watts, 150 Hz frequency, 890 nm wavelength) was demonstrated through 3H-concanavalin A binding by blood cells of daily irradiated (altogether 10 exposures) oncological and non-oncological patients as well as by changes in the proliferation of bone marrow cells of whole body gamma-irradiated (4 Gy) rats, partially laser-treated. The lectin binding of lymphocytes of oncological, as well as ischaemic heart disease patients was increased immediately after the first laser treatment. However, it was decreased after completion of the full course. In cases of inflammatory diseases the test parameters were either unchanged or decreased as compared to their self-control values. The platelets and erythrocytes did not react in any group. Gamma irradiation caused a deep inhibition of proliferation of rat bone marrow cells. The number of fibroblast colony-forming units (CFU-F) could be increased again if the animals were partially exposed to laser. Laser irradiation of one of the femurs led to some recovery of CFU-F values in the exposed as well as unexposed femur. Thus, local infrared laser treatment induces abscopal effects on the cell membrane and cell proliferation characteristics.

  5. Fetal hematopoietic alterations after maternal exposure to benzo[a]pyrene: A cytometric evaluation

    SciTech Connect

    Holladay, S.D.; Smith, B.J.

    1994-12-31

    In utero exposure to the environmental contaminant benzo[a]pyrene (BaP) was found to alter expression of murine thymocyte and liver fetal cell-surface markers. Pregnant mice were treated (via gavage) with 0, 50, 100, or 150 mg BaP/kg/d on gestational days (gd) 13-17, and offspring were examined on gd 18. Severe thymic atrophy and cellular depletion were found in BaP-exposed fetal mice. Flow cytometric analysis indicated that the BaP treatment resulted in a significant decrease in the percentage of CD4{sup +}8{sup +} fetal thymocytes, as well as significantly increased CD4{sup {minus}}8{sup {minus}} and CD4{sup {minus}}8{sup +} thymocytes. Staining of thymocytes with anti-mouse heat-stable antigen (HSA) and CD8 monoclonal antibodies produced similar results. These data suggest that BaP, in addition to producing thymic hypocellularity, inhibits normal thymocyte maturation processes. The BaP treatment was also found to decrease total fetal liver cellularity including numbers of cells within resident hematopoietic subpopulations. In particular, prolymphocytic cells, identified by CD44 and CD45R antigen expression and by presence of nuclear terminal deoxynucleotidyl transferase (TdT), were significantly decreased in animals gestationally exposed to BaP. These data, taken together, indicate that postnatal suppression of cell and humoral-mediated immune function following in utero exposure to BaP may result from multiple targeting of immune function following in utero exposure to BaP may result from multiple targeting of immune cells at different hematopoietic levels. Furthermore, results of the present study identify both qualitative and quantitative changes in fetal immune cell antigen expression that correlate well with the postnatal immunosuppression that occurs in experimental animals exposed to this carcinogenic polycyclic aromatic hydrocarbon. 41 refs., 4 figs., 3 tabs.

  6. Exposure to Acetylcholinesterase Inhibitors Alters the Physiology and Motor Function of Honeybees

    PubMed Central

    Williamson, Sally M.; Moffat, Christopher; Gomersall, Martha A. E.; Saranzewa, Nastja; Connolly, Christopher N.; Wright, Geraldine A.

    2013-01-01

    Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. PMID:23386834

  7. Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats.

    PubMed

    Ellgren, Maria; Spano, Sabrina M; Hurd, Yasmin L

    2007-03-01

    Cannabis use is a hypothesized gateway to subsequent abuse of other drugs such as heroin. We currently assessed whether Delta-9-tetrahydrocannabinol (THC) exposure during adolescence modulates opiate reinforcement and opioid neural systems in adulthood. Long-Evan male rats received THC (1.5 mg/kg intraperitoneally (i.p.)) or vehicle every third day during postnatal days (PNDs) 28-49. Heroin self-administration behavior (fixed ratio-1; 3-h sessions) was studied from young adulthood (PND 57) into full adults (PND 102). THC-pretreated rats showed an upward shift throughout the heroin self-administration acquisition (30 microg/kg/infusion) phase, whereas control animals maintained the same pattern once stable intake was obtained. Heightened opiate sensitivity in THC animals was also evidenced by higher heroin consumption during the maintenance phase (30 and 60 microg/kg/infusion) and greater responding for moderate-low heroin doses (dose-response curve: 7.5, 15, 30, 60, and 100 microg/kg/injection). Specific disturbance of the endogenous opioid system was also apparent in the brain of adults with adolescent THC exposure. Striatal preproenkephalin mRNA expression was exclusively increased in the nucleus accumbens (NAc) shell; the relative elevation of preproenkephalin mRNA in the THC rats was maintained even after heroin self-administration. Moreover, mu opioid receptor (muOR) GTP-coupling was potentiated in mesolimbic and nigrostriatal brainstem regions in THC-pretreated animals. muOR function in the NAc shell was specifically correlated to heroin intake. The current findings support the gateway hypothesis demonstrating that adolescence cannabis exposure has an enduring impact on hedonic processing resulting in enhanced opiate intake, possibly as a consequence of alterations in limbic opioid neuronal populations.

  8. Prenatal chlorpyrifos exposure alters motor behavior and ultrasonic vocalization in cd-1 mouse pups

    PubMed Central

    2009-01-01

    Background Chlorpyrifos (CPF) is a non-persistent organophosphate (OP) largely used as pesticide. Studies from animal models indicate that CPF is a developmental neurotoxicant able to target immature central nervous system at dose levels well below the threshold of systemic toxicity. So far, few data are available on the potential short- and long-term adverse effects in children deriving from low-level exposures during prenatal life and infancy. Methods Late gestational exposure [gestational day (GD) 14–17] to CPF at the dose of 6 mg/kg was evaluated in CD-1 mice during early development, by assessment of somatic and sensorimotor maturation [reflex-battery on postnatal days (PNDs) 3, 6, 9, 12 and 15] and ultrasound emission after isolation from the mother and siblings (PNDs 4, 7 and 10). Pups' motor skills were assessed in a spontaneous activity test on PND 12. Maternal behavior of lactating dams in the home cage and in response to presentation of a pup previously removed from the nest was scored on PND 4, to verify potential alterations in maternal care directly induced by CPF administration. Results As for the effects on the offspring, results indicated that on PND 10, CPF significantly decreased number and duration of ultrasonic calls while increasing latency to emit the first call after isolation. Prenatal CPF also reduced motor behavior on PND 12, while a tendency to hyporeflexia was observed in CPF pups by means of reflex-battery scoring. Dams administered during gestation with CPF showed baseline levels of maternal care comparable to those of controls, but higher levels of both pup-directed (licking) and explorative (wall rearing) responses. Conclusion Overall our results are consistent with previous epidemiological data on OP neurobehavioral toxicity, and also indicate ultrasonic vocalization as an early marker of CPF exposure during development in rodent studies, with potential translational value to human infants. PMID:19331648

  9. Association between lead exposure from electronic waste recycling and child temperament alterations.

    PubMed

    Liu, Junxiao; Xu, Xijin; Wu, Kusheng; Piao, Zhongxian; Huang, Jinrong; Guo, Yongyong; Li, Weiqiu; Zhang, Yuling; Chen, Aimin; Huo, Xia

    2011-08-01

    We aimed to evaluate the dose-dependent effects of lead exposure on temperament alterations in children from a primitive e-waste (obsolete electrical and electronic devices) recycling area in Guiyu of China and a control area (Chendian, China). Blood lead levels (BLL) might be correlated with temperament, health, and relevant factors that were evaluated through Parent Temperament Questionnaire (PTQ), physical examination, and residential questionnaires. We collected venipuncture blood samples from 303 children (aged 3-7 years old) between January and February 2008. Child BLL were higher in Guiyu than in Chendian (median 13.2 μg/dL, range 4.0-48.5 μg/dL vs. 8.2 μg/dL, 0-21.3 μg/dL) (P<0.01). Significant differences of mean scores in activity level (4.53±0.83 vs. 4.18±0.81), approach-withdrawal (4.62±0.85 vs. 4.31±0.89), and adaptability (4.96±0.73 vs. 4.67±0.83) were found between Guiyu and Chendian children (all P<0.01). High BLL (BLL≥10μg/dL) child had higher mean scores of approach-withdrawal when compared with those children with low BLL (BLL<10 μg/dL) (4.61±0.87 vs. 4.30±0.88, P<0.01). Location of child residence in Guiyu, and parents engagement in work related to e-waste were the risk factors related to child BLL, activity level, approach-withdrawal, adaptability, and mood. Child hand washing prior to food consumption was a protected factor for BLL and several dimensions. There are close relationships between BLL elevation, temperament alteration and the e-waste recycling activities in Guiyu. Primitive e-waste recycling may threaten the health of children by increasing BLL and altering children temperament, although the exposure to other toxicants needs to be examined in future studies.

  10. Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation.

    PubMed

    Liu, Yunlong; Balaraman, Yokesh; Wang, Guohua; Nephew, Kenneth P; Zhou, Feng C

    2009-10-01

    Alcohol exposure during development can cause variable neurofacial deficit and growth retardation known as fetal alcohol spectrum disorders (FASD). The mechanism underlying FASD is not fully understood. However, alcohol, which is known to affect methyl donor metabolism, may induce aberrant epigenetic changes contributing to FASD. Using a tightly controlled whole-embryo culture, we investigated the effect of alcohol exposure (88mM) at early embryonic neurulation on genome-wide DNA methylation and gene expression in the C57BL/6 mouse. The DNA methylation landscape around promoter CpG islands at early mouse development was analyzed using MeDIP (methylated DNA immunoprecipitation) coupled with microarray (MeDIP-chip). At early neurulation, genes associated with high CpG promoters (HCP) had a lower ratio of methylation but a greater ratio of expression. Alcohol-induced alterations in DNA methylation were observed, particularly in genes on chromosomes 7, 10, and X; remarkably, a >10 fold increase in the number of genes with increased methylation on chromosomes 10 and X was observed in alcohol-exposed embryos with a neural tube defect phenotype compared to embryos without a neural tube defect. Significant changes in methylation were seen in imprinted genes, genes known to play roles in cell cycle, growth, apoptosis, cancer, and in a large number of genes associated with olfaction. Altered methylation was associated with significant (p<0.01) changes in expression for 84 genes. Sequenom EpiTYPER DNA methylation analysis was used for validation of the MeDIP-chip data. Increased methylation of genes known to play a role in metabolism (Cyp4f13) and decreased methylation of genes associated with development (Nlgn3, Elavl2, Sox21 and Sim1), imprinting (Igf2r) and chromatin (Hist1h3d) was confirmed. In a mouse model for FASD, we show for the first time that alcohol exposure during early neurulation can induce aberrant changes in DNA methylation patterns with associated changes in

  11. Chronic lead exposure alters presynaptic calcium regulation and synaptic facilitation in Drosophila larvae.

    PubMed

    He, T; Hirsch, H V B; Ruden, D M; Lnenicka, G A

    2009-09-01

    Prolonged exposure to inorganic lead (Pb(2+)) during development has been shown to influence activity-dependent synaptic plasticity in the mammalian brain, possibly by altering the regulation of intracellular Ca(2+) concentration ([Ca(2+)](i)). To explore this possibility, we studied the effect of Pb(2+) exposure on [Ca(2+)](i) regulation and synaptic facilitation at the neuromuscular junction of larval Drosophila. Wild-type Drosophila (CS) were raised from egg stages through the third larval instar in media containing either 0 microM, 100 microM or 250 microM Pb(2+) and identified motor terminals were examined in late third-instar larvae. To compare resting [Ca(2+)](i) and the changes in [Ca(2+)](i) produced by impulse activity, the motor terminals were loaded with a Ca(2+) indicator, either Oregon Green 488 BAPTA-1 (OGB-1) or fura-2 conjugated to a dextran. We found that rearing in Pb(2+) did not significantly change the resting [Ca(2+)](i) nor the Ca(2+) transient produced in synaptic boutons by single action potentials (APs); however, the Ca(2+) transients produced by 10 Hz and 20 Hz AP trains were larger in Pb(2+)-exposed boutons and decayed more slowly. For larvae raised in 250 microM Pb(2+), the increase in [Ca(2+)](i) during an AP train (20 Hz) was 29% greater than in control larvae and the [Ca(2+)](i) decay tau was 69% greater. These differences appear to result from reduced activity of the plasma membrane Ca(2+) ATPase (PMCA), which extrudes Ca(2+) from these synaptic terminals. These findings are consistent with studies in mammals showing a Pb(2+)-dependent reduction in PMCA activity. We also observed a Pb(2+)-dependent enhancement of synaptic facilitation at these larval neuromuscular synapses. Facilitation of EPSP amplitude during AP trains (20 Hz) was 55% greater in Pb(2+)-reared larvae than in controls. These results showed that Pb(2+) exposure produced changes in the regulation of [Ca(2+)](i) during impulse activity, which could affect various

  12. Chronic lead exposure alters presynaptic calcium regulation and synaptic facilitation in Drosophila larvae

    PubMed Central

    He, T.; Hirsch, H.V.B.; Ruden, D. M.; Lnenicka, G. A.

    2009-01-01

    Prolonged exposure to inorganic lead (Pb2+) during development has been shown to influence activity-dependent synaptic plasticity in the mammalian brain, possibly by altering the regulation of intracellular Ca2+ concentration ([Ca2+]i). To explore this possibility, we studied the effect of Pb2+ exposure on [Ca2+]i regulation and synaptic facilitation at the neuromuscular junction of larval Drosophila. Wild-type Drosophila (CS) were raised from egg stages through the third larval instar in media containing either 0, 100 μM or 250 μM Pb2+ and identified motor terminals were examined in late third-instar larvae. To compare resting [Ca2+]i and the changes in [Ca2+]i produced by impulse activity, the motor terminals were loaded with a Ca2+ indicator, either Oregon Green 488 BAPTA-1 (OGB-1) or fura-2 conjugated to a dextran. We found that rearing in Pb2+ did not significantly change the resting [Ca2+]i nor the Ca2+ transient produced in synaptic boutons by single action potentials (APs); however, the Ca2+ transients produced by 10 and 20 Hz AP trains were larger in Pb2+-exposed boutons and decayed more slowly. For larvae raised in 250 μM Pb2+, the increase in [Ca2+]i during an AP train (20 Hz) was 29% greater than in control larvae and the [Ca2+]i decay τ was 69% greater. These differences appear to result from reduced activity of the plasma membrane Ca2+ ATPase (PMCA), which extrudes Ca2+ from these synaptic terminals. These findings are consistent with studies in mammals showing a Pb2+-dependent reduction in PMCA activity. We also observed a Pb2+-dependent enhancement of synaptic facilitation at these larval neuromuscular synapses. Facilitation of EPSP amplitude during AP trains (20 Hz) was 55% greater in Pb2+-reared larvae than in controls. These results showed that Pb2+ exposure produced changes in the regulation of [Ca2+]i during impulse activity, which could affect various aspects of nervous system development. At the mature synapse, this altered [Ca2+]i

  13. Staurosporines disrupt phosphatidylserine trafficking and mislocalize Ras proteins.

    PubMed

    Cho, Kwang-jin; Park, Jin-Hee; Piggott, Andrew M; Salim, Angela A; Gorfe, Alemaheyu A; Parton, Robert G; Capon, Robert J; Lacey, Ernest; Hancock, John F

    2012-12-21

    Oncogenic mutant Ras is frequently expressed in human cancers, but no anti-Ras drugs have been developed. Since membrane association is essential for Ras biological activity, we developed a high content assay for inhibitors of Ras plasma membrane localization. We discovered that staurosporine and analogs potently inhibit Ras plasma membrane binding by blocking endosomal recycling of phosphatidylserine, resulting in redistribution of phosphatidylserine from plasma membrane to endomembrane. Staurosporines are more active against K-Ras than H-Ras. K-Ras is displaced to endosomes and undergoes proteasomal-independent degradation, whereas H-Ras redistributes to the Golgi and is not degraded. K-Ras nanoclustering on the plasma membrane is also inhibited. Ras mislocalization does not correlate with protein kinase C inhibition or induction of apoptosis. Staurosporines selectively abrogate K-Ras signaling and proliferation of K-Ras-transformed cells. These results identify staurosporines as novel inhibitors of phosphatidylserine trafficking, yield new insights into the role of phosphatidylserine and electrostatics in Ras plasma membrane targeting, and validate a new target for anti-Ras therapeutics.

  14. Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation.

    PubMed

    Yanai, Joseph; Huleihel, Rabab; Izrael, Michal; Metsuyanim, Sally; Shahak, Halit; Vatury, Ori; Yaniv, Shiri P

    2003-09-01

    Opioid drugs act primarily on the opiate receptors; they also exert their effect on other innervations resulting in non-opioidergic behavioural deficits. Similarly, opioid neurobehavioural teratogenicity is attested in numerous behaviours and neural processes which hinder the research on the mechanisms involved. Therefore, in order to be able to ascertain the mechanism we have established an animal (mouse) model for the teratogenicity induced by opioid abuse, which focused on behaviours related to specific brain area and innervation. Diacetylmorphine (heroin) and not morphine was applied because heroin exerts a unique action, distinguished from that of morphine. Pregnant mice were exposed to heroin (10 mg/kg per day) and the offspring were tested for behavioural deficits and biochemical alterations related to the septohippocampal cholinergic innervation. Some studies employing the chick embryo were concomitantly added as a control for the confounding indirect variables. Prenatal exposure to heroin in mice induced global hyperactivation both pre- and post-synaptic along the septohippocampal cholinergic innervation, including basal protein kinase C (PKC) activity accompanied by a desensitization of PKC activity in response to cholinergic agonist. Functionally, the heroin-exposed offspring displayed deficits in hippocampus-related behaviours, suggesting deficits in the net output of the septohippocampal cholinergic innervation. Grafting of cholinergic cells to the impaired hippocampus reversed both pre- and post-synaptic hyperactivity, resensitized PKC activity, and restored the associated behaviours to normality. Consistently, correlation studies point to the relative importance of PKC to the behavioural deficits. The chick model, which dealt with imprinting related to a different brain region, confirmed that the effect of heroin is direct. Taken together with studies by others on the effect of prenatal exposure to opioids on the opioidergic innervation and with what

  15. Exposure of Persian sturgeon (Acipenser persicus) to cadmium results in biochemical, histological and transcriptional alterations.

    PubMed

    Miandare, Hamed Kolangi; Niknejad, Mahtab; Shabani, Ali; Safari, Roghieh

    2016-01-01

    Sturgeon is one of the endangered families of fish in the Caspian Sea region, where there is up to 80% of their global caching. Unfortunately, in recent years, increase of pollutants has been resulted in their total population reduction. Due to their benthic nature, sturgeons are at great risk of exposing to contaminants such as cadmium. Despite their endangered status in the Caspian Sea, there are only a few studies on characterizing the relative sensitivity of sturgeons to cadmium. Adverse effects associated with pollution on angiogenesis are mediated by hypoxia inducing factor-1 (HIF-1) and vascular endothelial growth factor (VEGF). In this investigation, gene expression of two distinct HIFs-1, HIF-1α and HIF-2α, and VEGF was investigated at the mRNA transcript levels after exposure of Persian sturgeon (Acipenser persicus) to cadmium. VEGF, HIF-1α and HIF-2α expressions in treated Persian sturgeon were greater than controls. Significant increases (P<0.05) were also observed in cortisol and glucose levels compared to the control group especially in the fish exposed to higher cadmium concentration (800 μg/L). Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactic acid dehydrogenase (LDH) levels were increased in the cadmium-exposed fish, although the observed increases were not significant between the control and 200 μg/L cadmium treatment at some sampling time points. Gill tissues also showed histopathological changes in the cadmium treatments. Overall, results indicated that cadmium resulted in some alterations in biochemical parameters, mRNA transcript level expression of two important angiogenesis related genes as well as histological alterations in Persian sturgeon.

  16. Neoplastic alterations induced in mammalian skin following mancozeb exposure using in vivo and in vitro models.

    PubMed

    Tyagi, Shilpa; George, Jasmine; Singh, Richa; Bhui, Kulpreet; Shukla, Yogeshwer

    2011-03-01

    Mancozeb, ethylene(bis)dithiocarbamate fungicides, has been well documented in the literature as a multipotent carcinogen, but the underlying mechanism remains unrevealed. Thus, mancozeb has been selected in this study with the objective to decipher the molecular mechanism that culminates in carcinogenesis. We employed two-dimensional gel electrophoresis and mass spectrometry to generate a comparative proteome profile of control and mancozeb (200 mg/kg body weight) exposed mouse skin. Although many differentially expressed proteins were found, among them, two significantly upregulated proteins, namely, S100A6 (Calcyclin) and S100A9 (Calgranulin-B), are known markers of keratinocyte differentiation and proliferation, which suggested their role in mancozeb-induced neoplastic alterations. Therefore, we verified these alterations in the human system by using HaCaT cells as an in vitro model for human skin keratinocyte carcinogenesis. Upregulation of these two proteins upon mancozeb (0.5 μg/mL) exposure in HaCaT cells indicated its neoplastic potential in human skin also. This potential was confirmed by increase in number of colonies in colony formation and anchorage-independent growth assays. Modulation of S100A6/S100A9 targets, elevated phosphorylation of extracellular signal regulated kinase (ERK1/2), Elk1, nuclear factor- kappa B and cell division cycle 25 C phosphatase, and cyclin D1 and cyclooxygenase-2 upregulation was seen. In addition, PD98059 (ERK1/2 inhibitor) reduced cell proliferation induced by mancozeb, confirming the involvement of ERK1/2 signaling. Conclusively, we herein present the first report asserting that the mechanism involving S100A6 and S100A9 regulated ERK1/2 signaling underlies the mancozeb-induced neoplastic potential in human skin.

  17. Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.

    PubMed

    Ngai, Ying Fai; Sulistyoningrum, Dian C; O'Neill, Ryan; Innis, Sheila M; Weinberg, Joanne; Devlin, Angela M

    2015-09-01

    Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE.

  18. Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

    PubMed Central

    Ngai, Ying Fai; Sulistyoningrum, Dian C.; O'Neill, Ryan; Innis, Sheila M.; Weinberg, Joanne

    2015-01-01

    Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE. PMID:26180184

  19. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation

    PubMed Central

    Rodgers, Ali B.; Morgan, Christopher P.; Bronson, Stefanie L.; Revello, Sonia; Bale, Tracy L.

    2013-01-01

    Neuropsychiatric disease frequently presents with an underlying hypo- or hyper- reactivity of the HPA stress axis, suggesting an exceptional vulnerability of this circuitry to external perturbations. Parental lifetime exposures to environmental challenges are associated with increased offspring neuropsychiatric disease risk, and likely contribute to stress dysregulation. While maternal influences have been extensively examined, much less is known regarding the specific role of paternal factors. To investigate the potential mechanisms by which paternal stress may contribute to offspring hypothalamic-pituitary-adrenal (HPA) axis dysregulation, we exposed mice to six weeks of chronic stress prior to breeding. As epidemiological studies support variation in paternal germ cell susceptibility to reprogramming across the lifespan, male stress exposure occurred either throughout puberty or in adulthood. Remarkably, offspring of sires from both paternal stress groups displayed significantly reduced HPA axis stress responsivity. Gene set enrichment analyses in offspring stress regulating brain regions, the paraventricular nucleus (PVN) and the bed nucleus of stria terminalis (BNST), revealed global pattern changes in transcription suggestive of epigenetic reprogramming and consistent with altered offspring stress responsivity, including increased expression of glucocorticoid-responsive genes in the PVN. In examining potential epigenetic mechanisms of germ cell transmission, we found robust changes in sperm miRNA (miR) content, where nine specific miRs were significantly increased in both paternal stress groups. Overall, these results demonstrate that paternal experience across the lifespan can induce germ cell epigenetic reprogramming and impact offspring HPA stress axis regulation, and may therefore offer novel insight into factors influencing neuropsychiatric disease risk. PMID:23699511

  20. Exposure of Soil Microbial Communities to Chromium and Arsenic Alters Their Diversity and Structure

    PubMed Central

    Rizvi, Fariha Z.; Rehman, Yasir; Faisal, Muhammad; Hasnain, Shahida; McInerney, Michael J.; Krumholz, Lee R.

    2012-01-01

    Extensive use of chromium (Cr) and arsenic (As) based preservatives from the leather tanning industry in Pakistan has had a deleterious effect on the soils surrounding production facilities. Bacteria have been shown to be an active component in the geochemical cycling of both Cr and As, but it is unknown how these compounds affect microbial community composition or the prevalence and form of metal resistance. Therefore, we sought to understand the effects that long-term exposure to As and Cr had on the diversity and structure of soil microbial communities. Soils from three spatially isolated tanning facilities in the Punjab province of Pakistan were analyzed. The structure, diversity and abundance of microbial 16S rRNA genes were highly influenced by the concentration and presence of hexavalent chromium (Cr (VI)) and arsenic. When compared to control soils, contaminated soils were dominated by Proteobacteria while Actinobacteria and Acidobacteria (which are generally abundant in pristine soils) were minor components of the bacterial community. Shifts in community composition were significant and revealed that Cr (VI)-containing soils were more similar to each other than to As contaminated soils lacking Cr (VI). Diversity of the arsenic resistance genes, arsB and ACR3 were also determined. Results showed that ACR3 becomes less diverse as arsenic concentrations increase with a single OTU dominating at the highest concentration. Chronic exposure to either Cr or As not only alters the composition of the soil bacterial community in general, but affects the arsenic resistant individuals in different ways. PMID:22768219

  1. Pesticide Exposure Alters Follicle-Stimulating Hormone Levels in Mexican Agricultural Workers

    PubMed Central

    Recio, Rogelio; Ocampo-Gómez, Guadalupe; Morán-Martínez, Javier; Borja-Aburto, Victor; López-Cervantes, Malaquías; Uribe, Marisela; Torres-Sánchez, Luisa; Cebrián, Mariano E.

    2005-01-01

    Organophosphorous pesticides (OPs) are suspected of altering reproductive function by reducing brain acetylcholinesterase activity and monoamine levels, thus impairing hypothalamic and/or pituitary endocrine functions and gonadal processes. Our objective was to evaluate in a longitudinal study the association between OP exposure and serum levels of pituitary and sex hormones. Urinary OP metabolite levels were measured by gas–liquid chromatography, and serum pituitary and sex hormone levels by enzymatic immunoassay and radioimmunoassay in 64 men. A total of 147 urine and blood samples were analyzed for each parameter. More than 80% of the participants had at least one OP metabolite in their urine samples. The most frequent metabolite found was diethylthiophosphate (DETP; 55%), followed by diethylphosphate (DEP; 46%), dimethylthiophosphate (DMTP; 32%), and dimethyldithiophosphate (DMDTP; 31%). However, the metabolites detected at higher concentrations were DMTP, DEP, DMDTP, and dimethylphosphate. There was a high proportion of individuals with follicle-stimulating hormone (FSH) concentrations outside the range of normality (48%). The average FSH serum levels were higher during the heavy pesticide spraying season. However, a multivariate analysis of data collected in all periods showed that serum FSH levels were negatively associated with urinary concentrations of both DMTP and DMDTP, whereas luteinizing hormone (LH) was negatively associated with DMTP. We observed no significant associations between estradiol or testosterone serum levels with OP metabolites. The hormonal disruption in agricultural workers presented here, together with results from experimental animal studies, suggests that OP exposure disrupts the hypothalamic–pituitary endocrine function and also indicates that FSH and LH are the hormones most affected. PMID:16140621

  2. Co-occurring exposure to perchlorate, nitrate and thiocyanate alters thyroid function in healthy pregnant women

    PubMed Central

    Horton, Megan K.; Blount, Benjamin C.; Valentin-Blasini, Liza; Wapner, Ronald; Whyatt, Robin; Gennings, Chris; Factor-Litvak, Pam

    2015-01-01

    Background Adequate maternal thyroid function during pregnancy is necessary for normal fetal brain development, making pregnancy a critical window of vulnerability to thyroid disrupting insults. Sodium/iodide symporter (NIS) inhibitors, namely perchlorate, nitrate, and thiocyanate, have been shown individually to competitively inhibit uptake of iodine by the thyroid. Several epidemiologic studies examined the association between these individual exposures and thyroid function. Few studies have examined the effect of this chemical mixture on thyroid function during pregnancy. Objectives We examined the cross sectional association between urinary perchlorate, thiocyanate and nitrate concentrations and thyroid function among healthy pregnant women living in New York City using weighted quantile sum (WQS) regression. Methods We measured thyroid stimulating hormone (TSH) and free thyroxine (FreeT4) in blood samples; perchlorate, thiocyanate, nitrate and iodide in urine samples collected from 284 pregnant women at 12 (± 2.8) weeks gestation. We examined associations between urinary analyte concentrations and TSH or FreeT4 using linear regression or WQS adjusting for gestational age, urinary iodide and creatinine. Results Individual analyte concentrations in urine were significantly correlated (Spearman’s r 0.4–0.5, p < 0.001). Linear regression analyses did not suggest associations between individual concentrations and thyroid function. The WQS revealed a significant positive association between the weighted sum of urinary concentrations of the three analytes and increased TSH. Perchlorate had the largest weight in the index, indicating the largest contribution to the WQS. Conclusions Co-exposure to perchlorate, nitrate and thiocyanate may alter maternal thyroid function, specifically TSH, during pregnancy. PMID:26408806

  3. Chronic exposure to a neonicotinoid pesticide alters the interactions between bumblebees and wild plants.

    PubMed

    Stanley, Dara A; Raine, Nigel E

    2016-07-01

    Insect pollinators are essential for both the production of a large proportion of world crops and the health of natural ecosystems. As important pollinators, bumblebees must learn to forage on flowers to feed both themselves and provision their colonies.Increased use of pesticides has caused concern over sublethal effects on bees, such as impacts on reproduction or learning ability. However, little is known about how sublethal exposure to field-realistic levels of pesticide might affect the ability of bees to visit and manipulate flowers.We observed the behaviour of individual bumblebees from colonies chronically exposed to a neonicotinoid pesticide (10 ppb thiamethoxam) or control solutions foraging for the first time on an array of morphologically complex wildflowers (Lotus corniculatus and Trifolium repens) in an outdoor flight arena.We found that more bees released from pesticide-treated colonies became foragers, and that they visited more L. corniculatus flowers than controls. Interestingly, bees exposed to pesticide collected pollen more often than controls, but control bees learnt to handle flowers efficiently after fewer learning visits than bees exposed to pesticide. There were also different initial floral preferences of our treatment groups; control bees visited a higher proportion of T. repens flowers, and bees exposed to pesticide were more likely to choose L. corniculatus on their first visit.Our results suggest that the foraging behaviour of bumblebees on real flowers can be altered by sublethal exposure to field-realistic levels of pesticide. This has implications for the foraging success and persistence of bumblebee colonies, but perhaps more importantly for the interactions between wild plants and flower-visiting insects and ability of bees to deliver the crucial pollination services to plants necessary for ecosystem functioning.

  4. Functional alterations in immature cultured rat hippocampal neurons after sustained exposure to static magnetic fields.

    PubMed

    Hirai, Takao; Yoneda, Yukio

    2004-01-15

    In cultured rat hippocampal neurons, gradual increases were seen in the expression of microtubule-associated protein-2 (MAP-2), neuronal nuclei (NeuN) and growth-associated protein-43 (GAP-43), in proportion to increased duration, up to 9 days in vitro (DIV). Sustained exposure to static magnetic fields at 100 mT for up to 9 DIV significantly decreased expression of MAP-2 and NeuN in cultured rat hippocampal neurons without markedly affecting GAP-43 expression. Although a significant increase was seen in the expression of glial fibrillary acidic protein (GFAP) in hippocampal neuronal preparations cultured for 6-9 DIV under sustained magnetism, GFAP and proliferating cell nuclear antigen expression were not affected markedly in cultured astrocytes prepared from rat hippocampus and neocortex, irrespective of cellular maturity. No significant alteration was seen in cell survivability of hippocampal neurons or astrocytes cultured under sustained magnetism. In hippocampal neurons cultured for 3 DIV under sustained magnetism, marked mRNA expression was seen for N-methyl-D-aspartate (NMDA) receptor subunits, NR1, NR2A-2C, NR2D, and NR3A. In addition, significant potentiation of the ability of NMDA to increase intracellular free Ca(2+) ions was observed. Differential display analysis revealed a significant decrease in mRNA expression for the transcription factor ALF1 in response to sustained magnetism for 3 DIV. These results suggest that sustained exposure to static magnetic fields may affect cellular functionality and maturity in immature cultured rat hippocampal neurons through modulation of expression of particular NMDA receptor subunits.

  5. Exposure to Synthetic Gray Water Inhibits Amoeba Encystation and Alters Expression of Legionella pneumophila Virulence Genes

    PubMed Central

    Lu, Jingrang; Ashbolt, Nicholas J.

    2014-01-01

    Water conservation efforts have focused on gray water (GW) usage, especially for applications that do not require potable water quality. However, there is a need to better understand environmental pathogens and their free-living amoeba (FLA) hosts within GW, given their growth potential in stored gray water. Using synthetic gray water (sGW) we examined three strains of the water-based pathogen Legionella pneumophila and its FLA hosts Acanthamoeba polyphaga, A. castellanii, and Vermamoeba vermiformis. Exposure to sGW for 72 h resulted in significant inhibition (P < 0.0001) of amoebal encystation versus control-treated cells, with the following percentages of cysts in sGW versus controls: A. polyphaga (0.6 versus 6%), A. castellanii (2 versus 62%), and V. vermiformis (1 versus 92%), suggesting sGW induced maintenance of the actively feeding trophozoite form. During sGW exposure, L. pneumophila culturability decreased as early as 5 h (1.3 to 2.9 log10 CFU, P < 0.001) compared to controls (Δ0 to 0.1 log10 CFU) with flow cytometric analysis revealing immediate changes in membrane permeability. Furthermore, reverse transcription-quantitative PCR was performed on total RNA isolated from L. pneumophila cells at 0 to 48 h after sGW incubation, and genes associated with virulence (gacA, lirR, csrA, pla, and sidF), the type IV secretion system (lvrB and lvrE), and metabolism (ccmF and lolA) were all shown to be differentially expressed. These results suggest that conditions within GW may promote interactions between water-based pathogens and FLA hosts, through amoebal encystment inhibition and alteration of bacterial gene expression, thus warranting further exploration into FLA and L. pneumophila behavior in GW systems. PMID:25381242

  6. Prenatal Oxycodone Exposure Alters CNS Endothelin Receptor Expression in Neonatal Rats.

    PubMed

    Devarapalli, M; Leonard, M; Briyal, S; Stefanov, G; Puppala, B L; Schweig, L; Gulati, A

    2016-05-01

    Prenatal opioid exposure such as oxycodone is linked to significant adverse effects on the developing brain. Endothelin (ET) and its receptors are involved in normal development of the central nervous system. Opioid tolerance and withdrawal are mediated through ET receptors. It is possible that adverse effect of oxycodone on the developing brain is mediated through ET receptors. We evaluated brain ETA and ETB receptor expression during postnatal development in rats with prenatal oxycodone exposure. Timed pregnant Sprague-Dawley rats received either oxycodone or placebo throughout gestation. After birth, male rat pups were sacrificed on postnatal day (PND) 1, 7, 14 or 28. Brain ETA and ETB receptor expression was determined by Western blot analysis. Oxycodone pups compared to placebo demonstrated congenital malformations of the face, mouth, and vertebrae at the time of birth [4/69 (5.7%) vs. 0/60 (0%); respectively] and intrauterine growth retardation [10/69 (15%) vs. 2/60 (3.3%); respectively]. On PND 28, oxycodone pups compared to placebo had lower body and kidney weight. ETA receptor expression in the oxycodone group was significantly higher compared to placebo on PND 1 (p=0.035), but was similar on PND 7, 14, or 28. ETB receptor expression decreased in oxycodone compared to placebo on PND 1 and 7 (p=0.001); and increased on PND 28 (p=0.002), but was similar on PND 14. Oxycodone-exposed rat pups had lower birth weight and postnatal weight gain and greater congenital malformations. ETB receptor expression is altered in the brain of oxycodone-treated rat pups indicating a possible delay in CNS development.

  7. Exposure to synthetic gray water inhibits amoeba encystation and alters expression of Legionella pneumophila virulence genes.

    PubMed

    Buse, Helen Y; Lu, Jingrang; Ashbolt, Nicholas J

    2015-01-01

    Water conservation efforts have focused on gray water (GW) usage, especially for applications that do not require potable water quality. However, there is a need to better understand environmental pathogens and their free-living amoeba (FLA) hosts within GW, given their growth potential in stored gray water. Using synthetic gray water (sGW) we examined three strains of the water-based pathogen Legionella pneumophila and its FLA hosts Acanthamoeba polyphaga, A. castellanii, and Vermamoeba vermiformis. Exposure to sGW for 72 h resulted in significant inhibition (P < 0.0001) of amoebal encystation versus control-treated cells, with the following percentages of cysts in sGW versus controls: A. polyphaga (0.6 versus 6%), A. castellanii (2 versus 62%), and V. vermiformis (1 versus 92%), suggesting sGW induced maintenance of the actively feeding trophozoite form. During sGW exposure, L. pneumophila culturability decreased as early as 5 h (1.3 to 2.9 log10 CFU, P < 0.001) compared to controls (Δ0 to 0.1 log10 CFU) with flow cytometric analysis revealing immediate changes in membrane permeability. Furthermore, reverse transcription-quantitative PCR was performed on total RNA isolated from L. pneumophila cells at 0 to 48 h after sGW incubation, and genes associated with virulence (gacA, lirR, csrA, pla, and sidF), the type IV secretion system (lvrB and lvrE), and metabolism (ccmF and lolA) were all shown to be differentially expressed. These results suggest that conditions within GW may promote interactions between water-based pathogens and FLA hosts, through amoebal encystment inhibition and alteration of bacterial gene expression, thus warranting further exploration into FLA and L. pneumophila behavior in GW systems.

  8. Sucrose Exposure in Early Life Alters Adult Motivation and Weight Gain

    PubMed Central

    Frazier, Cristianne R. M.; Mason, Peggy; Zhuang, Xiaoxi; Beeler, Jeff A.

    2008-01-01

    The cause of the current increase in obesity in westernized nations is poorly understood but is frequently attributed to a ‘thrifty genotype,’ an evolutionary predisposition to store calories in times of plenty to protect against future scarcity. In modern, industrialized environments that provide a ready, uninterrupted supply of energy-rich foods at low cost, this genetic predisposition is hypothesized to lead to obesity. Children are also exposed to this ‘obesogenic’ environment; however, whether such early dietary experience has developmental effects and contributes to adult vulnerability to obesity is unknown. Using mice, we tested the hypothesis that dietary experience during childhood and adolescence affects adult obesity risk. We gave mice unlimited or no access to sucrose for a short period post-weaning and measured sucrose-seeking, food consumption, and weight gain in adulthood. Unlimited access to sucrose early in life reduced sucrose-seeking when work was required to obtain it. When high-sugar/high-fat dietary options were made freely-available, however, the sucrose-exposed mice gained more weight than mice without early sucrose exposure. These results suggest that early, unlimited exposure to sucrose reduces motivation to acquire sucrose but promotes weight gain in adulthood when the cost of acquiring palatable, energy dense foods is low. This study demonstrates that early post-weaning experience can modify the expression of a ‘thrifty genotype’ and alter an adult animal's response to its environment, a finding consistent with evidence of pre- and peri-natal programming of adult obesity risk by maternal nutritional status. Our findings suggest the window for developmental effects of diet may extend into childhood, an observation with potentially important implications for both research and public policy in addressing the rising incidence of obesity. PMID:18797507

  9. Complementary probes reveal that phosphatidylserine is required for the proper transbilayer distribution of cholesterol.

    PubMed

    Maekawa, Masashi; Fairn, Gregory D

    2015-04-01

    Cholesterol is an essential component of metazoan cellular membranes and it helps to maintain the structural integrity and fluidity of the plasma membrane. Here, we developed a cholesterol biosensor, termed D4H, based on the fourth domain of Clostridium perfringens theta-toxin, which recognizes cholesterol in the cytosolic leaflet of the plasma membrane and organelles. The D4H probe disassociates from the plasma membrane upon cholesterol extraction and after perturbations in cellular cholesterol trafficking. When used in combination with a recombinant version of the biosensor, we show that plasmalemmal phosphatidylserine is essential for retaining cholesterol in the cytosolic leaflet of the plasma membrane. In vitro experiments reveal that 1-stearoy-2-oleoyl phosphatidylserine can induce phase separation in cholesterol-containing lipid bilayers and shield cholesterol from cholesterol oxidase. Finally, the altered transbilayer distribution of cholesterol causes flotillin-1 to relocalize to endocytic organelles. This probe should be useful in the future to study pools of cholesterol in the cytosolic leaflet of the plasma membrane and organelles.

  10. Chromatin Modifications during Repair of Environmental Exposure-Induced DNA Damage: A Potential Mechanism for Stable Epigenetic Alterations

    PubMed Central

    O’Hagan, Heather M.

    2014-01-01

    Exposures to environmental toxicants and toxins cause epigenetic changes that likely play a role in the development of diseases associated with exposure. The mechanism behind these exposure-induced epigenetic changes is currently unknown. One commonality between most environmental exposures is that they cause DNA damage either directly or through causing an increase in reactive oxygen species, which can damage DNA. Like transcription, DNA damage repair must occur in the context of chromatin requiring both histone modifications and ATP-dependent chromatin remodeling. These chromatin changes aid in DNA damage accessibility and signaling. Several proteins and complexes involved in epigenetic silencing during both development and cancer have been found to be localized to sites of DNA damage. The chromatin-based response to DNA damage is considered a transient event, with chromatin being restored to normal as DNA damage repair is completed. However, in individuals chronically exposed to environmental toxicants or with chronic inflammatory disease, repeated DNA damage-induced chromatin rearrangement may ultimately lead to permanent epigenetic alterations. Understanding the mechanism behind exposure-induced epigenetic changes will allow us to develop strategies to prevent or reverse these changes. This review focuses on epigenetic changes and DNA damage induced by environmental exposures, the chromatin changes that occur around sites of DNA damage, and how these transient chromatin changes may lead to heritable epigenetic alterations at sites of chronic exposure. PMID:24259318

  11. In Vitro Induction of Erythrocyte Phosphatidylserine Translocation by the Natural Naphthoquinone Shikonin

    PubMed Central

    Lupescu, Adrian; Bissinger, Rosi; Jilani, Kashif; Lang, Florian

    2014-01-01

    Shikonin, the most important component of Lithospermum erythrorhizon, has previously been shown to exert antioxidant, anti-inflammatory, antithrombotic, antiviral, antimicrobial and anticancer effects. The anticancer effect has been attributed to the stimulation of suicidal cell death or apoptosis. Similar to the apoptosis of nucleated cells, erythrocytes may experience eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include the increase of cytosolic Ca2+-activity ([Ca2+]i) and ceramide formation. The present study explored whether Shikonin stimulates eryptosis. To this end, Fluo 3 fluorescence was measured to quantify [Ca2+]i, forward scatter to estimate cell volume, annexin V binding to identify phosphatidylserine-exposing erythrocytes, hemoglobin release to determine hemolysis and antibodies to quantify ceramide abundance. As a result, a 48 h exposure of human erythrocytes to Shikonin (1 µM) significantly increased [Ca2+]i, increased ceramide abundance, decreased forward scatter and increased annexin V binding. The effect of Shikonin (1 µM) on annexin V binding was significantly blunted, but not abolished by the removal of extracellular Ca2+. In conclusion, Shikonin stimulates suicidal erythrocyte death or eryptosis, an effect at least partially due to the stimulation of Ca2+ entry and ceramide formation. PMID:24828755

  12. Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

    PubMed

    Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Frontczak-Baniewicz, Małgorzata; Gewartowska, Magdalena; Strużyńska, Lidia; Gutowska, Izabela; Chlubek, Dariusz; Adamczyk, Agata

    2016-10-29

    noticed in the cerebellum, while the expression of postsynaptic PSD-95 was significantly decreased in forebrain cortex and cerebellum, and raised in hippocampus. Additionally, we observed the lower level of BDNF in all brain structures in comparison to control animals. In conclusion, perinatal exposure to low doses of Pb caused pathological changes in nerve endings associated with the alterations in the level of key synaptic proteins. All these changes can lead to synaptic dysfunction, expressed by the impairment of the secretory mechanism and thereby to the abnormalities in neurotransmission as well as to the neuronal dysfunction.

  13. Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

    PubMed

    Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Frontczak-Baniewicz, Małgorzata; Gewartowska, Magdalena; Strużyńska, Lidia; Gutowska, Izabela; Chlubek, Dariusz; Adamczyk, Agata

    2016-12-12

    noticed in the cerebellum, while the expression of postsynaptic PSD-95 was significantly decreased in forebrain cortex and cerebellum, and raised in hippocampus. Additionally, we observed the lower level of BDNF in all brain structures in comparison to control animals. In conclusion, perinatal exposure to low doses of Pb caused pathological changes in nerve endings associated with the alterations in the level of key synaptic proteins. All these changes can lead to synaptic dysfunction, expressed by the impairment of the secretory mechanism and thereby to the abnormalities in neurotransmission as well as to the neuronal dysfunction.

  14. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L.

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival. We are studying two aspects of this vestibular adaptation: (1) How does long-term exposure to microgravity and hypergravity affect the development of vestibular afferents? (2) How does short- term exposure to extremely rapid changes in gravity, such as those that occur during launch and landing, affect the vestibular system. During space flight the gravistatic receptors in the otolith organs are effectively unloaded. In hypergravity conditions they are overloaded. However, the angular acceleration receptors of the semicircular canals receive relatively normal stimulation in both micro- and hypergravity.Rat embryos exposed to microgravity from gestation day 10 (prior to vestibular function) until gestation day 20 (vestibular system is somewhat functional) showed that afferents from the posterior vertical canal projecting to the medial vestibular nucleus developed similarly in microgravity, hypergravity, and in controls . However, afferents from the saccule showed delayed development in microgravity as compared to development in hypergravity and in controls. Cerebellar plasticity is crucial for modification of sensory-motor control and learning. Thus we explored the possibility that strong vestibular stimuli would modify cerebellar motor control (i.e., eye movement, postural control, gut motility) by altering the morphology of cerebellar Purkinje cells. To study the effects of short-term exposures to strong vestibular stimuli we focused on structural changes in the vestibulo-cerebellum that are caused by strong vestibular stimuli. Adult mice were exposed to various combinations of constant and/or rapidly changing angular and linear accelerations for 8.5 min (the time length of shuttle launch). Our data shows that these stimuli cause intense excitation of cerebellar Purkinje cells, inducing up-regulation of clathrin-mediated endocytosis

  15. TIME-DEPENDENT EFFECTS ON GENE EXPRESSION IN RAT SEMINAL VESICLE DEVELOPMENTALLY ALTERED BY IN UTERO EXPOSURE TO TCDD

    EPA Science Inventory

    TIME-DEPENDENT EFFECTS ON GENE EXPRESSION IN RAT SEMINAL VESICLE DEVELOPMENTALLY ALTERED BY IN UTERO EXPOSURE TO TCDD. V M Richardson', J T Hamm2, and L S Birnbaum1. 'USEPA, ORD/NHEERL/ETD, Research Triangle Park, NC, USA, 'Curriculum in Toxicology, University of North Carolina, ...

  16. Exposure to caregiver maltreatment alters expression levels of epigenetic regulators in the medial prefrontal cortex

    PubMed Central

    Blaze, Jennifer; Roth, Tania L

    2013-01-01

    Quality of maternal care experienced during infancy is a key factor that can confer vulnerability or resilience to psychiatric disorders later in life. Research continues to indicate that early-life experiences can affect developmental trajectories through epigenetic alterations capable of affecting gene regulation and neural plasticity. Previously, our lab has shown that experiences within an adverse caregiving environment (i.e. maltreatment) produce aberrant DNA methylation patterns at various gene loci in the medial prefrontal cortex (mPFC) of developing and adult rats. This study aimed to determine whether caregiver maltreatment likewise affects expression levels of several genes important in regulating DNA methylation patterns (Dnmt1, Dnmt3a, MeCP2, Gadd45b, and Hdac1). While we observed minimal changes in gene expression within the mPFC of developing rats, we observed expression changes for all genes in adult animals. Specifically, exposure to maltreatment produced a significant decrease in mRNA levels of all epigenetic regulators in adult males and a significant decrease in Gadd45b in adult females. Our results here provide further empirical support for the long-term and sex-specific epigenetic consequences of caregiver maltreatment on the mPFC. PMID:24120634

  17. Brood patches of American kestrels altered by experimental exposure to PCBs.

    PubMed

    Fisher, Sheri A; Bortolotti, Gary R; Fernie, Kim J; Bird, David M; Smits, Judit E

    2006-09-01

    Captive breeding (n = 25 pairs) and nonbreeding (n = 25) American kestrels were exposed to a mixture of polychlorinated biphenyls (PCBs) (Aroclor 1248:1254:1260) through their diet of day-old cockerels. Kestrels ingested approximately 7 mg/kg body weight each day of PCBs, and this dosage resulted in environmentally relevant total PCB residues in eggs (geometric mean of 34.1 microg/g). An equal number of unexposed birds served as controls. Bare areas of skin known as brood patches function during incubation to warm eggs; therefore, brood patch size could potentially influence hatching success, or patches may be a confounding factor in the relationship between poor incubation behavior and hatching failure observed in birds in toxicological studies. Exposure to PCBs altered the size of brood patches in American kestrels. PCB-exposed male and female nonbreeders had two of three brood patches that were larger than those of control nonbreeders. Breeding males exposed to PCBs had smaller patches than controls, whereas PCB-exposed female kestrels had one larger and one smaller patch than controls. Patch sizes were not related to total PCB residue levels in eggs of exposed birds. Brood patches were not related to various incubation behaviors or hatching success in either control or PCB-exposed kestrels.

  18. Prenatal nicotine exposure alters respiratory long term facilitation in neonatal rats

    PubMed Central

    Fuller, DD; Dougherty, BJ; Sandhu, MS; Doperalski, NJ; Reynolds, CR; Hayward, LF

    2009-01-01

    Intermittent hypoxia can evoke persistent increases in ventilation (ν̇ E) in neonates (i.e. long-term facilitation, LTF) (Julien et al. Am J Physiol Regul Integr Comp Physiol 294: R1356–R1366, 2008). Since prenatal nicotine (PN) exposure alters neonatal respiratory control (Fregosi & Pilarski. Respir. Physiol. Neurobiol. 164: 80–86, 2008), we hypothesized that PN would influence LTF of ventilation (ν̇ E) in neonatal rats. An osmotic minipump delivered nicotine (6 mg/kg/day) or saline to pregnant dams. ν̇ E was assessed in unanesthetized pups via whole body plethysmography at post-natal (P) days 9–11 or 15–17 during baseline (BL, 21% O2), hypoxia (10 × 5 min, 5% O2) and 30 min post-hypoxia. PN pups had reduced BL ν̇ E (p<0.05) but greater increases in ν̇ E during hypoxia (p<0.05). Post-hypoxia ν̇ E (i.e. LTF) showed an age × treatment interaction (p<0.01) with similar values at P9-11 but enhanced LTF in saline (30±8 %BL) vs. PN pups (6±5 %BL; p=0.01) at P15-17. We conclude that the post-natal developmental time course of hypoxia-induced LTF is influenced by PN. PMID:19818419

  19. Prenatal exposure to gamma/neutron irradiation: Sensorimotor alterations and paradoxical effects on learning

    SciTech Connect

    Di Cicco, D.; Antal, S.; Ammassari-Teule, M. )

    1991-01-01

    The effects of prenatal exposure on gamma/neutron radiations (0.5 Gy at about the 18th day of fetal life) were studied in a hybrid strain of mice (DBA/Cne males x C57BL/Cne females). During ontogeny, measurements of sensorimotor reflexes revealed in prenatally irradiated mice (1) a delay in sensorial development, (2) deficits in tests involving body motor control, and (3) a reduction of both motility and locomotor activity scores. In adulthood, the behaviour of prenatally irradiated and control mice was examined in the open field test and in reactivity to novelty. Moreover, their learning performance was compared in several situations. The results show that, in the open field test, only rearings were more frequent in irradiated mice. In the presence of a novel object, significant sex x treatment interactions were observed since ambulation and leaning against the novel object increased in irradiated females but decreased in irradiated males. Finally, when submitted to different learning tasks, irradiated mice were impaired in the radial maze, but paradoxically exhibited higher avoidance scores than control mice, possibly because of their low pain thresholds. Taken together, these observations indicate that late prenatal gamma/neutron irradiation induces long lasting alterations at the sensorimotor level which, in turn, can influence learning abilities of adult mice.

  20. Exposure to acute electromagnetic radiation of mobile phone exposure range alters transiently skin homeostasis of a model of pigmented reconstructed epidermis.

    PubMed

    Simon, D; Daubos, A; Pain, C; Fitoussi, R; Vié, K; Taieb, A; de Benetti, L; Cario-André, M

    2013-02-01

    Exposure to electromagnetic radiations (EMR) produced by mobile phone concerns half the world's population and raises the problem of their impact on human health. In this study, we looked at the effects of mobile phone exposure (GSM basic, 900 MHz, SAR 2 mW g(-1) , 6 h) on a model of pigmented skin. We have analysed the expression and localization of various markers of keratinocyte and melanocyte differentiation 2, 6, 18 and 24 h after EMR exposure of reconstructed epidermis containing either only keratinocytes or a combination of keratinocytes and melanocytes grown on dead de-epidermized dermis, using histology, immunohistochemistry and Western blot. No changes were found in epidermal architecture, localization of epidermal markers, presence of apoptotic cells and the induction of p53 in both types of epidermis (with or without melanocytes) after exposure to EMR. In pigmented reconstructs, no change in the location and dendricity of melanocytes and in melanin transfer to neighbouring keratinocytes was detected after EMR exposure. Loricrin, cytokeratin 14 were significantly decreased at 6 h. The level of all markers increased at 24 h as compared to 6 h post-EMR exposure, associated with a significant decrease of the 20S proteasome activity. Our data indicate that exposure to 900 MHz frequency induces a transient alteration of epidermal homoeostasis, which may alter the protective capacity of the skin against external factors. Presence or absence of melanocytes did not modify the behaviour of reconstructs after EMR exposure.

  1. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans

    PubMed Central

    Loiola, Rodrigo Azevedo; dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-01-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2. PMID:27292372

  2. Long-term in vivo polychlorinated biphenyl 126 exposure induces oxidative stress and alters proteomic profile on islets of Langerhans

    NASA Astrophysics Data System (ADS)

    Loiola, Rodrigo Azevedo; Dos Anjos, Fabyana Maria; Shimada, Ana Lúcia; Cruz, Wesley Soares; Drewes, Carine Cristiane; Rodrigues, Stephen Fernandes; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Pinto, Ernani; Farsky, Sandra Helena

    2016-06-01

    It has been recently proposed that exposure to polychlorinated biphenyls (PCBs) is a risk factor to type 2 diabetes mellitus (DM2). We investigated this hypothesis using long-term in vivo PCB126 exposure to rats addressing metabolic, cellular and proteomic parameters. Male Wistar rats were exposed to PCB126 (0.1, 1 or 10 μg/kg of body weight/day; for 15 days) or vehicle by intranasal instillation. Systemic alterations were quantified by body weight, insulin and glucose tolerance, and blood biochemical profile. Pancreatic toxicity was measured by inflammatory parameters, cell viability and cycle, free radical generation, and proteomic profile on islets of Langerhans. In vivo PCB126 exposure enhanced the body weight gain, impaired insulin sensitivity, reduced adipose tissue deposit, and elevated serum triglycerides, cholesterol, and insulin levels. Inflammatory parameters in the pancreas and cell morphology, viability and cycle were not altered in islets of Langerhans. Nevertheless, in vivo PCB126 exposure increased free radical generation and modified the expression of proteins related to oxidative stress on islets of Langerhans, which are indicative of early β-cell failure. Data herein obtained show that long-term in vivo PCB126 exposure through intranasal route induced alterations on islets of Langerhans related to early end points of DM2.

  3. Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson's disease.

    PubMed

    Richardson, Jason R; Caudle, W Michael; Wang, Minzheng; Dean, E Danielle; Pennell, Kurt D; Miller, Gary W

    2006-08-01

    Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.

  4. Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.

    PubMed Central

    Ma, Jane Y C; Rengasamy, Apavoo; Frazer, Dave; Barger, Mark W; Hubbs, Ann F; Battelli, Lori; Tomblyn, Seith; Stone, Samuel; Castranova, Vince

    2003-01-01

    Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential

  5. Association between occupational exposure to benzene and chromosomal alterations in lymphocytes of Brazilian petrochemical workers removed from exposure.

    PubMed

    Gonçalves, Rozana Oliveira; de Almeida Melo, Neli; Rêgo, Marco Antônio Vasconcelos

    2016-06-01

    We aimed to investigate the association between chronic exposure to benzene and genotoxicity in the lymphocytes of workers removed from exposure. The study included 20 workers with hematological disorders who had previously worked in the petrochemical industry of Salvador, Bahia, Brazil; 16 workers without occupational exposure to benzene served as the control group. Chromosomal analysis was performed on lymphocytes from peripheral blood, to assess chromosomal breaks and gaps and to identify aneuploidy. The Kruskal-Wallis test was used to compare the mean values between two groups, and Student's t test for comparison of two independent means. The frequency of gaps was statistically higher in and the exposed group than in the controls (2.13 ± 2.86 vs. 0.97 ± 1.27, p = 0.001). The frequency of chromosomal breaks was significantly higher among cases (0.21 ± 0.58) than among controls (0.12 ± 0.4) (p = 0.0002). An association was observed between chromosomal gaps and breaks and occupational exposure to benzene. Our study showed that even when removed from exposure for several years, workers still demonstrated genotoxic damage. Studies are still needed to clarify the long-term genotoxic potential of benzene after removal from exposure.

  6. Binge Toluene Exposure Alters Glutamate, Glutamine and GABA in the Adolescent Rat Brain as Measured by Proton Magnetic Resonance Spectroscopy*

    PubMed Central

    Perrine, Shane A.; O'Leary-Moore, Shonagh K.; Galloway, Matthew P.; Hannigan, John H.; Bowen, Scott E.

    2010-01-01

    Despite the high incidence of toluene abuse in adolescents, little is known regarding the effect of binge exposure on neurochemical profiles during this developmental stage. In the current study, the effects of binge toluene exposure during adolescence on neurotransmitter levels were determined using high-resolution proton magnetic resonance spectroscopy ex vivo at 11.7 T. Adolescent male Sprague-Dawley rats were exposed to toluene (0, 8,000 , or 12,000 ppm) for 15 min twice daily from postnatal day 28 (P28) through P34 and then euthanized either one or seven days later (on P35 or P42) to assess glutamate, glutamine, and GABA levels in intact tissue punches from the medial prefrontal cortex (mPFC), anterior striatum and hippocampus. In the mPFC, toluene reduced glutamate one day after exposure, with no effect on GABA, while after seven days, glutamate was no longer affected but there was an increase in GABA levels. In the hippocampus, neither GABA nor glutamate was altered one day after exposure, whereas seven days after exposure, increases were observed in GABA and glutamate. Striatal glutamate and GABA levels measured after either one or seven days were not altered after toluene exposure. These findings show that one week of binge toluene inhalation selectively alters these neurotransmitters in the mPFC and hippocampus in adolescent rats, and that some of these effects endure at least one week after the exposure. The results suggest that age-dependent, differential neurochemical responses to toluene may contribute to the unique behavioral patterns associated with drug abuse among older children and young teens. PMID:21126832

  7. Long-lasting alterations of hippocampal GABAergic neurotransmission in adult rats following perinatal Δ(9)-THC exposure.

    PubMed

    Beggiato, Sarah; Borelli, Andrea Celeste; Tomasini, Maria Cristina; Morgano, Lucia; Antonelli, Tiziana; Tanganelli, Sergio; Cuomo, Vincenzo; Ferraro, Luca

    2017-03-01

    The long-lasting effects of gestational cannabinoids exposure on the adult brain of the offspring are still controversial. It has already been shown that pre- or perinatal cannabinoids exposure induces learning and memory disruption in rat adult offspring, associated with permanent alterations of cortical glutamatergic neurotransmission and cognitive deficits. In the present study, the risk of long-term consequences induced by perinatal exposure to cannabinoids on rat hippocampal GABAergic system of the offspring, has been explored. To this purpose, pregnant rats were treated daily with Delta(9)-tetrahydrocannabinol (Δ(9)-THC; 5mg/kg) or its vehicle. Perinatal exposure to Δ(9)-THC induced a significant reduction (p<0.05) in basal and K(+)-evoked [(3)H]-GABA outflow of 90-day-old rat hippocampal slices. These effects were associated with a reduction of hippocampal [(3)H]-GABA uptake compared to vehicle exposed group. Perinatal exposure to Δ(9)-THC induced a significant reduction of CB1 receptor binding (Bmax) in the hippocampus of 90-day-old rats. However, a pharmacological challenge with either Δ(9)-THC (0.1μM) or WIN55,212-2 (2μM), similarly reduced K(+)-evoked [(3)H]-GABA outflow in both experimental groups. These reductions were significantly blocked by adding the selective CB1 receptor antagonist SR141716A. These findings suggest that maternal exposure to cannabinoids induces long-term alterations of hippocampal GABAergic system. Interestingly, previous behavioral studies demonstrated that, under the same experimental conditions as in the present study, perinatal cannabinoids exposure induced cognitive impairments in adult rats, thus resembling some effects observed in humans. Although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of hippocampus aminoacidergic transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of

  8. Alteration of Bacterial Antibiotic Sensitivity After Short-Term Exposure to Diagnostic Ultrasound

    PubMed Central

    Mortazavi, Seyed Mohammad Javad; Darvish, Leili; Abounajmi, Mohammad; Zarei, Samira; Zare, Tahereh; Taheri, Mohammad; Nematollahi, Samaneh

    2015-01-01

    inhibition zones in exposed and non-exposed samples of Klebsiella pneumonia and Streptococcus. Conclusions This study clearly shows that short-term exposure of microorganisms to diagnostic ultrasonic waves can significantly alter their sensitivity to antibiotics. We believe that this physical method of making the antibiotic-resistant population susceptible can open new horizons in antibiotic therapy of a broad range of diseases, including tuberculosis. PMID:26732124

  9. Acute Exposure to Microcystin-Producing Cyanobacterium Microcystis aeruginosa Alters Adult Zebrafish (Danio rerio) Swimming Performance Parameters.

    PubMed

    Kist, Luiza Wilges; Piato, Angelo Luis; da Rosa, João Gabriel Santos; Koakoski, Gessi; Barcellos, Leonardo José Gil; Yunes, João Sarkis; Bonan, Carla Denise; Bogo, Maurício Reis

    2011-01-01

    Microcystins (MCs) are toxins produced by cyanobacteria (blue-green algae), primarily Microcystis aeruginosa, forming water blooms worldwide. When an organism is exposed to environmental perturbations, alterations in normal behavioral patterns occur. Behavioral repertoire represents the consequence of a diversity of physiological and biochemical alterations. In this study, we assessed behavioral patterns and whole-body cortisol levels of adult zebrafish (Danio rerio) exposed to cell culture of the microcystin-producing cyanobacterium M. aeruginosa (MC-LR, strain RST9501). MC-LR exposure (100 μg/L) decreased by 63% the distance traveled and increased threefold the immobility time when compared to the control group. Interestingly, no significant alterations in the number of line crossings were found at the same MC-LR concentration and time of exposure. When animals were exposed to 50 and 100 μg/L, MC-LR promoted a significant increase (around 93%) in the time spent in the bottom portion of the tank, suggesting an anxiogenic effect. The results also showed that none of the MC-LR concentrations tested promoted significant alterations in absolute turn angle, path efficiency, social behavior, or whole-body cortisol level. These findings indicate that behavior is susceptible to MC-LR exposure and provide evidence for a better understanding of the ecological consequences of toxic algal blooms.

  10. An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring

    PubMed Central

    Wirbisky, Sara E.; Weber, Gregory J.; Sepúlveda, Maria S.; Lin, Tsang-Long; Jannasch, Amber S.; Freeman, Jennifer L.

    2016-01-01

    The herbicide atrazine, a suspected endocrine disrupting chemical (EDC), frequently contaminates potable water supplies. Studies suggest alterations in the neuroendocrine system along the hypothalamus-pituitary-gonadal axis; however, most studies address either developmental, pubertal, or adulthood exposures, with few investigations regarding a developmental origins hypothesis. In this study, zebrafish were exposed to 0, 0.3, 3, or 30 parts per billion (ppb) atrazine through embryogenesis and then allowed to mature with no additional chemical exposure. Reproductive function, histopathology, hormone levels, offspring morphology, and the ovarian transcriptome were assessed. Embryonic atrazine exposure resulted in a significant increase in progesterone levels in the 3 and 30 ppb groups. A significant decrease in spawning and a significant increase in follicular atresia in the 30 ppb group were observed. In offspring, a decrease in the head length to body ratio in the 30 ppb group, along with a significant increase in head width to body ratio in the 0.3 and 3 ppb groups occurred. Transcriptomic alterations involved genes associated with endocrine system development and function, tissue development, and behavior. This study provides evidence to support atrazine as an EDC causing reproductive dysfunction and molecular alterations in adults exposed only during embryogenesis and morphological alterations in their offspring. PMID:26891955

  11. Exposure to forced swim stress alters local circuit activity and plasticity in the dentate gyrus of the hippocampus.

    PubMed

    Yarom, Orli; Maroun, Mouna; Richter-Levin, Gal

    2008-01-01

    Studies have shown that, depending on its severity and context, stress can affect neural plasticity. Most related studies focused on synaptic plasticity and long-term potentiation (LTP) of principle cells. However, evidence suggests that following high-frequency stimulation, which induces LTP in principal cells, modifications also take place at the level of complex interactions with interneurons within the dentate gyrus, that is, at the local circuit level. So far, the possible effects of stress on local circuit activity and plasticity were not studied. Therefore, we set out to examine the possible alterations in local circuit activity and plasticity following exposure to stress. Local circuit activity and plasticity were measured by using frequency dependant inhibition (FDI) and commissural modulation protocols following exposure to a 15 minute-forced swim trial. Exposure to stress did not alter FDI. The application of theta-burst stimulation (TBS) reduced FDI in both control and stressed rats, but this type of plasticity was greater in stressed rats. Commissural-induced inhibition was significantly higher in stressed rats both before and after applying theta-burst stimulation. These findings indicate that the exposure to acute stress affects aspects of local circuit activity and plasticity in the dentate gyrus. It is possible that these alterations underlie some of the behavioral consequences of the stress experience.

  12. Honey Bee Gut Microbiome Is Altered by In-Hive Pesticide Exposures

    PubMed Central

    Kakumanu, Madhavi L.; Reeves, Alison M.; Anderson, Troy D.; Rodrigues, Richard R.; Williams, Mark A.

    2016-01-01

    Honey bees (Apis mellifera) are the primary pollinators of major horticultural crops. Over the last few decades, a substantial decline in honey bees and their colonies have been reported. While a plethora of factors could contribute to the putative decline, pathogens, and pesticides are common concerns that draw attention. In addition to potential direct effects on honey bees, indirect pesticide effects could include alteration of essential gut microbial communities and symbionts that are important to honey bee health (e.g., immune system). The primary objective of this study was to determine the microbiome associated with honey bees exposed to commonly used in-hive pesticides: coumaphos, tau-fluvalinate, and chlorothalonil. Treatments were replicated at three independent locations near Blacksburg Virginia, and included a no-pesticide amended control at each location. The microbiome was characterized through pyrosequencing of V2–V3 regions of the bacterial 16S rRNA gene and fungal ITS region. Pesticide exposure significantly affected the structure of bacterial but not fungal communities. The bee bacteriome, similar to other studies, was dominated by sequences derived from Bacilli, Actinobacteria, α-, β-, γ-proteobacteria. The fungal community sequences were dominated by Ascomycetes and Basidiomycetes. The Multi-response permutation procedures (MRPP) and subsequent Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that chlorothalonil caused significant change to the structure and functional potential of the honey bee gut bacterial community relative to control. Putative genes for oxidative phosphorylation, for example, increased while sugar metabolism and peptidase potential declined in the microbiome of chlorothalonil exposed bees. The results of this field-based study suggest the potential for pesticide induced changes to the honey bee gut microbiome that warrant further investigation. PMID:27579024

  13. Honey Bee Gut Microbiome Is Altered by In-Hive Pesticide Exposures.

    PubMed

    Kakumanu, Madhavi L; Reeves, Alison M; Anderson, Troy D; Rodrigues, Richard R; Williams, Mark A

    2016-01-01

    Honey bees (Apis mellifera) are the primary pollinators of major horticultural crops. Over the last few decades, a substantial decline in honey bees and their colonies have been reported. While a plethora of factors could contribute to the putative decline, pathogens, and pesticides are common concerns that draw attention. In addition to potential direct effects on honey bees, indirect pesticide effects could include alteration of essential gut microbial communities and symbionts that are important to honey bee health (e.g., immune system). The primary objective of this study was to determine the microbiome associated with honey bees exposed to commonly used in-hive pesticides: coumaphos, tau-fluvalinate, and chlorothalonil. Treatments were replicated at three independent locations near Blacksburg Virginia, and included a no-pesticide amended control at each location. The microbiome was characterized through pyrosequencing of V2-V3 regions of the bacterial 16S rRNA gene and fungal ITS region. Pesticide exposure significantly affected the structure of bacterial but not fungal communities. The bee bacteriome, similar to other studies, was dominated by sequences derived from Bacilli, Actinobacteria, α-, β-, γ-proteobacteria. The fungal community sequences were dominated by Ascomycetes and Basidiomycetes. The Multi-response permutation procedures (MRPP) and subsequent Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that chlorothalonil caused significant change to the structure and functional potential of the honey bee gut bacterial community relative to control. Putative genes for oxidative phosphorylation, for example, increased while sugar metabolism and peptidase potential declined in the microbiome of chlorothalonil exposed bees. The results of this field-based study suggest the potential for pesticide induced changes to the honey bee gut microbiome that warrant further investigation.

  14. Salmonid sexual development is not consistently altered by embryonic exposure to endocrine-active chemicals.

    PubMed Central

    Carlson, D B; Curtis, L R; Williams, D E

    2000-01-01

    Fish sexual development is sensitive to exogenous hormone manipulation, and salmonids have been used extensively as environmental sentinels and models for biomedical research. We simulated maternal transfer of contaminants by microinjecting rainbow trout (Oncorhynchus mykiss) and chinook salmon (Oncorhynchus tshawytscha) embryos. Fish were reared for 6 months and sexed, and gonads were removed for histology and measurement of in vitro steroid production. Analysis of fat samples showed that dichlorodiphenylethylene (DDE) levels, o, p'M-DDE and p,o, p'-DDE isomers, were elevated 6 months after treatment. A preliminary study showed an increased ratio of males to females after treatment with 80 mg/kg and 160 mg/kg of the xenoestrogen o,o, p'-DDE. One fish treated with 160 mg/kg o,o, p'-DDE had gonads with cells typical of both males and females. A follow-up study, using more fish and excluding the highly toxic 160 mg/kg o,o, p'-DDE dose, showed no effect on sex ratio or gonadal histology. Embryonic exposure of monosex male trout, monosex female trout, and mixed sex salmon to o, o, p'-DDE, p,o, p'-DDE, mixtures of DDE isomers, and octylphenol failed to alter sexual development. We observed no treatment-dependent changes in in vitro gonadal steroid production in any experiments. Trout exposed in ovo and reared to maturity spawned successfully. These results suggest that mortality attributable to the xenoestrogens o,o, p'-DDE, chlordecone, and octylphenol, and the antiandrogen p,o, p'-DDE, is likely to occur before the appearance of subtle changes in sexual development. Because trout appeared to be sensitive to endocrine disruption, we cannot dismiss the threat of heavily contaminated sites or complex mixtures to normal sexual development of salmonids or other aquatic organisms. Images Figure 1 Figure 2 Figure 3 PMID:10706532

  15. Lead (Pb) exposure reduces global DNA methylation level by non-competitive inhibition and alteration of dnmt expression.

    PubMed

    Sanchez, Oscar F; Lee, Jinyoung; Yu King Hing, Nathaphon; Kim, Seong-Eun; Freeman, Jennifer L; Yuan, Chongli

    2017-02-22

    Low-dose exposure to lead (Pb) is connected to developmental neurological alterations by inducing molecular changes, such as aberrant gene expression patterns. The attributing molecular mechanism, however, is not well-elucidated. In this study, we revealed epigenetic features and mechanisms that can alter gene expression patterns by identifying changes in DNA methyltransferase (DNMT) activity, expression pattern and DNA methylation level using moelcular studies and a zebrafish animal model. We characterized the effects of Pb on the activities of various DNMTs in vitro and determined the molecular role of Pb in modulating DNMT activity via kinetic experiments. An exposure of 100 or 500 ppb of Pb was found to significantly lower the activity of maintenance DNMTs. The inhibition mechanism can be described using non-competitive Michaelis-Menten kinetics. A zebrafish animal model was then used to assess the biological significance of our findings. An embryonic exposure to 100 or 500 ppb Pb resulted in a significant change in global methylation levels consistent with previous studies using human and rodent model. Our study also suggests that Pb exposure in zebrafish alters the expression patterns of dnmt3 and dnmt4 which are human DNMT3b orthologs. The knowledge from this study suggests that Pb exposure can affect the activity of maintenance DNMTs via non-competitive inhibition, which has not been reported previously. Meanwhile, the expression pattern of de novo methyltransferases can also be altered. Collectively, they result in a reduction in global DNA methylation level in Pb-exposed zebrafish model, which can be compared to findings in human and rodent studies.

  16. ONTOGENETIC ALTERATIONS IN MOLECULAR AND STRUCTURAL CORRELATES OF DENDRITIC GROWTH FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYLS.

    EPA Science Inventory

    This is the first report showing both molecular and structural changes in brain following developmental exposure to a neurotoxicant. It is known that perinatal exposure to a neurotoxicant, polychlorinated biphenyls (PCBs), is associated with decreased IQ scores, impaired learnin...

  17. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    INVESTIGATOR: Rolf A. Brekken CONTRACTING ORGANIZATION: U niveristy of Texas Southwestern Medical Center Dallas, TX 75390-9105 REPORT DATE: December...COVERED (From - To) 30 Sep 2012 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Phosphatidylserine for Radioimmunotherapy of Breast...antibody, PGN635, a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically

  18. Gradients of phosphatidylserine contribute to plasma membrane charge localization and cell polarity in fission yeast

    PubMed Central

    Haupt, Armin; Minc, Nicolas

    2017-01-01

    Surface charges at the inner leaflet of the plasma membrane may contribute to regulate the surface recruitment of key signaling factors. Phosphatidylserine (PS) is an abundant charged lipid that may regulate charge distribution in different cell types. Here we characterize the subcellular distribution and function of PS in the rod-shaped, polarized fission yeast. We find that PS preferably accumulates at cell tips and defines a gradient of negative charges along the cell surface. This polarization depends on actin-mediated endocytosis and contributes to the subcellular partitioning of charged polarity-regulating Rho GTPases like Rho1 or Cdc42 in a protein charge–dependent manner. Cells depleted of PS have altered cell dimensions and fail to properly regulate growth from the second end, suggesting a role for PS and membrane charge in polarized cell growth. PMID:27852900

  19. A single exposure to bisphenol A alters the levels of important neuroproteins in adult male and female mice.

    PubMed

    Viberg, Henrik; Lee, Iwa

    2012-10-01

    Bisphenol A (BPA) is widely used in polymer products in food and beverage containers, baby bottles, dental sealants and fillings, adhesives, protective coatings, flame retardants, water supply pipes, and compact discs, and is found in the environment and in placental tissue, fetuses and breast milk. We have recently reported that a single neonatal exposure to bisphenol A can induce persistent aberrations in spontaneous behavior, in a dose-dependent manner, and affect the adult response to the cholinergic agent nicotine. Furthermore, other recent reports indicate that pre- and perinatal exposure to bisphenol A can induce neurotoxic effects. The present study indicates that a single neonatal exposure to bisphenol A, on postnatal day 10, during the peak of the brain growth spurt, can alter the adult levels of proteins important for normal brain development (CaMKII and synaptophysin). These alterations are induced in both male and female mice and effects are seen in both hippocampus and cerebral cortex. These results further support our recent study showing that neonatal exposure to bisphenol A can act as a developmental neurotoxicant and the effects are similar to effects seen after a single postnatal exposure to other POPs, such as PBDEs, PCBs and PFCs.

  20. Cooperative binding of Annexin A5 to phosphatidylserine on apoptotic cell membranes

    NASA Astrophysics Data System (ADS)

    Janko, Christina; Jeremic, Ivica; Biermann, Mona; Chaurio, Ricardo; Schorn, Christine; Muñoz, Luis E.; Herrmann, Martin

    2013-12-01

    Healthy cells exhibit an asymmetric plasma membrane with phosphatidylserine (PS) located on the cytoplasmic leaflet of the plasma membrane bilayer. Annexin A5-FITC, a PS binding protein, is commonly used to evaluate apoptosis in flow cytometry. PS exposed by apoptotic cells serves as a major ‘eat-me’ signal for phagocytes. Although exposition of PS has been observed after alternative stimuli, no clearance of viable, PS exposing cells has been detected. Thus, besides PS exposure, membranes of viable and apoptotic cells might exhibit specific characteristics. Here, we show that Annexin A5 binds in a cooperative manner to different types of dead cells. Shrunken apoptotic cells thereby showed the highest Hill coefficient values. Contrarily, parafomaldehyde fixation of apoptotic cells completely abrogates the cooperativity effect seen with dead and dying cells. We tend to speculate that the cooperative binding of Annexin A5 to the membranes of apoptotic cells reflects higher fluidity of the exposed membranes facilitating PS clustering.

  1. Associations between personal exposures to VOCs and alterations in cardiovascular physiology: Detroit Exposure and Aerosol Research Study (DEARS) - presentation

    EPA Science Inventory

    Introduction: An adult cohort consisting of 63 participants engaged in the US EPA’s recent Detroit Exposure and Aerosol Research Study (DEARS) and a University of Michigan cardiovascular sub-study conducted during summer and winter periods over 3 years between 2004 and 2007...

  2. Associations between Personal Exposures to VOCs and Alterations in Cardiovascular Physiology: Detroit Exposure and Aerosol Research Study (DEARS)

    EPA Science Inventory

    Background: An adult cohort consisting of 63 participants engaged in the US EPA’s recent Detroit Exposure and Aerosol Research Study (DEARS) and a University of Michigan cardiovascular sub-study conducted during summer and winter periods over 3 years between 2004 and 2007 (5 seas...

  3. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons

    PubMed Central

    de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-01-01

    The CB1 cannabinoid receptor, the main target of Δ9-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling. PMID:26460022

  4. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.

    PubMed

    de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-11-03

    The CB1 cannabinoid receptor, the main target of Δ(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.

  5. Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

    PubMed Central

    Hiolski, Emma M; Kendrick, Preston S; Frame, Elizabeth R; Myers, Mark S; Bammler, Theo K; Beyer, Richard P; Farin, Federico M; Wilkerson, Hui-wen; Smith, Donald R; Marcinek, David J; Lefebvre, Kathi A

    2014-01-01

    Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: 1) identify transcriptional biomarkers of exposure; and 2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly-variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences. PMID:25033243

  6. Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

    PubMed Central

    Blossom, Sarah J.; Melnyk, Stepan; Cooney, Craig A.; Gilbert, Kathleen M.; James, S. Jill

    2012-01-01

    Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally-relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in the hippocampus, a brain region prone to oxidative stress. Instead of a continuous exposure, the mice were exposed to water only or two environmentally relevant doses of TCE in the drinking water postnatally from birth until 6 weeks of age. Biomarkers of plasma metabolites in the transsulfuration pathway and the transmethylation pathway of the methionine cycle were also examined. Gene expression of neurotrophins was examined to investigate a possible relationship between oxidative stress, redox imbalance and neurotrophic factor expression with TCE exposure. Our results show that hippocampi isolated from male mice exposed to TCE showed altered glutathione redox homeostasis indicating a more oxidized state. Also observed was a significant, dose dependent increase in glutathione precursors. Plasma from the TCE treated mice showed alterations in metabolites in the transsulfuration and transmethylation pathways indicating redox imbalance and altered methylation capacity. 3-Nitrotyrosine, a biomarker of protein oxidative stress, was also significantly higher in plasma and hippocampus of TCE-exposed mice compared to controls. In contrast, expression of key neurotrophic factors in the hippocampus (BDNF, NGF, and NT-3) was significantly reduced compared to controls. Our results demonstrate that low-level postnatal and early life TCE exposure modulates neurotrophin gene expression in the mouse hippocampus and may provide a mechanism for TCE-mediated neurotoxicity. PMID:22421312

  7. Functional Alteration of Natural Killer Cells and Cytotoxic T Lymphocytes upon Asbestos Exposure and in Malignant Mesothelioma Patients.

    PubMed

    Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Matsuzaki, Hidenori; Lee, Suni; Maeda, Megumi; Kishimoto, Takumi; Fukuoka, Kazuya; Nakano, Takashi; Otsuki, Takemi

    2015-01-01

    Malignant mesothelioma is caused by exposure to asbestos, which is known to have carcinogenic effects. However, the development of mesothelioma takes a long period and results from a low or intermediate dose of exposure. These findings have motivated us to investigate the immunological effects of asbestos exposure and analyze immune functions of patients with mesothelioma and pleural plaque, a sign of exposure to asbestos. Here, we review our knowledge concerning natural killer (NK) cells and cytotoxic T lymphocytes (CTL). NK cells showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, while induction of granzyme(+) cells in CD8(+) lymphocytes was suppressed by asbestos exposure. It is interesting that a decrease in NKp46, a representative activating receptor, is common between NK cells in PBMC culture with asbestos and those of mesothelioma patients. Moreover, it was observed that CD8(+) lymphocytes may be stimulated by some kind of "nonself" cells in plaque-positive individuals and in mesothelioma patients, whereas CTL in mesothelioma is impaired by poststimulation maintenance of cytotoxicity. These findings suggest that analysis of immunological parameters might contribute to the evaluation of health conditions of asbestos-exposed individuals and to a greater understanding of the pathology of malignant mesothelioma.

  8. Functional Alteration of Natural Killer Cells and Cytotoxic T Lymphocytes upon Asbestos Exposure and in Malignant Mesothelioma Patients

    PubMed Central

    Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Matsuzaki, Hidenori; Lee, Suni; Maeda, Megumi; Kishimoto, Takumi; Fukuoka, Kazuya; Nakano, Takashi; Otsuki, Takemi

    2015-01-01

    Malignant mesothelioma is caused by exposure to asbestos, which is known to have carcinogenic effects. However, the development of mesothelioma takes a long period and results from a low or intermediate dose of exposure. These findings have motivated us to investigate the immunological effects of asbestos exposure and analyze immune functions of patients with mesothelioma and pleural plaque, a sign of exposure to asbestos. Here, we review our knowledge concerning natural killer (NK) cells and cytotoxic T lymphocytes (CTL). NK cells showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, while induction of granzyme+ cells in CD8+ lymphocytes was suppressed by asbestos exposure. It is interesting that a decrease in NKp46, a representative activating receptor, is common between NK cells in PBMC culture with asbestos and those of mesothelioma patients. Moreover, it was observed that CD8+ lymphocytes may be stimulated by some kind of “nonself” cells in plaque-positive individuals and in mesothelioma patients, whereas CTL in mesothelioma is impaired by poststimulation maintenance of cytotoxicity. These findings suggest that analysis of immunological parameters might contribute to the evaluation of health conditions of asbestos-exposed individuals and to a greater understanding of the pathology of malignant mesothelioma. PMID:26161391

  9. Exposure to crude oil micro-droplets causes reduced food uptake in copepods associated with alteration in their metabolic profiles.

    PubMed

    Hansen, Bjørn Henrik; Altin, Dag; Nordtug, Trond; Øverjordet, Ida Beathe; Olsen, Anders J; Krause, Dan; Størdal, Ingvild; Størseth, Trond R

    2017-03-01

    Acute oil spills and produced water discharges may cause exposure of filter-feeding pelagic organisms to micron-sized dispersed oil droplets. The dissolved oil components are expected to be the main driver for oil dispersion toxicity; however, very few studies have investigated the specific contribution of oil droplets to toxicity. In the present work, the contribution of oil micro-droplet toxicity in dispersions was isolated by comparing exposures to oil dispersions (water soluble fraction with droplets) to concurrent exposure to filtered dispersions (water-soluble fractions without droplets). Physical (coloration) and behavioral (feeding activity) as well as molecular (metabolite profiling) responses to oil exposures in the copepod Calanus finmarchicus were studied. At high dispersion concentrations (4.1-5.6mg oil/L), copepods displayed carapace discoloration and reduced swimming activity. Reduced feeding activity, measured as algae uptake, gut filling and fecal pellet production, was evident also for lower concentrations (0.08mg oil/L). Alterations in metabolic profiles were also observed following exposure to oil dispersions. The pattern of responses were similar between two comparable experiments with different oil types, suggesting responses to be non-oil type specific. Furthermore, oil micro-droplets appear to contribute to some of the observed effects triggering a starvation-type response, manifested as a reduction in metabolite (homarine, acetylcholine, creatine and lactate) concentrations in copepods. Our work clearly displays a relationship between crude oil micro-droplet exposure and reduced uptake of algae in copepods.

  10. Alteration of extracellular enzymes in pinto bean leaves upon exposure to air pollutants, ozone and sulfur dioxide

    SciTech Connect

    Peters, J.L.; Castillo, F.J.; Heath, R.L. )

    1989-01-01

    Diamine oxidase and peroxidase, associated with the wall in pinto bean (Phaseolus vulgaris L. var Pinto) leaves, can be washed out by vacuum infiltration and assayed without grinding the leaf. The diamine oxidase activity is inhibited in vivo by exposure of the plants to ozone (dose of 0.6 microliters per liter {times} hour), whereas the peroxidase activity associated with the wall space is stimulated. This dose does not cause obvious necrosis or chlorosis of the leaf. These alterations are greater when the dose of ozone exposure is given as a triangular pulse (a slow rise to a peak of 0.24 microliters per liter followed by a slow fall) compared to that given as a constant square wave pulse of 0.15 microliters per liter for the same 4 hour period. Exposure of the plants to sulfur dioxide (at a concentration of 0.4 microliters per liter for 4 hours) does not result in any change in the diamine oxidase or peroxidase activities, yet the total sulfhydryl content of the leaf is increased, demonstrating the entry of sulfur dioxide. These two pollutants, with different chemical reactivities, affect the activities of the extracellular enzymes in different manners. In the case of ozone exposure, the inhibition of extracellular diamine oxidase could profoundly alter the movements of polyamines from cell to cell.

  11. Chemical alteration of poly(tetrafluoroethylene) TFE teflon induced by exposure to electrons and inert-gas ions.

    PubMed

    Everett, Michael L; Hoflund, Gar B

    2005-09-08

    In this study the chemical alterations of poly(tetrafluoroethylene) (TFE Teflon) by approximately 1.0-keV electrons and 1.0-keV He and Ar ions have been examined using X-ray photoelectron spectroscopy (XPS). The initial F/C atom ratio of 1.99 decreases to a steady-state value of 1.48 after 48 h of electron exposure. Exposure to either He+ or Ar+ decreases the initial F/C atom ratio from approximately 2 to a steady-state value of 1.12. The high-resolution XPS C 1s data indicate that new chemical states of carbon form as the F is removed and that the relative amounts of these states depend on the F content of the near-surface region. These states are most likely due to C bonded only to one F atom, C bonded only to other C atoms and C that have lost a pair of electrons through emission of F-. Exposures of the electron-damaged and He+- or Ar+-damaged surfaces to research-grade O2 result in chemisorption of very small amounts of O indicating that large quantities of reactive sites are not formed during the chemical erosion. Further exposure to the electron or ion fluxes quickly removes this chemisorbed oxygen. Exposure of the He+-damaged surface to air at room temperature results in the chemisorption of a larger amount of O than the O2 exposure but no N is adsorbed. The chemical alterations due to electrons and ions are compared with those caused by hyperthermal (approximately 5 eV) atomic oxygen (AO) and vacuum ultraviolet (VUV) radiation. The largest amount of damage is caused by AO followed by VUV, inert-gas ions, and then electrons.

  12. Prenatal ethanol exposure alters ethanol-induced Fos immunoreactivity and dopaminergic activity in the mesocorticolimbic pathway of the adolescent brain.

    PubMed

    Fabio, M C; Vivas, L M; Pautassi, R M

    2015-08-20

    Prenatal ethanol exposure (PEE) promotes alcohol intake during adolescence, as shown in clinical and pre-clinical animal models. The mechanisms underlying this effect of prenatal ethanol exposure on postnatal ethanol intake remain, however, mostly unknown. Few studies assessed the effects of moderate doses of prenatal ethanol on spontaneous and ethanol-induced brain activity on adolescence. This study measured, in adolescent (female) Wistar rats prenatally exposed to ethanol (0.0 or 2.0g/kg/day, gestational days 17-20) or non-manipulated (NM group) throughout pregnancy, baseline and ethanol-induced cathecolaminergic activity (i.e., colocalization of c-Fos and tyrosine hydroxylase) in ventral tegmental area (VTA), and baseline and ethanol-induced Fos immunoreactivity (ir) in nucleus accumbens shell and core (AcbSh and AcbC, respectively) and prelimbic (PrL) and infralimbic (IL) prefrontal cortex. The rats were challenged with ethanol (dose: 0.0, 1.25, 2.5 or 3.25g/kg, i.p.) at postnatal day 37. Rats exposed to vehicle prenatally (VE group) exhibited reduced baseline dopaminergic tone in VTA; an effect that was inhibited by prenatal ethanol exposure (PEE group). Dopaminergic activity in VTA after the postnatal ethanol challenge was greater in PEE than in VE or NM animals. Ethanol-induced Fos-ir at AcbSh was found after 1.25g/kg and 2.5g/kg ethanol, in VE and PEE rats, respectively. PEE did not alter ethanol-induced Fos-ir at IL but reduced ethanol-induced Fos-ir at PrL. These results suggest that prenatal ethanol exposure heightens dopaminergic activity in the VTA and alters the response of the mesocorticolimbic pathway to postnatal ethanol exposure. These effects may underlie the enhanced vulnerability to develop alcohol-use disorders of adolescents with a history of in utero ethanol exposure.

  13. Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat

    PubMed Central

    Lim, Wei Ling; Idris, Marshita Mohd; Kevin, Felix Suresh; Soga, Tomoko; Parhar, Ishwar S.

    2016-01-01

    Maternal dexamethasone [(DEX); a glucocorticoid receptor agonist] exposure delays pubertal onset and alters reproductive behavior in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring’s reproductive function by disrupting the gonadotropin-releasing hormone (GnRH) neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. Pregnant females were administered with DEX (0.1 mg/kg) or vehicle (VEH, water) daily during gestation day 13–20. Confocal imaging was used to examine the spine density of EGFP–GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP–GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0) males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT) was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the postsynaptic marker molecule, postsynaptic density 95, was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood. PMID:27630615

  14. Phosphatidylserine Outer Layer Translocation Is Implicated in IL-10 Secretion by Human Regulatory B Cells.

    PubMed

    Audo, Rachel; Hua, Charlotte; Hahne, Michael; Combe, Bernard; Morel, Jacques; Daien, Claire I

    2017-01-01

    B cells can have a regulatory role, mainly mediated by interleukin 10 (IL-10). IL-10 producing B cells (B10 cells) cells remain to be better characterized. Annexin V binds phosphatidylserine (PS), which is externalized during apoptosis. Previous works suggested that B10 cells are apoptotic cells since they bind Annexin V. Others showed that Annexin V binding could also be expressed on viable B cells. We aimed to explore if PS exposure can be a marker of B10 cells and if PS exposure has a functional role on B cell IL-10 production in healthy subjects. We found that B10 cells were significantly more often Annexin V+ than IL-10 non-producing B cells. After CpG activation, Annexin V+ B cells differentiated more often into B10 cells than Annexin Vneg B cells. Cell death and early apoptosis were similar between Annexin V+ and Annexin Vneg B cells. PS blockage, using biotinylated AnV and glyburide, decreased B10 cell differentiation. This study showed that B10 cells have an increased PS exposure independently of any apoptotic state. B cells exposing PS differentiate more into B10 cells whereas PS blockage inhibits B10 cells generation. These results strongly suggest a link between PS exposure and B10 cells.

  15. Variation in human cancer cell external phosphatidylserine is regulated by flippase activity and intracellular calcium.

    PubMed

    Vallabhapurapu, Subrahmanya D; Blanco, Víctor M; Sulaiman, Mahaboob K; Vallabhapurapu, Swarajya Lakshmi; Chu, Zhengtao; Franco, Robert S; Qi, Xiaoyang

    2015-10-27

    Viable cancer cells expose elevated levels of phosphatidylserine (PS) on the exoplasmic face of the plasma membrane. However, the mechanisms leading to elevated PS exposure in viable cancer cells have not been defined. We previously showed that externalized PS may be used to monitor, target and kill tumor cells. In addition, PS on tumor cells is recognized by macrophages and has implications in antitumor immunity. Therefore, it is important to understand the molecular details of PS exposure on cancer cells in order to improve therapeutic targeting. Here we explored the mechanisms regulating the surface PS exposure in human cancer cells and found that differential flippase activity and intracellular calcium are the major regulators of surface PS exposure in viable human cancer cells. In general, cancer cell lines with high surface PS exhibited low flippase activity and high intracellular calcium, whereas cancer cells with low surface PS exhibited high flippase activity and low intracellular calcium. High surface PS cancer cells also had higher total cellular PS than low surface PS cells. Together, our results indicate that the amount of external PS in cancer cells is regulated by calcium dependent flippase activity and may also be influenced by total cellular PS.

  16. Phosphatidylserine Outer Layer Translocation Is Implicated in IL-10 Secretion by Human Regulatory B Cells

    PubMed Central

    Hahne, Michael; Combe, Bernard; Morel, Jacques; Daien, Claire I.

    2017-01-01

    B cells can have a regulatory role, mainly mediated by interleukin 10 (IL-10). IL-10 producing B cells (B10 cells) cells remain to be better characterized. Annexin V binds phosphatidylserine (PS), which is externalized during apoptosis. Previous works suggested that B10 cells are apoptotic cells since they bind Annexin V. Others showed that Annexin V binding could also be expressed on viable B cells. We aimed to explore if PS exposure can be a marker of B10 cells and if PS exposure has a functional role on B cell IL-10 production in healthy subjects. We found that B10 cells were significantly more often Annexin V+ than IL-10 non-producing B cells. After CpG activation, Annexin V+ B cells differentiated more often into B10 cells than Annexin Vneg B cells. Cell death and early apoptosis were similar between Annexin V+ and Annexin Vneg B cells. PS blockage, using biotinylated AnV and glyburide, decreased B10 cell differentiation. This study showed that B10 cells have an increased PS exposure independently of any apoptotic state. B cells exposing PS differentiate more into B10 cells whereas PS blockage inhibits B10 cells generation. These results strongly suggest a link between PS exposure and B10 cells. PMID:28072868

  17. Ethanol exposure alters zebrafish development: a novel model of fetal alcohol syndrome.

    PubMed

    Bilotta, Joseph; Barnett, Jalynn A; Hancock, Laura; Saszik, Shannon

    2004-01-01

    Prenatal exposure to alcohol has been shown to produce the overt physical and behavioral symptoms known as fetal alcohol syndrome (FAS) in humans. Also, it is believed that low concentrations and/or short durations of alcohol exposure can produce more subtle effects. The purpose of this study was to investigate the effects of embryonic ethanol exposure on the zebrafish (Danio rerio) in order to determine whether this species is a viable animal model for studying FAS. Fertilized embryos were reared in varying concentrations of ethanol (1.5% and 2.9%) and exposure times (e.g., 0-8, 6-24, 12-24, and 48-72 h postfertilization; hpf); anatomical measures including eye diameter and heart rate were compared across groups. Results found that at the highest concentration of ethanol (2.9%), there were more abnormal physical distortions and significantly higher mortality rates than any other group. Embryos exposed to ethanol for a shorter duration period (0-8 hpf) at a concentration of 1.5% exhibited more subtle effects such as significantly smaller eye diameter and lower heart rate than controls. These results indicate that embryonic alcohol exposure affects external and internal physical development and that the severity of these effects is a function of both the amount of ethanol and the timing of ethanol exposure. Thus, the zebrafish represents a useful model for examining basic questions about the effects of embryonic exposure to ethanol on development.

  18. Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala

    PubMed Central

    Patisaul, Heather B.

    2013-01-01

    Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6–21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure. PMID:23457122

  19. Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats

    PubMed Central

    Albores-Garcia, Damaris; Hernandez, Alberto J.; Loera, Miriam J.

    2016-01-01

    Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined. PMID:26885512

  20. Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

    PubMed

    Albores-Garcia, Damaris; Acosta-Saavedra, Leonor C; Hernandez, Alberto J; Loera, Miriam J; Calderón-Aranda, Emma S

    2016-01-01

    Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.

  1. Continuous exposure to the deterrents cis-jasmone and methyl jasmonate does not alter the behavioural responses of Frankliniella occidentalis

    PubMed Central

    Egger, Barbara; Spangl, Bernhard; Koschier, Elisabeth Helene

    2016-01-01

    Behavioural responses of Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), a generalist, cell sap-feeding insect species with piercing-sucking mouthparts, after continuous exposure to two deterrent secondary plant compounds are investigated. We compared in choice assays on bean leaf discs, the settling, feeding, and oviposition preferences of F. occidentalis females that had no experience with the two fatty acid derivatives methyl jasmonate and cis-jasmone before testing (naïve thrips) vs. females that had been exposed to the deterrent compounds before testing (experienced thrips). The thrips were exposed to the deterrents at low or high concentrations for varied time periods and subsequently tested on bean leaf discs treated with the respective deterrent at either a low or a high concentration. Frankliniella occidentalis females avoided settling on the deterrent-treated bean leaf discs for an observation period of 6 h, independent of their previous experience. Our results demonstrate that feeding and oviposition deterrence of the jasmonates to the thrips were not altered by continuous exposure of the thrips to the jasmonates. Habituation was not induced, neither by exposure to the low concentration of the deterrents nor by exposure to the high concentration. These results indicate that the risk of habituation to two volatile deterrent compounds after repeated exposure is not evident in F. occidentalis. This makes the two compounds potential candidates to be integrated in pest management strategies. PMID:26726263

  2. VANADIUM EXPOSURE ALTERS SPONTANEOUS BEAT RATE AND GENE EXPRESSION OF CULTURED CARDIAC MYOCYTES

    EPA Science Inventory

    Ambient air pollution particulate matter (PM) exposure is associated with increased morbidity and mortality. Recent toxicological studies report PM-induced changes in a number of cardiac parameters, including heart rate variability, arrhythmias, repolarization, and internal defib...

  3. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat: in vivo studies.

    EPA Science Inventory

    Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the thyroid gland to reduce circulating levels of thyroid hormone. Neurological function accompanying developmental exposure to perchlorate was evaluated in the present study...

  4. Chronic exposure to alcohol alters network activity and morphology of cultured hippocampal neurons.

    PubMed

    Korkotian, Eduard; Botalova, Alena; Odegova, Tatiana; Segal, Menahem

    2015-03-01

    The effects of chronic exposure to moderate concentrations of ethanol were studied in cultured hippocampal neurons. Network activity, assessed by imaging of [Ca(2+)]i variations, was markedly suppressed following 5 days of exposure to 0.25-1% ethanol. The reduced activity was sustained following extensive washout of ethanol, but the activity recovered by blockade of inhibition with bicuculline. This reduction of network activity was associated with a reduction in rates of mEPSCs, but not in a change in inhibitory synaptic activity. Chronic exposure to ethanol caused a significant reduction in the density of mature dendritic spines, without an effect on dendritic length or arborization. These results indicate that chronic exposure to ethanol causes a reduction in excitatory network drive in hippocampal neurons adding another dimension to the chronic effects of alcohol abuse.

  5. IDENTIFICATION OF NEURAL BIOMARKERS OF ALTERED SEXUAL DIFFERENTIATION FOLLOWING GESTATIONAL EXPOSURE***

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

  6. Identification of neural biomarkers of altered sexual differentiation following gestational exposure###

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) duri...

  7. Identification of neural biomarkers of altered sexual differentiation following gestational exposure

    EPA Science Inventory

    Sexual differentiation of the brain occurs during late gestation through the early postnatal period. The development of the phenotypical male brain is dependent on the aromatization of circulating testosterone to estradiol. Exposure to endocrine disrupting chemicals (EDCs) during...

  8. Developmental Exposure to PCBs Differentially Alters Sensitivity to Audiogenic and Kindling-Induced Seizures in Rats

    EPA Science Inventory

    Previously we reported an increased incidence of audiogenic seizures in offspring of pregnant rats exposed to an environmental mixture of polychlorinated biphenyls (PCBs). This study compares the proconvulsant properties of PCB exposure in audiogenic and electrical kindling seizu...

  9. Paternal BPA exposure in early life alters Igf2 epigenetic status in sperm and induces pancreatic impairment in rat offspring.

    PubMed

    Mao, Zhenxing; Xia, Wei; Chang, Huailong; Huo, Wenqian; Li, Yuanyuan; Xu, Shunqing

    2015-11-04

    Exposure to endocrine disruptors in utero appears to alter epigenetics in the male germ-line and subsequently promote adult-onset disease in subsequent generations. Fetal exposure to bisphenol A (BPA), a highly prevalent endocrine disruptor in environment, has been shown to alter epigenetic modification and result in glucose intolerance in adulthood. However, whether fetal exposure to BPA can induce epigenetic modification and phenotypic changes in their subsequent offspring are still unclear. The present study was designed to investigate whether exposure to BPA in early life induced glucose intolerance in the offspring through male germ line, and the underlying epigenetic molecular basis. F0 pregnant SD rats were received corn oil or 40 μg/kg/day of BPA during gestation and lactation. F1 male rats were maintained to generate F2 offspring by mating with untreated female rats. Both the F1 rats after weaning and the F2 offspring were not received any other treatments. Our results showed that male F2 offspring in the BPA group exhibited glucose intolerance and β-cell dysfunction. Decreased expression of Igf2 and associated hypermethylation of Igf2 were observed in islets of male F2 offspring. In addition, similar effects were observed in female F2 animals, but the effects were more pronounced in males. Moreover, abnormal expression and methylation of Igf2 was observed in sperm of adult F1 male rats, indicating that epigenetic modification in germ cells can be partly progressed to the next generation. Overall, our study suggests that BPA exposure during early life can result in generational transmission of glucose intolerance and β-cell dysfunction in the offspring through male germ line, which is associated with hypermethylation of Igf2 in islets. The changes of epigenetics in germ cells may contribute to this generational transmission.

  10. Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development.

    PubMed

    Dhimolea, Eugen; Wadia, Perinaaz R; Murray, Tessa J; Settles, Matthew L; Treitman, Jo D; Sonnenschein, Carlos; Shioda, Toshi; Soto, Ana M

    2014-01-01

    Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns

  11. Alterations in autonomic function in the guinea pig eye following exposure to dichlorvos vapor.

    PubMed

    Taylor, James T; Davis, Emily; Dabisch, Paul; Horsmon, Mike; Li, Ming; Mioduszewski, Robert

    2008-10-01

    The present study investigated the effect of the organophosphate, dichlorvos (DDVP), on ocular function and cholinesterase activity in guinea pigs, using a single-animal-head-only vapor exposure system. All animals exhibited signs of mild organophosphate poisoning (e.g., salivation, chewing, lacrimation, urination, defecation, and rhinorrhea) after the 20-min exposure, regardless of the DDVP exposure concentration (e.g., 35 mg/m(3), 55 mg/m(3), and 75 mg/m(3)). Pupil constriction or miosis was the most pronounced effect seen after vapor exposure. The postexposure pupil size for the 35 mg/m(3) group was 45.8 +/- 3.68% of the preexposure baseline measurement. Postexposure pupil size in the 55- (38 +/- 1.36%) and 75 mg/m(3) (38.1 +/- 1.72%) groups was significantly less than both the preexposure baseline level and the 35 mg/m(3) group. All groups exhibited enhanced an pupillary response to light after DDVP exposure. The enhanced light response remained even after recovery from miosis (approximately 1 h after exposure). Measurement of cholinesterase activity revealed that even though pupil size had recovered, acetyl- and butyrylcholinesterase remained significantly inhibited in the blood.

  12. Exposure to ambient ultrafine particulate matter alters the expression of genes in primary human neurons.

    PubMed

    Solaimani, Parrisa; Saffari, Arian; Sioutas, Constantinos; Bondy, Stephen C; Campbell, Arezoo

    2017-01-01

    Exposure to ambient particulate matter (PM) has been associated with the onset of neurodevelopmental and neurodegenerative disorders, but the mechanism of toxicity remains unclear. To gain insight into this neurotoxicity, this study sought to examine global gene expression changes caused by exposure to ambient ultrafine PM. Microarray analysis was performed on primary human neurons derived from fetal brain tissue after a 24h exposure to 20μg/mL of ambient ultrafine particles. We found a majority of the changes in noncoding RNAs, which are involved in epigenetic regulation of gene expression, and thereby could impact the expression of several other protein coding gene targets. Although neurons from biologically different lot numbers were used, we found a significant increase in the expression of metallothionein 1A and 1F in all samples after exposure to particulate matter as confirmed by quantitative PCR. These metallothionein 1 proteins are responsible for neuroprotection after exposure to environmental insult but prolonged induction can be toxic. Epidemiological studies have reported that in utero exposure to ultrafine PM not only leads to neurodevelopmental and behavioral abnormalities, but may also predispose the progeny to neurodegenerative disease later in life by genetic imprinting. Our results pinpoint some of the PM-induced genetic changes that may underlie these findings.

  13. Cell biology, physiology and enzymology of phosphatidylserine decarboxylase.

    PubMed

    Di Bartolomeo, Francesca; Wagner, Ariane; Daum, Günther

    2017-01-01

    Phosphatidylethanolamine is one of the most abundant phospholipids whose major amounts are formed by phosphatidylserine decarboxylases (PSD). Here we provide a comprehensive description of different types of PSDs in the different kingdoms of life. In eukaryotes, type I PSDs are mitochondrial enzymes, whereas other PSDs are localized to other cellular compartments. We describe the role of mitochondrial Psd1 proteins, their function, enzymology, biogenesis, assembly into mitochondria and their contribution to phospholipid homeostasis in much detail. We also discuss briefly the cellular physiology and the enzymology of Psd2. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.

  14. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    PubMed

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms.

  15. Alteration of Blood Parameters and Histoarchitecture of Liver and Kidney of Silver Barb after Chronic Exposure to Quinalphos

    PubMed Central

    Mohammod Mostakim, Golam; Zahangir, Md. Mahiuddin; Monir Mishu, Mahbuba; Rahman, Md. Khalilur; Islam, M. Sadiqul

    2015-01-01

    Quinalphos (QP) is commonly used for pest control in the agricultural fields surrounding freshwater reservoirs. This study was conducted to evaluate the chronic toxicity of this pesticide on blood parameters and some organs of silver barb, Barbonymus gonionotus. Fish were exposed to two sublethal concentrations, 0.47 ppm and 0.94 ppm, of QP for a period of 28 days. All the blood parameters (red blood cell, hematocrit, and hemoglobin) and blood glucose except for white blood cells decreased with increasing concentration of toxicant and become significantly lower (p < 0.05) at higher concentration when compared with control. The derived hematological indices of mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were equally altered compared to control. Histoarchitectural changes of liver and kidney were observed after exposure to the QP. Hypertrophy of hepatocytes, mild to severe necrosis, ruptured central vein, and vacuolation were observed in the liver of treated groups. Highly degenerated kidney tubules and hematopoietic tissue, degeneration of renal corpuscle, vacuolization, and necrosis were evident in the kidney of treated groups. In conclusion, chronic exposure to QP at sublethal concentrations induced hematological and histological alterations in silver barb and offers a simple tool to evaluate toxicity derived alterations. PMID:26635877

  16. Chronic fetal exposure to caffeine altered resistance vessel functions via RyRs-BKCa down-regulation in rat offspring

    PubMed Central

    Li, Na; Li, Yongmei; Gao, Qinqin; Li, Dawei; Tang, Jiaqi; Sun, Miao; Zhang, Pengjie; Liu, Bailin; Mao, Caiping; Xu, Zhice

    2015-01-01

    Caffeine modifies vascular/cardiac contractility. Embryonic exposure to caffeine altered cardiac functions in offspring. This study determined chronic influence of prenatal caffeine on vessel functions in offspring. Pregnant Sprague-Dawley rats (5-month-old) were exposed to high dose of caffeine, their offspring (5-month-old) were tested for vascular functions in mesenteric arteries (MA) and ion channel activities in smooth muscle cells. Prenatal exposure to caffeine increased pressor responses and vasoconstrictions to phenylephrine, accompanied by enhanced membrane depolarization. Large conductance Ca2+-activated K+ (BKCa) channels in buffering phenylephrine-induced vasoconstrictions was decreased, whole cell BKCa currents and spontaneous transient outward currents (STOCs) were decreased. Single channel recordings revealed reduced voltage/Ca2+ sensitivity of BKCa channels. BKCa α-subunit expression was unchanged, BKCa β1-subunit and sensitivity of BKCa to tamoxifen were reduced in the caffeine offspring as altered biophysical properties of BKCa in the MA. Simultaneous [Ca2+]i fluorescence and vasoconstriction testing showed reduced Ca2+, leading to diminished BKCa activation via ryanodine receptor Ca2+ release channels (RyRs), causing enhanced vascular tone. Reduced RyR1 was greater than that of RyR3. The results suggest that the altered STOCs activity in the caffeine offspring could attribute to down-regulation of RyRs-BKCa, providing new information for further understanding increased risks of hypertension in developmental origins. PMID:26277840

  17. Developmental exposures to waterborne abused drugs alter physiological function and larval locomotion in early life stages of medaka fish.

    PubMed

    Liao, Pei-Han; Hwang, Chiu-Chu; Chen, Te-Hao; Chen, Pei-Jen

    2015-08-01

    Environmental pollution by neuroactive pharmaceuticals from wastewater discharge is a major threat to aquatic ecosystems. However, the ecotoxicologic effect of waterborne abused drugs remains unclear. Embryos of medaka fish (Oryzias latipes) were exposed to aqueous solutions of 2 hallucinogenic drugs, ketamine (KET) and methamphetamine (MET) (0.004-40μM) to assess developmental toxicity, oxidative stress and behavioral alteration in early life stages. The environmentally relevant concentration (0.004μM) of both KET and MET significantly delayed blood circulation and hatching time in embryos and altered larval swimming behavior (e.g., maximum velocity and relative turn angle). KET and MET induced similar oxidative stress responses in embryos, which were unrecoverable in hatchlings in drug-free solutions. Early life exposure to the 2 drugs conferred distinct patterns in larval locomotion: KET induced hyperactivity and a less tortuous swimming path, but MET-treated larvae showed hypoactivity and a clockwise swimming direction at high doses. The alteration in locomotor responses were generally similar in mammals and zebrafish. We report sensitive biomarkers (e.g., heartbeat, hatching and swimming behavior) by developmental stage of medaka that reflect environmentally relevant exposures of abused drugs. They could be useful for ecological risk assessment of waterborne neuroactive drugs. The toxicity results implicate a potential ecotoxicological impact of controlled or abused drugs on fish development and populations in aquatic environments.

  18. Alteration of the kidney membrane proteome of Mizuhopecten yessoensis induced by low-level methyl parathion exposure.

    PubMed

    Huang, Xiang; Huang, He-Qing

    2012-06-15

    Methyl parathion (MP) is a widely used organophosphorus pesticide that causes severe health and environmental effects. We investigated the alteration of the proteomic profile in the membrane enriched fraction of the kidneys of the scallop Mizuhopecten yessoensis exposed to low-level MP. Gas chromatography analysis showed that MP residues were significantly accumulated in the kidneys and the digestive glands of the scallops. According to two-dimensional electrophoresis, 17 proteins were differentially modulated under MP exposure. The mRNA expressions of 12 differential proteins were analyzed using quantitative PCR, and 10 showed consistent alteration of mRNA level with that of protein expression level. Altered expressions of two proteins (mitochondrial processing peptidase and α-tubulin) were also examined using Western blotting, showing that the mitochondrial processing peptidase was down-regulated but α-tubulin remained unchanged in response to MP exposure. Subcellular locations of all the identified proteins that were predicted using bioinformatics tools indicate that few of them are permanently located in the membrane. The differentially expressed proteins are involved in several critical biological processes, and their relevance to human health has been illuminated. These data taken together have provided some novel insights into the chronic toxicity mechanism of MP and have suggested mitochondrial processing peptidase as a potential biomarker for human health and environmental monitoring.

  19. Grapevine Plasticity in Response to an Altered Microclimate: Sauvignon Blanc Modulates Specific Metabolites in Response to Increased Berry Exposure1

    PubMed Central

    du Plessis, Kari; Jacobson, Dan A.

    2016-01-01

    In this study, the metabolic and physiological impacts of an altered microclimate on quality-associated primary and secondary metabolites in grape (Vitis vinifera) ‘Sauvignon Blanc’ berries was determined in a high-altitude vineyard. The leaf and lateral shoot removal in the bunch zones altered the microclimate by increasing the exposure of the berries. The physical parameters (berry diameter and weight), primary metabolites (sugars and organic acids), as well as bunch temperature and leaf water potential were predominantly not affected by the treatment. The increased exposure led to higher levels of specific carotenoids and volatile terpenoids in the exposed berries, with earlier berry stages reacting distinctly from the later developmental stages. Plastic/nonplastic metabolite responses could be further classified to identify metabolites that were developmentally controlled and/or responded to the treatment in a predictable fashion (assessed over two consecutive vintages). The study demonstrates that grapevine berries exhibit a degree of plasticity within their secondary metabolites and respond physiologically to the increased exposure by increasing metabolites with potential antioxidant activity. Taken together, the data provide evidence that the underlying physiological responses relate to the maintenance of stress pathways by modulating antioxidant molecules in the berries. PMID:26628747

  20. Sleep Alterations Following Exposure to Stress Predict Fear-Associated Memory Impairments in a Rodent Model of PTSD

    PubMed Central

    Vanderheyden, William M.; George, Sophie A.; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R.

    2015-01-01

    Sleep abnormalities such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of post-traumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating these sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stress exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops in rats. SPS resulted in acutely increased REM sleep, transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. We also report reductions in theta (4–10 Hz) and sigma (10–15 Hz) band power during transition to REM sleep which also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  1. Developmental exposure to bisphenol A alters the differentiation and functional response of the adult rat uterus to estrogen treatment.

    PubMed

    Vigezzi, Lucía; Bosquiazzo, Verónica L; Kass, Laura; Ramos, Jorge G; Muñoz-de-Toro, Mónica; Luque, Enrique H

    2015-04-01

    We assessed the long-term effect of perinatal exposure to bisphenol A (BPA) on the rat uterus and the uterine response to estrogen (E2) replacement therapy. BPA (0.5 or 50μg/kg/day) was administered in the drinking water from gestational day 9 until weaning. We studied the uterus of female offspring on postnatal day (PND) 90 and 360, and the uterine E2 response on PND460 (PND460-E2). On PND90, BPA-exposed rats showed altered glandular proliferation and α-actin expression. On PND360, BPA exposure increased the incidence of abnormalities in the luminal and glandular epithelium. On PND460-E2, the multiplicity of glands with squamous metaplasia increased in BPA50 while the incidence of glands with daughter glands increased in BPA0.5. The expression of steroid receptors, p63 and IGF-I was modified in BPA-exposed rats on PND460-E2. The long-lasting effects of perinatal exposure to BPA included induction of abnormalities in uterine tissue and altered response to E2 replacement therapy.

  2. Auditory Brainstem Response Altered in Humans With Noise Exposure Despite Normal Outer Hair Cell Function

    PubMed Central

    Bramhall, Naomi F.; Konrad-Martin, Dawn; McMillan, Garnett P.; Griest, Susan E.

    2017-01-01

    Objectives Recent animal studies demonstrated that cochlear synaptopathy, a partial loss of inner hair cell-auditory nerve fiber synapses, can occur in response to noise exposure without any permanent auditory threshold shift. In animal models, this synaptopathy is associated with a reduction in the amplitude of wave I of the auditory brainstem response (ABR). The goal of this study was to determine whether higher lifetime noise exposure histories in young people with clinically normal pure-tone thresholds are associated with lower ABR wave I amplitudes. Design Twenty-nine young military Veterans and 35 non Veterans (19 to 35 years of age) with normal pure-tone thresholds were assigned to 1 of 4 groups based on their self-reported lifetime noise exposure history and Veteran status. Suprathreshold ABR measurements in response to alternating polarity tone bursts were obtained at 1, 3, 4, and 6 kHz with gold foil tiptrode electrodes placed in the ear canal. Wave I amplitude was calculated from the difference in voltage at the positive peak and the voltage at the following negative trough. Distortion product otoacoustic emission input/output functions were collected in each participant at the same four frequencies to assess outer hair cell function. Results After controlling for individual differences in sex and distortion product otoacoustic emission amplitude, the groups containing participants with higher reported histories of noise exposure had smaller ABR wave I amplitudes at suprathreshold levels across all four frequencies compared with the groups with less history of noise exposure. Conclusions Suprathreshold ABR wave I amplitudes were reduced in Veterans reporting high levels of military noise exposure and in non Veterans reporting any history of firearm use as compared with Veterans and non Veterans with lower levels of reported noise exposure history. The reduction in ABR wave I amplitude in the groups with higher levels of noise exposure cannot be accounted

  3. Exposure to extremely low frequency electromagnetic fields alters the calcium dynamics of cultured entorhinal cortex neurons.

    PubMed

    Luo, Fen-Lan; Yang, Nian; He, Chao; Li, Hong-Li; Li, Chao; Chen, Fang; Xiong, Jia-Xiang; Hu, Zhi-An; Zhang, Jun

    2014-11-01

    Previous studies have revealed that extremely low frequency electromagnetic field (ELF-EMF) exposure affects neuronal dendritic spine density and NMDAR and AMPAR subunit expressions in the entorhinal cortex (EC). Although calcium signaling has a critical role in control of EC neuronal functions, however, it is still unclear whether the ELF-EMF exposure affects the EC neuronal calcium homeostasis. In the present study, using whole-cell recording and calcium imaging, we record the whole-cell inward currents that contain the voltage-gated calcium currents and show that ELF-EMF (50Hz, 1mT or 3mT, lasting 24h) exposure does not influence these currents. Next, we specifically isolate the high-voltage activated (HVA) and low-voltage activated (LVA) calcium channels-induced currents. Similarly, the activation and inactivation characteristics of these membrane calcium channels are also not influenced by ELF-EMF. Importantly, ELF-EMF exposure reduces the maximum amplitude of the high-K(+)-evoked calcium elevation in EC neurons, which is abolished by thapsigargin, a Ca(2+) ATPase inhibitor, to empty the intracellular calcium stores of EC neurons. Together, these findings indicate that ELF-EMF exposure specifically influences the intracellular calcium dynamics of cultural EC neurons via a calcium channel-independent mechanism.

  4. Developmental timing of sodium perchlorate exposure alters angiogenesis, thyroid follicle proliferation and sexual maturation in stickleback

    PubMed Central

    Furin, Christoff G.; von Hippel, Frank A.; Postlethwait, John H.; Buck, C. Loren; Cresko, William A.; O’Hara, Todd M.

    2015-01-01

    Perchlorate, a common aquatic contaminant, is well known to disrupt homeostasis of the hypothalamus-pituitary-thyroid axis. This study utilizes the threespine stickleback (Gasterosteus aculeatus) fish to determine if perchlorate exposure during certain windows of development has morphological effects on thyroid and gonads. Fish were moved from untreated water to perchlorate-contaminated water (30 and 100 mg/L) starting at 0, 3, 7, 14, 21, 42, 154 and 305 days post fertilization until approximately one year old. A reciprocal treatment (fish in contaminated water switched to untreated water) was conducted on the same schedule. Perchlorate exposure increased angiogenesis and follicle proliferation in thyroid tissue, delayed gonadal maturity, and skewed sex ratios towards males; effects depended on concentration and timing of exposure. This study demonstrates that perchlorate exposure beginning during the first 42 days of development has profound effects on stickleback reproductive and thyroid tissues, and by implication can impact population dynamics. Long-term exposure studies that assess contaminant effects at various stages of development provide novel information to characterize risk to aquatic organisms, to facilitate management of resources, and to determine sensitive developmental windows for further study of underlying mechanisms. PMID:25865142

  5. Alteration in Pimephales promelas mucus production after exposure to nanosilver or silver nitrate.

    PubMed

    Hawkins, Adam D; Thornton, Cammi; Steevens, Jeffery A; Willett, Kristine L

    2014-12-01

    The fish gill's ability to produce mucus effectively is a critical part of the stress response and protection against xenobiotic toxicity. Adult fathead minnows were exposed to silver nitrate (0.82 µg/L or 13.2 µg/L), polyvinylpyrrolidone-coated silver nanoparticles (11.1 µg/L or 208 µg/L), and citrate-coated silver nanoparticles (10.1 µg/L or 175 µg/L) for 96 h. Mucus concentrations based on glucose as a surrogate were determined at 0 h, 1 h, 2 h, 3 h, 4 h and 24 h after re-dosing each day. Higher mucus production rates following silver treatment were observed at the beginning as compared to controls and compared to after 3 d of exposure. Control fish produced consistent mucus concentrations throughout the exposure (0.62 mg/L and 0.40 mg/L at 24 h and 96 h, respectively). Following 24 h of exposure, all silver treatment groups produced significantly more mucus than controls. Following 96 h of exposure, mucus concentrations in treatment groups were significantly reduced compared with each respective treatment at 24 h. Reduced mucus production following long-term silver exposure could prevent the gills from removing silver, and thus increase toxicity.

  6. Enhancement of Anti-Inflammatory Activity of Curcumin Using Phosphatidylserine-Containing Nanoparticles in Cultured Macrophages.

    PubMed

    Wang, Ji; Kang, Yu-Xia; Pan, Wen; Lei, Wan; Feng, Bin; Wang, Xiao-Juan

    2016-06-20

    Macrophages are one kind of innate immune cells, and produce a variety of inflammatory cytokines in response to various stimuli, such as oxidized low density lipoprotein found in the pathogenesis of atherosclerosis. In this study, the effect of phosphatidylserine on anti-inflammatory activity of curcumin-loaded nanostructured lipid carriers was investigated using macrophage cultures. Different amounts of phosphatidylserine were used in the preparation of curcumin nanoparticles, their physicochemical properties and biocompatibilities were then compared. Cellular uptake of the nanoparticles was investigated using a confocal laser scanning microscope and flow cytometry analysis in order to determine the optimal phosphatidylserine concentration. In vitro anti-inflammatory activities were evaluated in macrophages to test whether curcumin and phosphatidylserine have interactive effects on macrophage lipid uptake behavior and anti-inflammatory responses. Here, we showed that macrophage uptake of phosphatidylserine-containing nanostructured lipid carriers increased with increasing amount of phosphatidylserine in the range of 0%-8%, and decreased when the phosphatidylserine molar ratio reached over 12%. curcumin-loaded nanostructured lipid carriers significantly inhibited lipid accumulation and pro-inflammatory factor production in cultured macrophages, and evidently promoted release of anti-inflammatory cytokines, when compared with curcumin or phosphatidylserine alone. These results suggest that the delivery system using PS-based nanoparticles has great potential for efficient delivery of drugs such as curcumin, specifically targeting macrophages and modulation of their anti-inflammatory functions.

  7. Phosphatidylserine recognition and induction of apoptotic cell clearance by Drosophila engulfment receptor Draper.

    PubMed

    Tung, Tran Thanh; Nagaosa, Kaz; Fujita, Yu; Kita, Asana; Mori, Hiroki; Okada, Ryo; Nonaka, Saori; Nakanishi, Yoshinobu

    2013-05-01

    The membrane phospholipid phosphatidylserine is exposed on the cell surface during apoptosis and acts as an eat-me signal in the phagocytosis of apoptotic cells in mammals and nematodes. However, whether this is also true in insects was unclear. When milk fat globule-epidermal growth factor 8, a phosphatidylserine-binding protein of mammals, was ectopically expressed in Drosophila, the level of phagocytosis was reduced, whereas this was not the case for the same protein lacking a domain responsible for the binding to phosphatidylserine. We found that the extracellular region of Draper, an engulfment receptor of Drosophila, binds to phosphatidylserine in an enzyme-linked immunosorbent assay-like solid-phase assay and in an assay for surface plasmon resonance. A portion of Draper containing domains EMI and NIM located close to the N-terminus was required for binding to phosphatidylserine, and a Draper protein lacking this region was not active in Drosophila. Finally, the level of tyrosine-phosphorylated Draper, indicative of the activation of Draper, in a hemocyte-derived cell line was increased after treatment with phosphatidylserine-containing liposome. These results indicated that phosphatidylserine serves as an eat-me signal in the phagocytic removal of apoptotic cells in Drosophila and that Draper is a phosphatidylserine-binding receptor for phagocytosis.

  8. Exposure to Radiofrequency Radiation Emitted from Common Mobile Phone Jammers Alters the Pattern of Muscle Contractions: an Animal Model Study

    PubMed Central

    Rafati, A.; Rahimi, S.; Talebi, A.; Soleimani, A.; Haghani, M.; Mortazavi, S. M. J.

    2015-01-01

    Introduction The rapid growth of wireless communication technologies has caused public concerns regarding the biological effects of electromagnetic radiations on human health. Some early reports indicated a wide variety of non-thermal effects of electromagnetic radiation on amphibians such as the alterations of the pattern of muscle extractions. This study is aimed at investigating the effects of exposure to radiofrequency (RF) radiation emitted from mobile phone jammers on the pulse height of contractions, the time interval between two subsequent contractions and the latency period of frog’s isolated gastrocnemius muscle after stimulation with single square pulses of 1V (1 Hz). Materials and Methods Frogs were kept in plastic containers in a room. Animals in the jammer group were exposed to radiofrequency (RF) radiation emitted from a common Jammer at a distance of 1m from the jammer’s antenna for 2 hours while the control frogs were only sham exposed. Then animals were sacrificed and isolated gastrocnemius muscles were exposed to on/off jammer radiation for 3 subsequent 10 minute intervals. Isolated gastrocnemius muscles were attached to the force transducer with a string. Using a PowerLab device (26-T), the pattern of muscular contractions was monitored after applying single square pulses of 1V (1 Hz) as stimuli. Results The findings of this study showed that the pulse height of muscle contractions could not be affected by the exposure to electromagnetic fields. However, the latency period was effectively altered in RF-exposed samples. However, none of the experiments could show an alteration in the time interval between two subsequent contractions after exposure to electromagnetic fields. Conclusion These findings support early reports which indicated a wide variety of non-thermal effects of electromagnetic radiation on amphibians including the effects on the pattern of muscle extractions. PMID:26396969

  9. Exposure to an urban environment alters the local bias of a remote culture.

    PubMed

    Caparos, Serge; Ahmed, Lubna; Bremner, Andrew J; de Fockert, Jan W; Linnell, Karina J; Davidoff, Jules

    2012-01-01

    There is substantial evidence that populations in the Western world exhibit a local bias compared to East Asian populations that is widely ascribed to a difference between individualistic and collectivist societies. However, we report that traditional Himba - a remote interdependent society - exhibit a strong local bias compared to both Japanese and British participants in the Ebbinghaus illusion and in a similarity-matching task with hierarchical figures. Critically, we measured the effect of exposure to an urban environment on local bias in the Himba. Even a brief exposure to an urban environment caused a shift in processing style: the local bias was reduced in traditional Himba who had visited a local town and even more reduced in urbanised Himba who had moved to that town on a permanent basis. We therefore propose that exposure to an urban environment contributes to the global bias found in Western and Japanese populations.

  10. [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT].

    PubMed

    Iaglova, N V; Iaglov, V V

    2014-01-01

    Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89±0.86 мg/kg/day and 7.77±0.17 мg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins.

  11. Prenatal Alcohol Exposure and Chronic Mild Stress Differentially Alter Depressive- and Anxiety-Like Behaviors in Male and Female Offspring

    PubMed Central

    Hellemans, Kim G. C.; Verma, Pamela; Yoon, Esther; Yu, Wayne K.; Young, Allan H.; Weinberg, Joanne

    2016-01-01

    Background Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neuro behavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamic-pituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals. Methods Male and female offspring from prenatal alcohol (PAE), pair-fed (PF), and ad libitumfed control (C) treatment groups were tested in adulthood. Animals were exposed to 10 consecutive days of chronic mild stress (CMS), and assessed in a battery of well-validated tasks sensitive to differences in depressive- and / or anxiety-like behaviors. Results We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of “behavioral despair” in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females. Conclusions These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations. PMID:20102562

  12. Effect of membrane-associated f1 bacteriophage coat protein upon the activity of Escherichia coli phosphatidylserine synthetase.

    PubMed Central

    Chamberlain, B K; Webster, R E

    1978-01-01

    The effects of insertion of the major coat protein of f1 bacteriophage into Escherichia coli membranes were investigated under conditions allowing in vivo analysis of phosphatidylserine synthesis. An E. coli strain possessing a temperature-sensitive phosphatidylserine decarboxylase was utilized under conditions in which the decarboxylase activity was reduced but nonlethal. The presence of the coat protein in the host membranes inhibits the activity of the phosphatidylserine synthetase and perhaps affects the activity of the phosphatidylserine decarboxylase. PMID:211116

  13. Ethanol increases affinity of protein kinase C for phosphatidylserine

    SciTech Connect

    Chin, J.H.

    1986-03-01

    Protein kinase C is a calcium-dependent enzyme that requires phospholipid for its activation. It is present in relatively high concentration in the brain and may be involved in neuronal function. The present experiments test whether the membrane disorder induced by ethanol affects the activity of kinase C by changing its interaction with membrane lipid. Fractions rich in kinase C were purified from rat brain cytosol by DEAE-cellulose chromatography and Sephadex G-200 gel filtration. Enzyme activity was assayed by measuring the phosphorylation of histone H1. As expected, phosphatidylserine activated the enzyme, and the stimulation was further increased by the addition of calcium and/or diacylglycerol. At low concentration of free calcium (0.5-1..mu..M), ethanol (800 mM0 enhanced kinase C activity if the presence of phospholipid. similar results were observed in the absence of calcium. Double reciprocal plots of the data showed that ethanol increased the affinity of the enzyme for phosphatidylserine without affecting the V/sub max. The stimulation of kinase C activity by ethanol was not observed at high calcium concentrations. These experiments suggest that ethanol may activated protein kinase C at physiological levels of calcium by facilitating its transfer into the hydrophobic membrane environment.

  14. Acute Chlorine Gas Exposure Produces Transient Inflammation and a Progressive Alteration in Surfactant Composition with Accompanying Mechanical Dysfunction

    PubMed Central

    Massa, Christopher B; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L; Gow, Andrew J

    2014-01-01

    Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl2 dose, and were sacrificed 3, 24 and 48 hours later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 hours, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 hours. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3− or NO2−. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 hours, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation. PMID:24582687

  15. Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development

    SciTech Connect

    Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana; Tou, Janet C.; Barnett, John B.

    2010-01-15

    Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/beta-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/beta-catenin pathways. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4{sup +} cells and a subpopulation of double-negative cells (DN; CD4{sup -}CD8{sup -}), DN4 (CD44{sup -}CD25{sup -}). Shh and Wnt/beta-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/beta-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.

  16. POTENTIAL ALTERATIONS IN GENE EXPRESSION ASSOCIATED WITH CARCINOGEN EXPOSURE IN MYA ARENARIA

    EPA Science Inventory

    Gonadal cancers in soft-shell clams (Mya arenaria) have been found at high prevalences (20-40%) in populations in eastern Maine. The aetiology of these tumours is unknown. We hypothesized that gene expression would be altered in gonadal tumours and that examination of gene expres...

  17. EXPOSURE TO CONCENTRATED AMBIENT PARTICLES IN DETROIT ALTERS HEART RATE VARIABILITY IN SPONTANEOUSLY HYPERTENSIVE RATS

    EPA Science Inventory

    Elevations in airborne particulate matter (PM) are linked to increased mortality and morbidity in humans with cardiopulmonary disease. Clinical studies show that PM is associated with altered heart rate variability (HRV) and suggests that loss of autonomic control may underlie ca...

  18. Chronic alcohol exposure alters transcription broadly in a key integrative brain nucleus for homeostasis: the nucleus tractus solitarius.

    PubMed

    Covarrubias, Maria Yolanda; Khan, Rishi L; Vadigepalli, Rajanikanth; Hoek, Jan B; Schwaber, James S

    2005-12-14

    Chronic exposure to alcohol modifies physiological processes in the brain, and the severe symptoms resulting from sudden removal of alcohol from the diet indicate that these modifications are functionally important. We investigated the gene expression patterns in response to chronic alcohol exposure (21-28 wk) in the rat nucleus tractus solitarius (NTS), a brain nucleus with a key integrative role in homeostasis and cardiorespiratory function. Using methods and an experimental design optimized for detecting transcriptional changes less than twofold, we found 575 differentially expressed genes. We tested these genes for significant associations with physiological functions and signaling pathways using Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, respectively. Chronic alcohol exposure resulted in significant NTS gene regulation related to the general processes of synaptic transmission, intracellular signaling, and cation transport as well as specific neuronal functions including plasticity and seizure behavior that could be related to alcohol withdrawal symptoms. The differentially expressed genes were also significantly enriched for enzymes of lipid metabolism, glucose metabolism, oxidative phosphorylation, MAP kinase signaling, and calcium signaling pathways from KEGG. Intriguingly, many of the genes we found to be differentially expressed in the NTS are known to be involved in alcohol-induced oxidative stress and/or cell death. The study provides evidence of very extensive alterations of physiological gene expression in the NTS in the adapted state to chronic alcohol exposure.

  19. Neuroprotective Effect of Ginseng against Alteration of Calcium Binding Proteins Immunoreactivity in the Mice Hippocampus after Radiofrequency Exposure

    PubMed Central

    Maskey, Dhiraj

    2013-01-01

    Calcium binding proteins (CaBPs) such as calbindin D28-k, parvalbumin, and calretinin are able to bind Ca2+ with high affinity. Changes in Ca2+ concentrations via CaBPs can disturb Ca2+ homeostasis. Brain damage can be induced by the prolonged electromagnetic field (EMF) exposure with loss of interacellular Ca2+ balance. The present study investigated the radioprotective effect of ginseng in regard to CaBPs immunoreactivity (IR) in the hippocampus through immunohistochemistry after one-month exposure at 1.6 SAR value by comparing sham control with exposed and ginseng-treated exposed groups separately. Loss of dendritic arborization was noted with the CaBPs in the Cornu Ammonis areas as well as a decrease of staining intensity of the granule cells in the dentate gyrus after exposure while no loss was observed in the ginseng-treated group. A significant difference in the relative mean density was noted between control and exposed groups but was nonsignificant in the ginseng-treated group. Decrease in CaBP IR with changes in the neuronal staining as observed in the exposed group would affect the hippocampal trisynaptic circuit by alteration of the Ca2+ concentration which could be prevented by ginseng. Hence, ginseng could contribute as a radioprotective agent against EMF exposure, contributing to the maintenance of Ca2+ homeostasis by preventing impairment of intracellular Ca2+ levels in the hippocampus. PMID:24069603

  20. Estrogenic Exposure Alters the Spermatogonial Stem Cells in the Developing Testis, Permanently Reducing Crossover Levels in the Adult

    PubMed Central

    Vrooman, Lisa A.; Oatley, Jon M.; Griswold, Jodi E.; Hassold, Terry J.; Hunt, Patricia A.

    2015-01-01

    Bisphenol A (BPA) and other endocrine disrupting chemicals have been reported to induce negative effects on a wide range of physiological processes, including reproduction. In the female, BPA exposure increases meiotic errors, resulting in the production of chromosomally abnormal eggs. Although numerous studies have reported that estrogenic exposures negatively impact spermatogenesis, a direct link between exposures and meiotic errors in males has not been evaluated. To test the effect of estrogenic chemicals on meiotic chromosome dynamics, we exposed male mice to either BPA or to the strong synthetic estrogen, ethinyl estradiol during neonatal development when the first cells initiate meiosis. Although chromosome pairing and synapsis were unperturbed, exposed outbred CD-1 and inbred C3H/HeJ males had significantly reduced levels of crossovers, or meiotic recombination (as defined by the number of MLH1 foci in pachytene cells) by comparison with placebo. Unexpectedly, the effect was not limited to cells exposed at the time of meiotic entry but was evident in all subsequent waves of meiosis. To determine if the meiotic effects induced by estrogen result from changes to the soma or germline of the testis, we transplanted spermatogonial stem cells from exposed males into the testes of unexposed males. Reduced recombination was evident in meiocytes derived from colonies of transplanted cells. Taken together, our results suggest that brief exogenous estrogenic exposure causes subtle changes to the stem cell pool that result in permanent alterations in spermatogenesis (i.e., reduced recombination in descendent meiocytes) in the adult male. PMID:25615633

  1. Altered spatial learning and delay discounting in a rat model of human third trimester binge ethanol exposure

    PubMed Central

    Bañuelos, Cristina; Gilbert, Ryan J.; Montgomery, Karienn S.; Fincher, Annette S.; Wang, Haiying; Frye, Gerald D.; Setlow, Barry; Bizon, Jennifer L.

    2012-01-01

    Ethanol exposure during perinatal development can cause cognitive abnormalities including difficulties in learning, attention, and memory, as well as heightened impulsivity. The purpose of this study was to assess performance in spatial learning and impulsive choice tasks in rats subjected to an intragastric intubation model of binge ethanol exposure during human third trimester-equivalent brain development. Male and female Sprague–Dawley rat pups were intubated with ethanol (5.25 g/kg/day) on postnatal days 4–9. At adolescence (between postnatal days 35–38), these rats and sham intubated within-litter controls were trained in both spatial and cued versions of the Morris water maze. A subset of the male rats was subsequently tested on a delay-discounting task to assess impulsive choice. Ethanol-exposed rats were spatially impaired relative to controls, but performed comparably to controls on the cued version of the water maze. Ethanol-exposed rats also showed greater preference for large delayed rewards on the delay discounting task, but no evidence for altered reward sensitivity or perseverative behavior. These data demonstrate that early postnatal intermittent binge-like ethanol exposure has prolonged, detrimental, but selective effects on cognition, suggesting that even relatively brief ethanol exposure late in human pregnancy can be deleterious for cognitive function. PMID:22129556

  2. The characteristics of coarse particulate matter air pollution associated with alterations in blood pressure and heart rate during controlled exposures

    PubMed Central

    Morishita, Masako; Bard, Robert L.; Wang, Lu; Das, Ritabrata; Dvonch, J. Timothy; Spino, Catherine; Mukherjee, Bhramar; Sun, Qinghua; Harkema, Jack R.; Rajagopalan, Sanjay; Brook, Robert D.

    2015-01-01

    Although fine particulate matter (PM) air pollution <2.5 μm in aerodynamic diameter (PM2.5) is a leading cause of global morbidity and mortality, the potential health effects of coarse PM (2.5–10 μm in aerodynamic diameter; PM10–2.5) remain less clearly understood. We aimed to elucidate the components within coarse PM most likely responsible for mediating these hemodynamic alterations. Thirty-two healthy adults (25.9 ± 6.6 years) were exposed to concentrated ambient coarse PM (CAP) (76.2 ± 51.5 μg/m3) and filtered air (FA) for 2 h in a rural location in a randomized double-blind crossover study. The particle constituents (24 individual elements, organic and elemental carbon) were analyzed from filter samples and associated with the blood pressure (BP) and heart rate (HR) changes occurring throughout CAP and FA exposures in mixed model analyses. Total coarse PM mass along with most of the measured elements were positively associated with similar degrees of elevations in both systolic BP and HR. Conversely, total PM mass was unrelated, whereas only two elements (Cu and Mo) were positively associated with and Zn was inversely related to diastolic BP changes during exposures. Inhalation of coarse PM from a rural location rapidly elevates systolic BP and HR in a concentration-responsive manner, whereas the particulate composition does not appear to be an important determinant of these responses. Conversely, exposure to certain PM elements may be necessary to trigger a concomitant increase in diastolic BP. These findings suggest that particulate mass may be an adequate metric of exposure to predict some, but not all, hemodynamic alterations induced by coarse PM mass. PMID:25227729

  3. Trichloroethylene alters central and peripheral immune function in autoimmune-prone MRL(+/+) mice following continuous developmental and early life exposure.

    PubMed

    Blossom, Sarah J; Doss, Jason C

    2007-04-01

    Trichloroethylene (TCE) is a widespread environmental toxicant known to promote CD4(+) T-lymphocyte activation, IFNgamma production, and autoimmunity in adult MRL(+/+) mice. Because developing tissues may be more sensitive to toxicant exposure, it was hypothesized that continuous TCE exposure beginning at conception might induce even more pronounced CD4(+) T-lymphocyte effects and exacerbate the development of autoimmunity in MRL(+/+) mice. In the current study, MRL(+/+) mice were exposed to occupationally-relevant doses of TCE from conception until adulthood (i.e., 7-8 wk-of-age). The CD4(+) T-lymphocyte effects in the thymus and periphery were evaluated, as well as serum antibody levels. TCE exposure altered the number of thymocyte subsets, and reduced the capacity of the most immature CD4-/CD8- thymocytes to undergo apoptosis in vitro. In the periphery, T-lymphocyte IFN(gamma) production was monitored in the blood prior to sacrifice by intracellular cytokine staining and flow cytometry. TCE induced a dose-dependent increase in T-lymphocyte IFN(gamma) as early as 4-5-week-of-age. However, these effects were transient, and not observed in splenic T-lymphocytes in 7-8-week-old mice. In contrast, the serum levels of anti-histone autoantibodies and total IgG(2a) were significantly elevated in the TCE-exposed offspring. The data illustrated that occupationally-relevant doses of TCE administered throughout development until adulthood affected central and peripheral immune function in association with early signs of autoimmunity. Future studies will address the possibility that early-life exposure to TCE may alter some aspect of self tolerance in the thymus, leading to autoimmune disease later in life.

  4. Exposure to a low dose of bisphenol A during fetal life or in adulthood alters maternal behavior in mice.

    PubMed Central

    Palanza, Paola L; Howdeshell, Kembra L; Parmigiani, Stefano; vom Saal, Frederick S

    2002-01-01

    Maternal behavior in mammals is the result of a complex interaction between the lactating dam and her developing offspring. Slight perturbations of any of the components of the mother-infant interaction may result in alterations of the behavior of the mother and/or of the offspring. We studied the effects of exposure of female CD-1 mice to the estrogenic chemical bisphenol A (BPA) during fetal life and/or in adulthood during the last part of pregnancy on subsequent maternal behavior. Pregnant females were fed daily doses of corn oil (controls) or 10 microg/kg body weight BPA during gestation days 14-18. As adults, the prenatally treated female offspring were time-mated and again fed either corn oil (controls) or the same doses of BPA on gestation days 14-18, resulting in four treatment groups: controls, prenatal BPA exposure, adult BPA exposure, and both prenatal and adult BPA exposure. Maternal behavior was then observed on postnatal days 2-15 and reflex responses were examined in the offspring. Dams exposed to BPA either as fetuses or in adulthood spent less time nursing their pups and more time out of the nest compared with the control group. Females exposed to BPA both as fetuses and in adulthood did not significantly differ from controls. No alterations in postnatal reflex development were observed in the offspring of the females exposed to BPA. The changes seen in maternal behavior may be the result of a direct effect of BPA on the neuroendocrine substrates underlying the initiation of maternal behavior. PMID:12060838

  5. Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal axis-associated proteins

    PubMed Central

    Zuloaga, Damian G.; Siegel, Jessica A.; Acevedo, Summer F.; Agam, Maayan; Raber, Jacob

    2013-01-01

    Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or Saline from postnatal day (P) 11–20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR-immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and area occupied by vasopressin-immunoreactiviy in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin-immunoreactivity in the PVN, or GR-immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, area occupied by GR-immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin-immunoreactivity no longer differed from Saline controls. No effects of MA were found on oxytocin or GR-immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin-immunoreactivity and short-term effects on GR-immunoreactivity. PMID:23860125

  6. Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal-axis-associated proteins.

    PubMed

    Zuloaga, Damian G; Siegel, Jessica A; Acevedo, Summer F; Agam, Maayan; Raber, Jacob

    2013-01-01

    Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or saline from postnatal day (P) 11 to P20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and the area occupied by vasopressin immunoreactivity in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin immunoreactivity in the PVN, or GR immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, the area occupied by GR immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin immunoreactivity no longer differed from saline controls. No effects of MA were found on oxytocin or GR immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin immunoreactivity and short-term effects on GR immunoreactivity.

  7. Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

    PubMed Central

    Capilla-Gonzalez, Vivian; Gil-Perotin, Sara; Ferragud, Antonio; Bonet-Ponce, Luis; Canales, Juan Jose; Garcia-Verdugo, Jose Manuel

    2012-01-01

    Background Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. Methodology/Principal Findings 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. Conclusions/Significance The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits. PMID:22238669

  8. Staurosporines decrease ORMDL proteins and enhance sphingomyelin synthesis resulting in depletion of plasmalemmal phosphatidylserine

    PubMed Central

    Maekawa, Masashi; Lee, Minhyoung; Wei, Kuiru; Ridgway, Neale D.; Fairn, Gregory D.

    2016-01-01

    Accumulation of phosphatidylserine in the inner leaflet of the plasma membrane is a hallmark of eukaryotes. Sublethal levels of staurosporine and related compounds deplete phosphatidylserine from the plasma membrane and abrogate K-Ras signaling. Here, we report that low-dose staurosporine and related compounds increase sphingomyelin mass. Mass-spectrometry and metabolic tracer analysis revealed an increase in both the levels and rate of synthesis of sphingomyelin in response to sublethal staurosporine. Mechanistically, it was determined that the abundance of the ORMDL proteins, which negatively regulate serine-palmitoyltransferase, are decreased by low-dose staurosporine. Finally, inhibition of ceramide synthesis, and thus sphingomyelin, prevented the displacement of phosphatidylserine and cholesterol from the inner leaflet of the plasma membrane. The results establish that an optimal level of sphingomyelin is required to maintain the distribution of phosphatidylserine and cholesterol in the plasma membrane and further demonstrate a complex relationship between the trafficking of phosphatidylserine and sphingomyelin. PMID:27805006

  9. Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain.

    PubMed

    Anderson, Joel G; Fordahl, Steve C; Cooney, Paula T; Weaver, Tara L; Colyer, Christa L; Erikson, Keith M

    2008-11-01

    Unlike other essential trace elements (e.g., zinc and iron) it is the toxicity of manganese (Mn) that is more common in human populations than its deficiency. Data suggest alterations in dopamine biology may drive the effects associated with Mn neurotoxicity, though recently gamma-aminobutyric acid (GABA) has been implicated. In addition, iron deficiency (ID), a common nutritional problem, may cause disturbances in neurochemistry by facilitating accumulation of Mn in the brain. Previous data from our lab have shown decreased brain tissue levels of GABA as well as decreased (3)H-GABA uptake in synaptosomes as a result of Mn exposure and ID. These results indicate a possible increase in the concentration of extracellular GABA due to alterations in expression of GABA transport and receptor proteins. In this study weanling-male Sprague-Dawley rats were randomly placed into one of four dietary treatment groups: control (CN; 35mg Fe/kg diet), iron-deficient (ID; 6mg Fe/kg diet), CN with Mn supplementation (via the drinking water; 1g Mn/l) (CNMn), and ID with Mn supplementation (IDMn). Using in vivo microdialysis, an increase in extracellular GABA concentrations in the striatum was observed in response to Mn exposure and ID although correlational analysis reveals that extracellular GABA is related more to extracellular iron levels and not Mn. A diverse effect of Mn exposure and ID was observed in the regions examined via Western blot and RT-PCR analysis, with effects on mRNA and protein expression of GAT-1, GABA(A), and GABA(B) differing between and within the regions examined. For example, Mn exposure reduced GAT-1 protein expression by approximately 50% in the substantia nigra, while increasing mRNA expression approximately four-fold, while in the caudate putamen mRNA expression was decreased with no effect on protein expression. These data suggest that Mn exposure results in an increase in extracellular GABA concentrations via altered expression of transport and

  10. Exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1.

    PubMed

    Ingram, R J; Harris, A; Ascough, S; Metan, G; Doganay, M; Ballie, L; Williamson, E D; Dyson, H; Robinson, J H; Sriskandan, S; Altmann, D M

    2013-07-01

    Anthrax is a toxin-mediated disease, the lethal effects of which are initiated by the binding of protective antigen (PA) with one of three reported cell surface toxin receptors (ANTXR). Receptor binding has been shown to influence host susceptibility to the toxins. Despite this crucial role for ANTXR in the outcome of disease, and the reported immunomodulatory consequence of the anthrax toxins during infection, little is known about ANTXR expression on human leucocytes. We characterized the expression levels of ANTXR1 (TEM8) on human leucocytes using flow cytometry. In order to assess the effect of prior toxin exposure on ANTXR1 expression levels, leucocytes from individuals with no known exposure, those exposed to toxin through vaccination and convalescent individuals were analysed. Donors could be defined as either 'low' or 'high' expressers based on the percentage of ANTXR1-positive monocytes detected. Previous exposure to toxins appears to modulate ANTXR1 expression, exposure through active infection being associated with lower receptor expression. A significant correlation between low receptor expression and high anthrax toxin-specific interferon (IFN)-γ responses was observed in previously infected individuals. We propose that there is an attenuation of ANTXR1 expression post-infection which may be a protective mechanism that has evolved to prevent reinfection.

  11. Exposure to Lipopolysaccharide in Utero Alters the Postnatal Metabolic Response in Heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine the effect of prenatal lipopolysaccharide (LPS) exposure on the postnatal metabolic response to an LPS challenge in beef heifers. Pregnant crossbred cows (n = 50) were assigned to a prenatal immune stimulation (PIS; n = 25; administered 0.1 micrograms/kg BW LPS s...

  12. In Utero Exposure to Lipopolysaccharide Alters the Postnatal Acute Phase Response in Beef Heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine the potential effect of prenatal lipopolysaccharide (LPS) exposure on the postnatal acute phase response (APR) to an LPS challenge in heifers. Pregnant crossbred cows (n = 50) were separated into prenatal immune stimulation (PIS; n = 25; administered 0.1 microgr...

  13. GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE PERMANENTLY ALTERS REPRODUCTIVE COMPETENCE IN THE CD-1 MOUSE

    EPA Science Inventory

    While the adult mouse Leydig cell (LC) has been considered refractory to cytotoxic destruction by ethane dimethanesulfonate (EDS), the potential consequences of exposure during reproductive development in this species are unknown. Herein pregnant CD-1 mice were treated with 160 m...

  14. Developmental Exposure to a Dopaminergic Toxicant Produces Altered Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after developmental exposure to various classes of prototypic drugs that act on the central nervous system. ...

  15. Exposure to hyperoxia in the neonatal period alters bone marrow function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxygen is often life saving in preterm infants, however, excessive exposure may lead to blood vessel and tissue injury in the lung and retina. Oxygen-treated neonates often exhibit bone marrow (BM) suppression requiring blood product transfusions. However, we do not know whether oxygen is directly t...

  16. Acute exposure to 17α-ethinylestradiol alters boldness behavioral syndrome in female Siamese fighting fish.

    PubMed

    Dzieweczynski, Teresa L; Campbell, Brennah A; Marks, Jodi M; Logan, Brittney

    2014-09-01

    The role of anthropogenic sources in generating, maintaining, and influencing behavioral syndromes has recently been identified as an important area of future research. Endocrine disrupting chemicals are prevalent and persistent in aquatic ecosystems worldwide. These chemicals are known to have marked effects on the morphology and behavior of exposed individuals and, as such, may serve as a potential influence on behavioral syndromes. However, both the effects of exposure on behaviors beyond courtship and aggression and how exposure might affect behavioral variation at the individual level are understudied. To address this question, we examined boldness behavior in female Siamese fighting fish in three different assays (Novel Environment, Empty Tank, Shoaling) both before and after they were exposed to the estrogen mimic, 17α-ethinylestradiol (EE2). EE2 influences courtship, aggression, and boldness in males of this species but its effects have not been examined in females, to our knowledge. Females were tested multiple times in each assay before and after exposure so that behavioral consistency could be examined. A behavioral syndrome for boldness and activity level occurred across the three assays. The reductions in boldness and loss of the behavioral syndrome that resulted from EE2 exposure were surprising and suggest that the effects of EE2 exposure on female behavior and physiology should be examined more frequently. This study is one of the first to examine the effects of EE2 in females as well as on correlated behaviors and emphasizes the importance of examining the effects of endocrine disrupting chemicals on individual behavioral variation and consistency.

  17. Temperature, hydric environment, and prior pathogen exposure alter the experimental severity of chytridiomycosis in boreal toads

    USGS Publications Warehouse

    Murphy, Peter J.; St-Hilaire, Sophie; Corn, Paul Stephen

    2011-01-01

    Prevalence of the pathogen Batrachochytrium dendrobatidis (Bd), implicated in amphibian population declines worldwide, is associated with habitat moisture and temperature, but few studies have varied these factors and measured the response to infection in amphibian hosts. We evaluated how varying humidity, contact with water, and temperature affected the manifestation of chytridiomycosis in boreal toads Anaxyrus (Bufo) boreas boreas and how prior exposure to Bd affects the likelihood of survival after re-exposure, such as may occur seasonally in long-lived species. Humidity did not affect survival or the degree of Bd infection, but a longer time in contact with water increased the likelihood of mortality. After exposure to ~106 Bd zoospores, all toads in continuous contact with water died within 30 d. Moreover, Bd-exposed toads that were disease-free after 64 d under dry conditions, developed lethal chytridiomycosis within 70 d of transfer to wet conditions. Toads in unheated aquaria (mean = 15°C) survived less than 48 d, while those in moderately heated aquaria (mean = 18°C) survived 115 d post-exposure and exhibited behavioral fever, selecting warmer sites across a temperature gradient. We also found benefits of prior Bd infection: previously exposed toads survived 3 times longer than Bd-naïve toads after re-exposure to 106 zoospores (89 vs. 30 d), but only when dry microenvironments were available. This study illustrates how the outcome of Bd infection in boreal toads is environmentally dependent: when continuously wet, high reinfection rates may overwhelm defenses, but periodic drying, moderate warming, and previous infection may allow infected toads to extend their survival.

  18. Preclinical Evaluation of Sequential Combination of Oncolytic Adenovirus Delta-24-RGD and Phosphatidylserine-Targeting Antibody in Pancreatic Ductal Adenocarcinoma.

    PubMed

    Dai, Bingbing; Roife, David; Kang, Ya'an; Gumin, Joy; Rios Perez, Mayrim V; Li, Xinqun; Pratt, Michael; Brekken, Rolf A; Fueyo-Margareto, Juan; Lang, Frederick F; Fleming, Jason B

    2017-04-01

    Delta-24-RGD (DNX-2401) is a conditional replication-competent oncolytic virus engineered to preferentially replicate in and lyse tumor cells with abnormality of p16/RB/E2F pathway. In a phase I clinical trial, Delta-24-RGD has shown favorable safety profile and promising clinical efficacy in brain tumor, which prompted us to evaluate its anticancer activity in pancreatic ductal adenocarcinoma (PDAC), which also has high frequency of homozygous deletion and promoter methylation of CDKN2A encoding the p16 protein. Our results demonstrate that Delta-24-RGD can induce dramatic cytotoxicity in a subset of PDAC cell lines with high cyclin D1 expression. Induction of autophagy and apoptosis by Delta-24-RGD in sensitive PDAC cells was confirmed with LC3B-GFP autophagy reporter and acridine orange staining as well as Western blotting analysis of LC3B-II expression. Notably, we found that Delta-24-RGD induced phosphatidylserine exposure in infected cells independent of cells' sensitivity to Delta-24-RGD, which renders a rationale for combination of Delta-24-RGD viral therapy and phosphatidylserine targeting antibody for PDAC. In a mouse PDAC model derived from a liver metastatic pancreatic cancer cell line, Delta-24-RGD significantly inhibited tumor growth compared with control (P < 0.001), and combination of phosphatidylserine targeting antibody 1N11 further enhanced its anticancer activity (P < 0.01) possibly through inducing synergistic anticancer immune responses. Given that these 2 agents are currently in clinical evaluation, our study warrants further clinical evaluation of this novel combination strategy in pancreatic cancer therapy. Mol Cancer Ther; 16(4); 662-70. ©2016 AACR.

  19. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction

    SciTech Connect

    Massa, Christopher B.; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L.; Gow, Andrew J.

    2014-07-01

    Acute Cl{sub 2} exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl{sub 2} inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl{sub 2} dose, and were euthanized 3, 24 and 48 h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 h. Cl{sub 2} exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO{sub 3}{sup −} or NO{sub 2}{sup −}. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl{sub 2} exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl{sub 2} inhalation. - Highlights: • Effect of 60 ppm*hr Cl{sub 2} gas on lung inflammation and mechanical function examined. • Pulmonary inflammation is transient and minor.

  20. Exposure to Green Tea Extract Alters the Incidence of Specific Cyclophosphamide-Induced Malformations

    PubMed Central

    Logsdon, Amanda L.; Herring, Betty J.; Lockard, Jarrett E.; Miller, Brittany M.; Kim, Hanna; Hood, Ronald D.; Bailey, Melissa M.

    2012-01-01

    BACKGROUND Green tea extract (GTE) has been shown to have antioxidative properties due to its high content of polyphenols and catechin gallates. Previous studies indicated that catechin gallates scavenge free radicals and attenuate the effects of reactive oxidative species (ROS). Cyclophosphamide (CP) produces ROS, which can have adverse effects on development, causing limb, digit, and cranial abnormalities. The current study was performed to determine if exposure to GTE can decrease teratogenic effects induced by CP in CD-1 mice. METHODS From gestation days (GD) 6–13, mated CD-1 mice were dosed with 400 or 800 mg/kg/d GTE; 100, 200, 400, or 800 mg/kg/d GTE + CP; CP alone, or the vehicle. GTE was given by gavage. CP (20 mg/kg) was given by intraperitoneal injection on GD 10. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS The highest GTE dose did not effectively attenuate, and in some cases exacerbated the negative effect of CP. GTE alone was also associated with an increased incidence of microblepharia. Conversely, moderate GTE doses (200 &/or 400 mg/kg/d) attenuated the effect of CP on fetal weight and (GTE 200 mg/kg/d) decreased the incidences of certain defects resulting from CP exposure. CONCLUSIONS Exposure of a developing mammal to moderate doses of GTE can modulate the effects of exposure to CP during development, possibly by affecting biotransformation, while a higher GTE dose tended to exacerbate the developmental toxicity of CP. GTE alone appeared to cause an adverse effect on eyelid development. PMID:22447743

  1. Prenatal and lactational lead exposure enhanced oxidative stress and altered apoptosis status in offspring rats' hippocampus.

    PubMed

    Lu, Xiaobo; Jin, Cuihong; Yang, Jinghua; Liu, Qiufang; Wu, Shengwen; Li, Dandan; Guan, Yangyang; Cai, Yuan

    2013-01-01

    Oxidative stress and apoptosis facilitation in the developing central nervous system (CNS) have been inferred as two mechanisms related to lead's neurotoxicity, and excessive reactive oxygen species (ROS) can promote oxidative stress and apoptosis facilitation. Few studies systematically investigated the potential relationship among oxidative stress, ROS generation, and apoptosis facilitation after lead exposure in earlier life as a whole. To better understand the adverse effect on the developing central nervous system (CNS) after lead exposure during pregnancy and lactation, the indexes of oxidative stress, apoptosis status, and Bax and Bcl-2 expression of offspring rats' hippocampus were determined. Pregnant rats were randomly divided into four groups and given free access to drinking water which contained 0 %, 0.05 %, 0.1 %, and 0.2 % Pb(AC)(2) respectively from gestation day 0 to postnatal day 21 (PND21). Results showed that ROS and malondialdehyde level of either PND7 or PND21 pups' hippocampus were significantly raised; reduced glutathione level and superoxide dismutase activity were obviously decreased following the increase of blood and brain lead level. Similar to apoptotic indexes, Bax/Bcl-2 ratio increased after 0.1 % and 0.2 % Pb(AC)(2) exposure, especially for the pups on PND7. Comparing with cortex, the hippocampus seemed much more sensitive to damage induced by lead. We concluded that the disruption of pro-oxidant and antioxidant balance and apoptosis facilitation could be associated with the mechanisms of neurotoxicity after lead exposure in earlier life.

  2. Histopathologic Alterations Associated with Global Gene Expression Due to Chronic Dietary TCDD Exposure in Juvenile Zebrafish

    PubMed Central

    Liu, Qing; Spitsbergen, Jan M.; Cariou, Ronan; Huang, Chun-Yuan; Jiang, Nan; Goetz, Giles; Hutz, Reinhold J.; Tonellato, Peter J.; Carvan, Michael J.

    2014-01-01

    The goal of this project was to investigate the effects and possible developmental disease implication of chronic dietary TCDD exposure on global gene expression anchored to histopathologic analysis in juvenile zebrafish by functional genomic, histopathologic and analytic chemistry methods. Specifically, juvenile zebrafish were fed Biodiet starter with TCDD added at 0, 0.1, 1, 10 and 100 ppb, and fish were sampled following 0, 7, 14, 28 and 42 d after initiation of the exposure. TCDD accumulated in a dose- and time-dependent manner and 100 ppb TCDD caused TCDD accumulation in female (15.49 ppb) and male (18.04 ppb) fish at 28 d post exposure. Dietary TCDD caused multiple lesions in liver, kidney, intestine and ovary of zebrafish and functional dysregulation such as depletion of glycogen in liver, retrobulbar edema, degeneration of nasal neurosensory epithelium, underdevelopment of intestine, and diminution in the fraction of ovarian follicles containing vitellogenic oocytes. Importantly, lesions in nasal epithelium and evidence of endocrine disruption based on alternatively spliced vasa transcripts are two novel and significant results of this study. Microarray gene expression analysis comparing vehicle control to dietary TCDD revealed dysregulated genes involved in pathways associated with cardiac necrosis/cell death, cardiac fibrosis, renal necrosis/cell death and liver necrosis/cell death. These baseline toxicological effects provide evidence for the potential mechanisms of developmental dysfunctions induced by TCDD and vasa as a biomarker for ovarian developmental disruption. PMID:24988445

  3. Traffic pollution exposure is associated with altered brain connectivity in school children.

    PubMed

    Pujol, Jesus; Martínez-Vilavella, Gerard; Macià, Dídac; Fenoll, Raquel; Alvarez-Pedrerol, Mar; Rivas, Ioar; Forns, Joan; Blanco-Hinojo, Laura; Capellades, Jaume; Querol, Xavier; Deus, Joan; Sunyer, Jordi

    2016-04-01

    Children are more vulnerable to the effects of environmental elements due to their active developmental processes. Exposure to urban air pollution has been associated with poorer cognitive performance, which is thought to be a result of direct interference with brain maturation. We aimed to assess the extent of such potential effects of urban pollution on child brain maturation using general indicators of vehicle exhaust measured in the school environment and a comprehensive imaging evaluation. A group of 263 children, aged 8 to 12 years, underwent MRI to quantify regional brain volumes, tissue composition, myelination, cortical thickness, neural tract architecture, membrane metabolites, functional connectivity in major neural networks and activation/deactivation dynamics during a sensory task. A combined measurement of elemental carbon and NO2 was used as a putative marker of vehicle exhaust. Air pollution exposure was associated with brain changes of a functional nature, with no evident effect on brain anatomy, structure or membrane metabolites. Specifically, a higher content of pollutants was associated with lower functional integration and segregation in key brain networks relevant to both inner mental processes (the default mode network) and stimulus-driven mental operations. Age and performance (motor response speed) both showed the opposite effect to that of pollution, thus indicating that higher exposure is associated with slower brain maturation. In conclusion, urban air pollution appears to adversely affect brain maturation in a critical age with changes specifically concerning the functional domain.

  4. Neonatal Idiotypic Exposure Alters Subsequent Cytokine, Pathology, and Survival Patterns in Experimental Schistosoma mansoni Infections

    PubMed Central

    Angela Montesano, M.; Colley, Daniel G.; Eloi-Santos, Silvana; Freeman, George L.; Secor, W. Evan

    1999-01-01

    Exposure to maternal idiotypes (Ids) or antigens might predispose a child to develop an immunoregulated, asymptomatic clinical presentation of schistosomiasis. We have used an experimental murine system to address the role of Ids in this immunoregulation. Sera from mice with 8-wk Schistosoma mansoni infection, chronic (20-wk infection) moderate splenomegaly syndrome (MSS), or chronic hypersplenomegaly syndrome (HSS) were passed over an S. mansoni soluble egg antigen (SEA) immunoaffinity column to prepare Ids (8WkId, MSS Id, HSS Id). Newborn mice were injected with 8WkId, MSS Id, HSS Id, or normal mouse immunoglobulin (NoMoIgG) and infected with S. mansoni 8 wk later. Mice exposed to 8WkId or MSS Id as newborns had prolonged survival and decreased morbidity compared with mice that received HSS Id or NoMoIgG. When stimulated with SEA, 8WkId, or MSS Id, spleen cells from mice neonatally injected with 8WkId or MSS Id produced more interferon γ than spleen cells from mice neonatally injected with HSS Id or NoMoIgG. Furthermore, neonatal exposure to 8WkId or MSS Id, but not NoMoIgG or HSS Id, led to significantly smaller granuloma size and lower hepatic fibrosis levels in infected mice. Together, these results indicate that perinatal exposure to appropriate anti-SEA Ids induces long-term effects on survival, pathology, and immune response patterns in mice subsequently infected with S. mansoni. PMID:9989978

  5. Prenatal Cocaine Exposure Alters Cortisol Stress Reactivity in 11 Year Old Children

    PubMed Central

    Lester, Barry M.; LaGasse, Linda L.; Shankaran, Seetha; Bada, Henrietta S.; Bauer, Charles R.; Lin, Richard; Das, Abhik; Higgins, Rosemary

    2011-01-01

    Objective Determine the association between prenatal cocaine exposure and postnatal environmental adversity on salivary cortisol stress reactivity in school aged children. Study design Subjects included 743 11 year old children (n=320 cocaine exposed; 423 comparison) followed since birth in a longitudinal prospective multisite study. Saliva samples were collected to measure cortisol at baseline and after a standardized procedure to induce psychological stress. Children were divided into those who showed an increase in cortisol from baseline to post stress and those who showed a decrease or blunted cortisol response. Covariates measured included site, birthweight, maternal pre and postnatal use of alcohol, tobacco or marijuana, social class, changes in caretakers, maternal depression and psychological symptoms, domestic and community violence, child abuse and quality of the home. Results With adjustment for confounding variables, cortisol reactivity to stress was more likely to be blunted in children with prenatal cocaine exposure. Cocaine exposed children exposed to domestic violence showed the strongest effects. Conclusion The combination of prenatal cocaine exposure and an adverse postnatal environment could down regulate the hypothalamic-pituitary-adrenal axis (HPA) resulting in the blunted cortisol response to stress possibly increasing risk for later psychopathology and adult disease. PMID:20400094

  6. Mitochondrial proteomic alterations caused by long-term low-dose copper exposure in mouse cortex.

    PubMed

    Lin, Xuemei; Wei, Gang; Huang, Zhijun; Qu, Zhongsen; Huang, Xinfeng; Xu, Hua; Liu, Jianjun; Zhuang, Zhixiong; Yang, Xifei

    2016-11-30

    Mitochondrial dysfunction is involved in neurotoxicity caused by exposure of various chemicals such as copper. However, the effects of long-term low-dose copper exposure on mitochondrial proteome remain unclear. In this study, we found the treatment of copper (0.13ppm copper sulfate in drinking water) for 12 months caused abnormal expression of a total of 13 mitochondrial proteins (7 up-regulated and 6 down-regulated) as revealed by two-dimensional electrophoresis coupled with mass spectrometry in mouse cortex. Protein functional analysis revealed that these differentially expressed proteins mainly included apoptosis-associated proteins, axon guidance-associated proteins, axonogenesis-associated proteins and mitochondrial respiratory chain complex. Among these differentially expressed mitochondrial proteins, GRP75 (75kDa glucose-regulated protein) and GRP78 (78kDa glucose-regulated protein) were found to be significantly down-regulated as confirmed by Western-blot analysis. The down-regulation of GRP75 was shown to promote apoptosis. The down-regulation of GRP78/BiP could up-regulate endoplasmic reticulum (ER) stress mediators and thus cause apoptosis. Our study suggested that these differentially expressed mitochondrial proteins such as GRP75 and GRP78 could be involved in neurotoxicity caused by long-term low-dose copper exposure and serve as potential molecular targets for the treatment of copper neurotoxicity.

  7. Altered resistance to Trichinella spiralis infection following subchronic exposure of adult mice to chemicals of environmental concern

    SciTech Connect

    Luebke, R.W.

    1981-01-01

    The effects of subchronic chemical exposure on expulsion of adult Trichinella spiralis from the small intestine of mice and encystment of newborn larvae in the host's musculature were investigated. Exposure to diethylstilbestrol, benzo(a)pyrene, tris-(1,3-dichloro-2-propyl) phosphate, cyclophosphamide, phorbol myristate acetate, and dimethylvinylchloride prior to infection of mice with 200 infective larvae resulted in larger worm burdens in treated animals than in controls 14 days after infection. Worm expulsion was not affected by exposure to tris-(2,3-dibromopropyl)phosphate, orthophenylphenol, and indomethacin. Increased burdens of muscle-phase larvae were found in animals that maintained significant numbers of adult worms in the gut at 14 days, except in mice administered diethylstilbestrol and dimethylvinylchloride. Exposure to diethylstilbestrol and cyclophosphamide resulted in decreased inflammatory reactions in the tissues of the small intestine and development of bone marrow eosinophilia in infected mice. Marrow eosinophilia was likewise decreased in mice given tris-(1,3-dichloro-2-propyl)phosphate before infection. Additional studies with diethylstilbestrol administered either before, at the time of, or after infection showed inhibition of worm expulsion. Drug exposure during a primary infection inhibited the expulsion of a second T. spiralis infection, but did not affect worm elimination when given during a second infection. Treatment with diethylstilbestrol after artificial sensitization of mice with Trichinella antigens decreased delayed hypersensitivity responses to the sensitizing antigen. Immune functions, assessed by lymphoproliferative responses to mitogens and antibody responses to sheep red blood cells, generally correlated with altered host resistance to T. spiralis infection.

  8. Repeated ethanol exposure during late gestation alters the maturation and innate immune status of the ovine fetal lung.

    PubMed

    Sozo, Foula; O'Day, Luke; Maritz, Gert; Kenna, Kelly; Stacy, Victoria; Brew, Nadine; Walker, David; Bocking, Alan; Brien, James; Harding, Richard

    2009-03-01

    Little is known about the effects of fetal ethanol exposure on lung development. Our aim was to determine the effects of repeated ethanol exposure during late gestation on fetal lung growth, maturation, and inflammatory status. Pregnant ewes were chronically catheterized at 91 days of gestational age (DGA; term approximately 147 days). From 95-133 DGA, ewes were given a 1-h daily infusion of either 0.75 g ethanol/kg (n = 9) or saline (n = 8), with tissue collection at 134 DGA. Fetal lungs were examined for changes in tissue growth, structure, maturation, inflammation, and oxidative stress. Between treatment groups, there were no differences in lung weight, DNA and protein contents, percent proliferating and apoptotic cells, tissue and air-space fractions, alveolar number and mean linear intercept, septal thickness, type-II cell number and elastin content. Ethanol exposure caused a 75% increase in pulmonary collagen I alpha1 mRNA levels (P < 0.05) and a significant increase in collagen deposition. Surfactant protein (SP)-A and SP-B mRNA levels were approximately one third of control levels following ethanol exposure (P < 0.05). The mRNA levels of the proinflammatory cytokines interleukin (IL)-1beta and IL-8 were also lower (P < 0.05) in ethanol-exposed fetuses compared with controls. Pulmonary malondialdehyde levels tended to be increased (P = 0.07) in ethanol-exposed fetuses. Daily exposure of the fetus to ethanol during the last third of gestation alters extracellular matrix deposition and surfactant protein gene expression, which could increase the risk of respiratory distress syndrome after birth. Changes to the innate immune status of the fetus could increase the susceptibility of the neonatal lungs to infection.

  9. Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse.

    PubMed

    Hashikawa, Naoya; Ogawa, Takumi; Sakamoto, Yusuke; Ogawa, Mami; Matsuo, Yumi; Zamami, Yoshito; Hashikawa-Hobara, Narumi

    2015-08-01

    Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test.

  10. In vivo tungsten exposure alters B-cell development and increases DNA damage in murine bone marrow.

    PubMed

    Kelly, Alexander D R; Lemaire, Maryse; Young, Yoon Kow; Eustache, Jules H; Guilbert, Cynthia; Molina, Manuel Flores; Mann, Koren K

    2013-02-01

    High environmental tungsten levels were identified near the site of a childhood pre-B acute lymphoblastic leukemia cluster; however, a causal link between tungsten and leukemogenesis has not been established. The major site of tungsten deposition is bone, the site of B-cell development. In addition, our in vitro data suggest that developing B lymphocytes are susceptible to tungsten-induced DNA damage and growth inhibition. To extend these results, we assessed whether tungsten exposure altered B-cell development and induced DNA damage in vivo. Wild-type mice were exposed to tungsten in their drinking water for up to 16 weeks. Tungsten concentration in bone was analyzed by inductively coupled plasma mass spectrometry and correlated with B-cell development and DNA damage within the bone marrow. Tungsten exposure resulted in a rapid deposition within the bone following 1 week, and tungsten continued to accumulate thereafter albeit at a decreased rate. Flow cytometric analyses revealed a transient increase in mature IgD(+) B cells in the first 8 weeks of treatment, in animals of the highest and intermediate exposure groups. Following 16 weeks of exposure, all tungsten groups had a significantly greater percentage of cells in the late pro-/large pre-B developmental stages. DNA damage was increased in both whole marrow and isolated B cells, most notably at the lowest tungsten concentration tested. These findings confirm an immunological effect of tungsten exposure and suggest that tungsten could act as a tumor promoter, providing leukemic "hits" in multiple forms to developing B lymphocytes within the bone marrow.

  11. Alteration of the Carbon and Nitrogen Isotopic Composition in the Martian Surface Rocks Due to Cosmic Ray Exposure

    NASA Technical Reports Server (NTRS)

    Pavlov, A. A.; Pavlov, A. K.; Ostryakov, V. M.; Vasilyev, G. I.; Mahaffy, P.; Steele, A.

    2014-01-01

    C-13/C-12 and N-15/N-14 isotopic ratios are pivotal for our understanding of the Martian carbon cycle, history of the Martian atmospheric escape, and origin of the organic compounds on Mars. Here we demonstrate that the carbon and nitrogen isotopic composition of the surface rocks on Mars can be significantly altered by the continuous exposure of Martian surface to cosmic rays. Cosmic rays can effectively produce C-13 and N-15 isotopes via spallation nuclear reactions on oxygen atoms in various Martian rocks. We calculate that in the top meter of the Martian rocks, the rates of production of both C-13 and N-15 due to galactic cosmic rays (GCRs) exposure can vary within 1.5-6 atoms/cm3/s depending on rocks' depth and chemical composition. We also find that the average solar cosmic rays can produce carbon and nitrogen isotopes at a rate comparable to GCRs in the top 5-10 cm of the Martian rocks. We demonstrate that if the total carbon content in a surface Martian rock is <10 ppm, then the "light," potentially "biological" C-13/C-12 ratio would be effectively erased by cosmic rays over 3.5 billion years of exposure. We found that for the rocks with relatively short exposure ages (e.g., 100 million years), cosmogenic changes in N-15/N-14 ratio are still very significant. We also show that a short exposure to cosmic rays of Allan Hills 84001 while on Mars can explain its high-temperature heavy nitrogen isotopic composition (N-15/N-14). Applications to Martian meteorites and the current Mars Science Laboratory mission are discussed.

  12. Stable and episodic/bolus patterns of methylmercury exposure on mercury accumulation and histopathologic alterations in the nervous system.

    PubMed

    Sakamoto, Mineshi; Kakita, Akiyoshi; Domingo, José L; Yamazaki, Hiroshi; Oliveira, Ricardo B; Sarrazin, Sandra L F; Eto, Komyo; Murata, Katsuyuki

    2017-01-01

    The main purpose of the present study was to compare the blood and brain mercury (Hg) accumulation and neurological alterations in adult male and pregnant female/fetal rats following stable and episodic/bolus patterns of methylmercury (MeHg) exposure. In addition, MeHg accumulation in the human body was estimated by a one-compartment model using three different patterns of MeHg exposure. In the adult male rat experiment, doses of 0.3 and 1.5mg MeHg/kg/day were orally administered to the stable groups for 5 weeks, while 7-fold higher doses of 2.1 and 10.5mg MeHg/kg/once a week were administered to the bolus groups. The blood Hg levels increased constantly in the stable groups, but increased with repeated waves in the bolus groups. At completion of the experiment, there were no significant differences in the brain Hg concentrations or neurological alterations between the stable and bolus groups, when the total doses of MeHg were the same. In the pregnant female rat experiment, a dose of 1mg MeHg/kg/day was administered orally to the stable group for 20 days (until 1day before expected parturition), while a 5-fold higher dose of 5mg MeHg/kg/once every 5 days was administered to the bolus group. In the brains of the maternal/fetal rats, there were no significant differences in the Hg concentrations and neurological alterations between the stable and bolus groups. The mean Hg concentrations in the fetal brains were approximately 2-fold higher than those in the maternal brains for both stable and bolus groups. Using the one-compartment model, the Hg accumulation curves in humans at doses of 7µg MeHg/day, 48µg MeHg/once a week, and 96µg MeHg/once every 2 weeks were estimated to be similar, while the bolus groups showed dose-dependent amplitudes of repeated waves. These results suggest that stable and episodic/bolus patterns of MeHg exposure do not cause differences in Hg accumulation in the blood and brain, or in neurological alterations, when the total doses are the

  13. Prenatal alcohol exposure alters expression of neurogenesis-related genes in an ex vivo cell culture model

    PubMed Central

    Tyler, Christina R.; Allan, Andrea M.

    2014-01-01

    Prenatal alcohol exposure can lead to long-lasting changes in functional and genetic programs of the brain, which may underlie behavioral alterations seen in Fetal Alcohol Spectrum Disorder (FASD). Aberrant fetal programming during gestational alcohol exposure is a possible mechanism by which alcohol imparts teratogenic effects on the brain; however, current methods used to investigate the effects of alcohol on development often rely on either direct application of alcohol in vitro or acute high doses in vivo. In this study, we used our established moderate prenatal alcohol exposure (PAE) model, resulting in maternal blood alcohol content of approximately 20 mM, and subsequent ex vivo cell culture to assess expression of genes related to neurogenesis. Proliferating and differentiating neural progenitor cell culture conditions were established from telencephalic tissue derived from embryonic day (E) 15–17 tissue exposed to alcohol via maternal drinking throughout pregnancy. Gene expression analysis on mRNA derived in vitro was performed using a microarray, and quantitative PCR was conducted for genes to validate the microarray. Student's t tests were performed for statistical comparison of each exposure under each culture condition using a 95% confidence interval. Eleven percent of genes on the array had significantly altered mRNA expression in the prenatal alcohol-exposed neural progenitor culture under proliferating conditions. These include reduced expression of Adora2a, Cxcl1, Dlg4, Hes1, Nptx1, and Vegfa and increased expression of Fgf13, Ndn, and Sox3; bioinformatics analysis indicated that these genes are involved in cell growth and proliferation. Decreased levels of Dnmt1 and Dnmt3a were also found under proliferating conditions. Under differentiating conditions, 7.3% of genes had decreased mRNA expression; these include Cdk5rap3, Gdnf, Hey2, Heyl, Pard6b, and Ptn, which are associated with survival and differentiation as indicated by bioinformatics

  14. Prenatal alcohol exposure alters expression of neurogenesis-related genes in an ex vivo cell culture model.

    PubMed

    Tyler, Christina R; Allan, Andrea M

    2014-08-01

    Prenatal alcohol exposure can lead to long-lasting changes in functional and genetic programs of the brain, which may underlie behavioral alterations seen in Fetal Alcohol Spectrum Disorder (FASD). Aberrant fetal programming during gestational alcohol exposure is a possible mechanism by which alcohol imparts teratogenic effects on the brain; however, current methods used to investigate the effects of alcohol on development often rely on either direct application of alcohol in vitro or acute high doses in vivo. In this study, we used our established moderate prenatal alcohol exposure (PAE) model, resulting in maternal blood alcohol content of approximately 20 mM, and subsequent ex vivo cell culture to assess expression of genes related to neurogenesis. Proliferating and differentiating neural progenitor cell culture conditions were established from telencephalic tissue derived from embryonic day (E) 15-17 tissue exposed to alcohol via maternal drinking throughout pregnancy. Gene expression analysis on mRNA derived in vitro was performed using a microarray, and quantitative PCR was conducted for genes to validate the microarray. Student's t tests were performed for statistical comparison of each exposure under each culture condition using a 95% confidence interval. Eleven percent of genes on the array had significantly altered mRNA expression in the prenatal alcohol-exposed neural progenitor culture under proliferating conditions. These include reduced expression of Adora2a, Cxcl1, Dlg4, Hes1, Nptx1, and Vegfa and increased expression of Fgf13, Ndn, and Sox3; bioinformatics analysis indicated that these genes are involved in cell growth and proliferation. Decreased levels of Dnmt1 and Dnmt3a were also found under proliferating conditions. Under differentiating conditions, 7.3% of genes had decreased mRNA expression; these include Cdk5rap3, Gdnf, Hey2, Heyl, Pard6b, and Ptn, which are associated with survival and differentiation as indicated by bioinformatics analysis

  15. Intravenous Prenatal Nicotine Exposure Alters METH-Induced Hyperactivity, Conditioned Hyperactivity, and BDNF in Adult Rat Offspring.

    PubMed

    Lacy, Ryan T; Brown, Russell W; Morgan, Amanda J; Mactutus, Charles F; Harrod, Steven B

    2016-01-01

    In the USA, approximately 15% of women smoke tobacco cigarettes during pregnancy. In utero tobacco smoke exposure produces somatic growth deficits like intrauterine growth restriction and low birth weight in offspring, but it can also negatively influence neurodevelopmental outcomes in later stages of life, such as an increased incidence of obesity and drug abuse. Animal models demonstrate that prenatal nicotine (PN) alters the development of the mesocorticolimbic system, which is important for organizing goal-directed behavior. In the present study, we determined whether intravenous (IV) PN altered the initiation and/or expression of methamphetamine (METH)-induced locomotor sensitization as a measure of mesocorticolimbic function in adult rat offspring. We also determined whether PN and/or METH exposure altered protein levels of BDNF (brain-derived neurotrophic factor) in the nucleus accumbens, the dorsal striatum, and the prefrontal cortex of adult offspring. BDNF was of interest because of its role in the development and maintenance of the mesocorticolimbic pathway and its ability to modulate neural processes that contribute to drug abuse, such as sensitization of the dopamine system. Dams were injected with IV nicotine (0.05 mg/kg/injection) or saline, 3×/day on gestational days 8-21. Testing was conducted when offspring reached adulthood (around postnatal day 90). Following 3 once daily habituation sessions the animals received a saline injection and baseline locomotor activity was measured. PN and prenatal saline (PS)-exposed offspring then received 10 once daily injections of METH (0.3 mg/kg) to induce locomotor sensitization. The animals received a METH injection (0.3 mg/kg) to assess the expression of sensitization following a 14-day period of no injections. A day later, all animals were injected with saline and conditioned hyperactivity was assessed. Brain tissue was harvested 24 h later. PN animals habituated more slowly to the activity chambers

  16. Phosphatidylserine index as a marker of the procoagulant phenotype of acute myelogenous leukemia cells

    NASA Astrophysics Data System (ADS)

    Tormoen, Garth W.; Recht, Olivia; Gruber, András; Levine, Ross L.; McCarty, Owen J. T.

    2013-10-01

    Patients with acute myelogenous leukemia (AML) are at risk for thrombotic complications. Risk to develop thrombosis is closely tied to leukemia subtype, and studies have shown an association between leukocytosis and thrombosis in AML M3. We evaluated the relative roles of cell count and the surface expression of tissue factor (TF) and phosphatidylserine (PS) in the procoagulant phenotype of AML cell lines. The TF-positive AML M3 cell lines, NB4 and HL60, and AML M2 cell line, AML14, exhibited both extrinsic tenase and prothrombinase activity in a purified system and promoted experimental thrombus formation. In contrast, the TF-negative AML cell line, HEL, exhibited only prothrombinase activity and did not affect the rate of occlusive thrombus formation. In plasma, NB4, HL60 and AML14 shortened clotting times in a cell-count, PS- and TF-dependent manner. Exposure of cultured NB4, HL60, and AML14 cells to the chemotherapeutic agent daunorubicin increased their extrinsic tenase activity and PS expression. Clot initiation time inversely correlated with logarithm of PS index, defined as the product of multiplying leukocyte count with cell surface PS exposure. We propose that leukemia cell PS index may serve as a biomarker for procoagulant activity.

  17. Acute effects of tetracycline exposure in the freshwater fish Gambusia holbrooki: antioxidant effects, neurotoxicity and histological alterations.

    PubMed

    Nunes, B; Antunes, S C; Gomes, R; Campos, J C; Braga, M R; Ramos, A S; Correia, A T

    2015-02-01

    A large body of evidence was compiled in the recent decades showing a noteworthy increase in the detection of pharmaceutical drugs in aquatic ecosystems. Due to its ubiquitous presence, chemical nature, and practical purpose, this type of contaminant can exert toxic effects in nontarget organisms. Exposure to pharmaceutical drugs can result in adaptive alterations, such as changes in tissues, or in key homeostatic mechanisms, such as antioxidant mechanisms, biochemical/physiological pathways, and cellular damage. These alterations can be monitored to determine the impact of these compounds on exposed aquatic organisms. Among pharmaceutical drugs in the environment, antibiotics are particularly important because they include a variety of substances widely used in medical and veterinary practice, livestock production, and aquaculture. This wide use constitutes a decisive factor contributing for their frequent detection in the aquatic environment. Tetracyclines are the individual antibiotic subclass with the second highest frequency of detection in environmental matrices. The characterization of the potential ecotoxicological effects of tetracycline is a much-required task; to attain this objective, the present study assessed the acute toxic effects of tetracycline in the freshwater fish species Gambusia holbrooki by the determination of histological changes in the gills and liver, changes in antioxidant defense [glutathione S-transferase (GST), catalase (CAT), and lipoperoxidative damage] as well as potential neurotoxicity (acetylcholinesterase activity). The obtained results suggest the existence of a cause-and-effect relationship between the exposure to tetracycline and histological alterations (more specifically in gills) and enzymatic activity (particularly the enzyme CAT in liver and GST in gills) indicating that this compound can exert a pro-oxidative activity.

  18. Tetrachlorodibenzo-p-dioxin exposure alters radial arm maze performance and hippocampal morphology in female AhR mice.

    PubMed

    Powers, B E; Lin, T-M; Vanka, A; Peterson, R E; Juraska, J M; Schantz, S L

    2005-02-01

    Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter spatial learning in rats tested on a radial arm maze (RAM). TCDD is believed to exert most of its effects through binding to the aryl hydrocarbon receptor (AhR). To determine whether the AhR mediates TCDD-induced alterations in spatial learning, we tested male and female AhR-knockout (AhR-/-), heterozygous (AhR+/-) and wild-type (AhR+/+) mice on the RAM. AhR+/- male and female mice were time mated, and treated dams were dosed with 5 microg TCDD/kg body weight on day 13 of gestation. When offspring reached adulthood, male and female AhR+/+, AhR+/- and AhR-/- mice from TCDD-exposed and unexposed litters were tested on the eight-arm RAM. After testing, we examined hippocampal morphology as visualized by the Timm's silver sulfide stain. TCDD-exposed female AhR+/- mice made more errors than their respective controls on the RAM and exhibited a decrease in the size of the intra- and infrapyramidal mossy fiber (IIP-MF) field of the hippocampus. None of the other TCDD-exposed groups differed from their respective control groups with regard to maze performance or hippocampal morphology. The reduction of IIP-MF field indicates a possible morphological basis for the learning deficit that was observed in the female AhR+/- mice. It is hypothesized that the effect of TCDD exposure is AhR dependent and that TCDD may alter GABAergic activity in the hippocampus of female mice during development.

  19. Maternal exposure to fish oil primes offspring to harbor intestinal pathobionts associated with altered immune cell balance.

    PubMed

    Gibson, D L; Gill, S K; Brown, K; Tasnim, N; Ghosh, S; Innis, S; Jacobson, K

    2015-01-01

    Our previous studies revealed that offspring from rat dams fed fish oil (at 8% and 18% energy), developed impaired intestinal barriers sensitizing the colon to exacerbated injury later in life. To discern the mechanism, we hypothesized that in utero exposure to fish oil, rich in n-3 polyunsaturated fatty acid (PUFA), caused abnormal intestinal reparative responses to mucosal injury through differences in intestinal microbiota and the presence of naïve immune cells. To identify such mechanisms, gut microbes and naïve immune cells were compared between rat pups born to dams fed either n-6 PUFA, n-3 PUFA or breeder chow. Maternal exposure to either of the PUFA rich diets altered the development of the intestinal microbiota with an overall reduction in microbial density. Using qPCR, we found that each type of PUFA differentially altered the major gut phyla; fish oil increased Bacteroidetes and safflower oil increased Firmicutes. Both PUFA diets reduced microbes known to dominate the infant gut like Enterobacteriaceae and Bifidobacteria spp. when compared to the chow group. Uniquely, maternal fish oil diets resulted in offspring showing blooms of opportunistic pathogens like Bilophila wadsworthia, Enterococcus faecium and Bacteroides fragilis in their gut microbiota. As well, fish oil groups showed a reduction in colonic CD8+ T cells, CD4+ Foxp3+ T cells and arginase+ M2 macrophages. In conclusion, fish oil supplementation in pharmacological excess, at 18% by energy as shown in this study, provides an example where excess dosing in utero can prime offspring to harbor intestinal pathobionts and alter immune cell homeostasis.

  20. Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.

    PubMed

    Duncan, Jhodie R; Garland, Marianne; Myers, Michael M; Fifer, William P; Yang, May; Kinney, Hannah C; Stark, Raymond I

    2009-11-01

    During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

  1. Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome

    PubMed Central

    Duncan, Jhodie R.; Garland, Marianne; Myers, Michael M.; Fifer, William P.; Yang, May; Stark, Raymond I.

    2009-01-01

    During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT1A receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors. PMID:19729586

  2. Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain.

    PubMed

    D'Addario, Claudio; Caputi, Francesca F; Rimondini, Roberto; Gandolfi, Ottavio; Del Borrello, Elia; Candeletti, Sanzio; Romualdi, Patrizia

    2013-05-01

    Molecular mechanisms of adaptive transformations caused by alcohol exposure on opioid dynorphin and nociceptin systems have been investigated in the rat brain. Alcohol was intragastrically administered to rats to resemble human drinking with several hours of exposure: water or alcohol (20% in water) at a dose of 1.5 g/kg three times daily for 1 or 5 days. The development of tolerance and dependence were recorded daily. Brains were dissected 30 minutes (1- and 5-day groups) or 1, 3 or 7 days after the last administration for the three other 5-day groups (groups under withdrawal). Specific alterations in opioid genes expression were ascertained. In the amygdala, an up-regulation of prodynorphin and pronociceptin was observed in the 1-day group; moreover, pronociceptin and the kappa opioid receptor mRNAs in the 5-day group and both peptide precursors in the 1-day withdrawal group were also up-regulated. In the prefrontal cortex, an increase in prodynorhin expression in the 1-day group was detected. These data indicate a relevant role of the dynorphinergic system in the negative hedonic states associated with multiple alcohol exposure. The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides. Our findings could help to the understanding of how alcohol differentially affects the opioid systems in the brain and also suggest the dynorphin and nociceptin systems as possible targets for the treatment and/or prevention of alcohol dependence.

  3. In Utero Environmental Tobacco Smoke Exposure Alters Gene Expression in Lungs of Adult BALB/c Mice

    PubMed Central

    Rouse, Rodney L.; Boudreaux, Marc J.; Penn, Arthur L.

    2007-01-01

    Background In utero environmental tobacco smoke (ETS) exposure exacerbates initial lung responses of adult mice to ovalbumin (OVA), a common allergen in rodent models of allergic asthma. Objective We tested the hypothesis that in utero ETS exposure alters expression of genes (including asthma-related and inflammatory genes) in the lungs of adult mice and that this differential expression is reflected in differential respiratory and immune responses to nontobacco allergens. Methods Using Affymetrix Mouse Genome 430 2.0 arrays, we examined gene expression changes in lungs of BALB/c mice exposed to ETS in utero, OVA, or saline aerosol at weeks 7–8, and OVA sensitization and challenge at weeks 11–15. Data sets were filtered by transcript p-value (≤ 0.05), false discovery rate (≤ 0.05), and fold change (≥ 1.5). Differential expression of selected genes was confirmed by polymerase chain reaction (PCR). Results Genes differentially expressed as a result of in utero ETS exposure are involved in regulation of biological processes (immune response, cell proliferation, apoptosis, cell metabolism) through altered cytoskeleton, adhesion, transcription, and enzyme molecules. A number of genes prominent in lung inflammation were differentially expressed on PCR but did not pass selection criteria for microarray, including arginase (Arg1), chitinases (Chia, Chi3l3, Chi3l4), eotaxins (Ccl11, Ccl24), small proline-rich protein 2a (Sprr2a), and cytokines (Il4, Il6, Il10, Il13, Tnfa) . Conclusion The differential lung gene expression reported here is consistent with previously reported functional changes in lungs of mice exposed in utero to ETS and as adults to the nontobacco allergen OVA. PMID:18087596

  4. Exposure to a glyphosate-based herbicide during pregnancy and lactation induces neurobehavioral alterations in rat offspring.

    PubMed

    Gallegos, Cristina E; Bartos, Mariana; Bras, Cristina; Gumilar, Fernanda; Antonelli, Marta C; Minetti, Alejandra

    2016-03-01

    The impact of sub-lethal doses of herbicides on human health and the environment is a matter of controversy. Due to the fact that evidence particularly of the effects of glyphosate on the central nervous system of rat offspring by in utero exposure is scarce, the purpose of the present study was to assess the neurobehavioral effects of chronic exposure to a glyphosate-containing herbicide during pregnancy and lactation. To this end, pregnant Wistar rats were exposed through drinking water to 0.2% or 0.4% of a commercial formulation of glyphosate (corresponding to a concentration of 0.65 or 1.30g/L of glyphosate, respectively) during pregnancy and lactation and neurobehavioral alterations in offspring were analyzed. The postnatal day on which each pup acquired neonatal reflexes (righting, cliff aversion and negative geotaxis) and that on which eyes and auditory canals were fully opened were recorded for the assessment of sensorimotor development. Locomotor activity and anxiety levels were monitored via open field test and plus maze test, respectively, in 45- and 90-day-old offspring. Pups exposed to a glyphosate-based herbicide showed early onset of cliff aversion reflex and early auditory canal opening. A decrease in locomotor activity and in anxiety levels was also observed in the groups exposed to a glyphosate-containing herbicide. Findings from the present study reveal that early exposure to a glyphosate-based herbicide affects the central nervous system in rat offspring probably by altering mechanisms or neurotransmitter systems that regulate locomotor activity and anxiety.

  5. Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice.

    PubMed

    Buscariollo, Daniela L; Fang, Xiefan; Greenwood, Victoria; Xue, Huiling; Rivkees, Scott A; Wendler, Christopher C

    2014-01-01

    Evidence indicates that disruption of normal prenatal development influences an individual's risk of developing obesity and cardiovascular disease as an adult. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. Our aim was to determine whether adenosine A1 receptors (A1ARs) mediate the long-term effects of in utero caffeine exposure on cardiac function and whether these long-term effects are the result of changes in DNA methylation patterns in adult hearts. Pregnant A1AR knockout mice were treated with caffeine (20 mg/kg) or vehicle (0.09% NaCl) i.p. at embryonic day 8.5. This caffeine treatment results in serum levels equivalent to the consumption of 2-4 cups of coffee in humans. After dams gave birth, offspring were examined at 8-10 weeks of age. A1AR+/+ offspring treated in utero with caffeine were 10% heavier than vehicle controls. Using echocardiography, we observed altered cardiac function and morphology in adult mice exposed to caffeine in utero. Caffeine treatment decreased cardiac output by 11% and increased left ventricular wall thickness by 29% during diastole. Using DNA methylation arrays, we identified altered DNA methylation patterns in A1AR+/+ caffeine treated hearts, including 7719 differentially methylated regions (DMRs) within the genome and an overall decrease in DNA methylation of 26%. Analysis of genes associated with DMRs revealed that many are associated with cardiac hypertrophy. These data demonstrate that A1ARs mediate in utero caffeine effects on cardiac function and growth and that caffeine exposure leads to changes in DNA methylation.

  6. Next generation effects of female adolescent morphine exposure: sex-specific alterations in response to acute morphine emerge before puberty.

    PubMed

    Vassoler, Fair M; Johnson-Collins, Nicole L; Carini, Lindsay M; Byrnes, Elizabeth M

    2014-04-01

    Prescription opiate use by adolescent girls has increased significantly in the past decade. Preclinical studies using rats report alterations in morphine sensitivity in the adult offspring of adolescent morphine-exposed females (MOR-F1) when compared with the offspring of adolescent saline-exposed females (SAL-F1). To begin to elucidate the development of these next generation modifications, the present study examined the effects of acute morphine administration on sedation and corticosterone secretion in prepubescent SAL-F1 and MOR-F1 male and female rats. In addition, alterations in proopiomelanocortin (POMC) gene expression in the arcuate nucleus, as well as in tyrosine hydroxylase (TH) and μ-opioid receptor (OPRM1) gene expressions in the ventral tegmental area, were analyzed using quantitative PCR, to determine whether differential regulation of these genes was correlated with the observed behavioral and/or endocrine effects. Increased morphine-induced sedation, coupled with an attenuation of morphine-induced corticosterone secretion, was observed in MOR-F1 males. Significant alterations in both POMC and OPRM1 gene expressions were also observed in MOR-F1 males, with no change in TH mRNA expression. Overall, these data suggest that the transgenerational effects of adolescent morphine exposure can be discerned before pubertal development and are more pronounced in males, and suggest dysregulation of the hypothalamic-pituitary-adrenal axis in the offspring of adolescent morphine-exposed females.

  7. Rim Structure, Stratigraphy, and Aqueous Alteration Exposures Along Opportunity Rover's Traverse of the Noachian Endeavour Crater

    NASA Technical Reports Server (NTRS)

    Crumpler, L.S.; Arvidson, R. E.; Golombek, M.; Grant, J. A.; Jolliff, B. L.; Mittlefehldt, D. W.

    2017-01-01

    The Mars Exploration Rover Opportunity has traversed 10.2 kilometers along segments of the west rim of the 22-kilometer-diameter Noachian Endeavour impact crater as of sol 4608 (01/09/17). The stratigraphy, attitude of units, lithology, and degradation state of bedrock outcrops exposed on the crater rim have been examined in situ and placed in geologic context. Structures within the rim and differences in physical properties of the identified lithologies have played important roles in localizing outcrops bearing evidence of aqueous alteration.

  8. Short-term exposure of arsenite disrupted thyroid endocrine system and altered gene transcription in the HPT axis in zebrafish.

    PubMed

    Sun, Hong-Jie; Li, Hong-Bo; Xiang, Ping; Zhang, Xiaowei; Ma, Lena Q

    2015-10-01

    Arsenic (As) pollution in aquatic environment may adversely impact fish health by disrupting their thyroid hormone homeostasis. In this study, we explored the effect of short-term exposure of arsenite (AsIII) on thyroid endocrine system in zebrafish. We measured As concentrations, As speciation, and thyroid hormone thyroxine levels in whole zebrafish, oxidative stress (H2O2) and damage (MDA) in the liver, and gene transcription in hypothalamic-pituitary-thyroid (HPT) axis in the brain and liver tissues of zebrafish after exposing to different AsIII concentrations for 48 h. Result indicated that exposure to AsIII increased inorganic As in zebrafish to 0.46-0.72 mg kg(-1), induced oxidative stress with H2O2 being increased by 1.4-2.5 times and caused oxidative damage with MDA being augmented by 1.6 times. AsIII exposure increased thyroxine levels by 1.3-1.4 times and modulated gene transcription in HPT axis. Our study showed AsIII caused oxidative damage, affected thyroid endocrine system and altered gene transcription in HPT axis in zebrafish.

  9. Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring

    PubMed Central

    Zumbrun, Elizabeth E.; Sido, Jessica M.; Nagarkatti, Prakash S.

    2015-01-01

    Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as coexisting drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects. PMID:25618446

  10. Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring.

    PubMed

    Zumbrun, Elizabeth E; Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2015-06-01

    Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as co-existing drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects.

  11. Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation.

    PubMed

    Icenogle, Laura M; Christopher, N Channelle; Blackwelder, W Paul; Caldwell, D Patrick; Qiao, Dan; Seidler, Frederic J; Slotkin, Theodore A; Levin, Edward D

    2004-01-01

    The widely used organophosphate insecticide, chlorpyrifos (CPF), elicits neurobehavioral abnormalities after apparently subtoxic neonatal exposures. In the current study, we administered 1 or 5 mg/kg/day of CPF to pregnant rats on gestational days 9-12, the embryonic phase spanning formation and closure of the neural tube. Although there were no effects on growth or viability, offspring showed behavioral abnormalities when tested in adolescence and adulthood. In the CPF-exposed groups, locomotor hyperactivity was noted in early T-maze trials, and in the elevated plus-maze; alterations in the rate of habituation were also identified. Learning and memory were adversely affected, as assessed using the 16-arm radial maze. Although all CPF-exposed animals eventually learned the task, reference and working memory were impaired in the early training sessions. After training, rats in the CPF group did not show the characteristic amnestic effect of scopolamine, a muscarinic acetylcholine antagonist, suggesting that, unlike the situation in the control group, muscarinic pathways were not used to solve the maze. These results indicate that apparently subtoxic CPF exposure during neurulation adversely affects brain development, leading to behavioral anomalies that selectively include impairment of cholinergic circuits used in learning and memory. The resemblance of these findings to those of late gestational or neonatal CPF exposure indicates a prolonged window of vulnerability of brain development to CPF.

  12. Abuse pattern of gestational toluene exposure alters behavior in rats in a "waiting-for-reward" task.

    PubMed

    Bowen, Scott E; Hannigan, John H; Cooper, Patrick B

    2009-01-01

    Toluene abuse during pregnancy is a world-wide public health concern although the neurobehavioral teratogenic effects of toluene at the high concentrations and binge-like exposure patterns typical of abuse remain understudied. We assessed the effects of binge prenatal toluene exposure on behavior reflective of impulsivity in rat offspring using a "waiting-for-reward" operant task. Timed-pregnant Sprague-Dawley rats were exposed for 15 min, twice daily, from gestational day (GD) 8 through GD20 to either air, 8000 ppm, 12,000 ppm or 16,000 ppm toluene in a static exposure system. At postnatal day 60, male and female offspring were trained to stable lever pressing in a standard fixed-ratio 50 (FR50) paradigm. A wait requirement was then introduced such that after each FR completion, a "free" pellet was delivered at increasing time intervals (2 s, 4 s, 6 s, etc.) until the rat pressed another lever which reinstated the FR50 component ("FR Reset"). A pattern of increased FR Resets and fewer total pellets received overall and during the wait component is interpretable as "impulsivity." The "wait" component assessment was repeated after the rats had been injected with varying doses of amphetamine. Consistent with our hypotheses, repeated binge prenatal toluene exposure appeared to increase impulsivity based upon decreases in the total number of free pellets received and mean waiting time. However, a toluene dose-dependent decrease in the number of FR Resets and in response rates under all conditions indicated there was a general impairment in performance in rats exposed prenatally to higher doses of toluene. Also, prenatal exposure to 12,000 ppm and 16,000 ppm toluene resulted in a hyposensitivity to the stimulatory effects of the amphetamine challenge in male rats. For female rats, amphetamine further interfered with performance on the task. These results suggest that acute binge prenatal toluene exposure alters performance in this task but the results are not consistent

  13. Developmental exposure to bisphenol A (BPA) alters sexual differentiation in painted turtles (Chrysemys picta)

    USGS Publications Warehouse

    Jandegian, Caitlin M.; Deem, Sharon L.; Bhandari, Ramji K.; Holliday, Casey M.; Nicks, Diane; Rosenfeld, Cheryl S.; Selcer, Kyle; Tillitt, Donald E.; vom Saal, Fredrick S.; Velez, Vanessa; Yang, Ying; Holliday, Dawn K.

    2015-01-01

    Environmental chemicals can disrupt endocrine signaling and adversely impact sexual differentiation in wildlife. Bisphenol A (BPA) is an estrogenic chemical commonly found in a variety of habitats. In this study, we used painted turtles (Chrysemys picta), which have temperature-dependent sex determination (TSD), as an animal model for ontogenetic endocrine disruption by BPA. We hypothesized that BPA would override TSD and disrupt sexual development. We incubated farm-raised turtle eggs at the male-producing temperature (26 °C), randomly assigned individuals to treatment groups: control, vehicle control, 17β-estradiol (E2, 20 ng/g-egg) or 0.01, 1.0, 100 μg BPA/g-egg and harvested tissues at hatch. Typical female gonads were present in 89% of the E2-treated “males”, but in none of the control males (n = 35). Gonads of BPA-exposed turtles had varying amounts of ovarian-like cortical (OLC) tissue and disorganized testicular tubules in the medulla. Although the percentage of males with OLCs increased with BPA dose (BPA-low = 30%, BPA-medium = 33%, BPA-high = 39%), this difference was not significant (p = 0.85). In all three BPA treatments, SOX9 patterns revealed disorganized medullary testicular tubules and β-catenin expression in a thickened cortex. Liver vitellogenin, a female-specific liver protein commonly used as an exposure biomarker, was not induced by any of the treatments. Notably, these results suggest that developmental exposure to BPA disrupts sexual differentiation in painted turtles. Further examination is necessary to determine the underlying mechanisms of sex reversal in reptiles and how these translate to EDC exposure in wild populations.

  14. Developmental exposure to bisphenol A (BPA) alters sexual differentiation in painted turtles (Chrysemys picta).

    PubMed

    Jandegian, Caitlin M; Deem, Sharon L; Bhandari, Ramji K; Holliday, Casey M; Nicks, Diane; Rosenfeld, Cheryl S; Selcer, Kyle W; Tillitt, Donald E; Vom Saal, Frederick S; Vélez-Rivera, Vanessa; Yang, Ying; Holliday, Dawn K

    2015-05-15

    Environmental chemicals can disrupt endocrine signaling and adversely impact sexual differentiation in wildlife. Bisphenol A (BPA) is an estrogenic chemical commonly found in a variety of habitats. In this study, we used painted turtles (Chrysemys picta), which have temperature-dependent sex determination (TSD), as an animal model for ontogenetic endocrine disruption by BPA. We hypothesized that BPA would override TSD and disrupt sexual development. We incubated farm-raised turtle eggs at the male-producing temperature (26°C), randomly assigned individuals to treatment groups: control, vehicle control, 17β-estradiol (E2, 20ng/g-egg) or 0.01, 1.0, 100μgBPA/g-egg and harvested tissues at hatch. Typical female gonads were present in 89% of the E2-treated "males", but in none of the control males (n=35). Gonads of BPA-exposed turtles had varying amounts of ovarian-like cortical (OLC) tissue and disorganized testicular tubules in the medulla. Although the percentage of males with OLCs increased with BPA dose (BPA-low=30%, BPA-medium=33%, BPA-high=39%), this difference was not significant (p=0.85). In all three BPA treatments, SOX9 patterns revealed disorganized medullary testicular tubules and β-catenin expression in a thickened cortex. Liver vitellogenin, a female-specific liver protein commonly used as an exposure biomarker, was not induced by any of the treatments. Notably, these results suggest that developmental exposure to BPA disrupts sexual differentiation in painted turtles. Further examination is necessary to determine the underlying mechanisms of sex reversal in reptiles and how these translate to EDC exposure in wild populations.

  15. Alterations in Rat Fetal Morphology Following Abuse Patterns of Toluene Exposure

    PubMed Central

    Bowen, Scott E.; Irtenkauf, Susan; Hannigan, John H.; Stefanski, Adrianne L.

    2009-01-01

    Toluene is a commonly abused organic solvent. Inhalant abusers are increasingly women in their prime childbearing years. Children born to mothers who abused solvents during pregnancy may exhibit characteristics of a “fetal solvent syndrome” which may include dysmorphic features. This study examined the teratological effects of an abuse pattern of binge toluene exposure during gestation on skeletal and soft tissue abnormalities, body weight, and body size in fetal rats. Pregnant Sprague–Dawley rats were exposed for 30 min, twice daily, from gestational day (GD) 8 through GD20 to either air (0 ppm), 8,000 ppm, 12,000 ppm, or 16,000 ppm toluene. Two-thirds of each litter was prepared for skeletal examination using Alizarin Red S staining while the remaining third of each litter was fixed in Bouin’s solution for Wilson’s soft tissue evaluation. Exposure to toluene at all levels significantly reduced growth, including decreases in placental weight, fetal weight, and crown-rump length. In addition, numerous gross morphological anomalies were observed such as short or missing digits and missing limbs. Skeletal examination revealed that ossification of the extremities was significantly reduced as a result of toluene exposure at all levels. Specific skeletal defects included misshapen scapula, missing and supernumerary vertebrae and ribs, and fused digits. Soft tissue anomalies were also observed at all toluene levels and there was a dose-dependent increase in the number of anomalies which included cryptorchidism, displaced abdominal organs, gastromegaly, distended/hypoplastic bladder, and delayed cardiac development, among others. These results indicate that animals exposed prenatally to levels and patterns of toluene typical of inhalant abuse are at increased risk for skeletal and soft tissue abnormalities. PMID:19429395

  16. Alterations of cognitive function and 5-HT system in rats after long term microwave exposure.

    PubMed

    Li, Hai-Juan; Peng, Rui-Yun; Wang, Chang-Zhen; Qiao, Si-Mo; Yong, Zou; Gao, Ya-Bing; Xu, Xin-Ping; Wang, Shao-Xia; Dong, Ji; Zuo, Hong-Yan; Li, Zhao; Zhou, Hong-Mei; Wang, Li-Feng; Hu, Xiang-Jun

    2015-03-01

    The increased use of microwaves raises concerns about its impact on health including cognitive function in which neurotransmitter system plays an important role. In this study, we focused on the serotonin system and evaluated the long term effects of chronic microwave radiation on cognition and correlated items. Wistar rats were exposed or sham exposed to 2.856GHz microwaves with the average power density of 5, 10, 20 or 30mW/cm(2) respectively for 6min three times a week up to 6weeks. At different time points after the last exposure, spatial learning and memory function, morphology structure of the hippocampus, electroencephalogram (EEG) and neurotransmitter content (amino acid and monoamine) of rats were tested. Above results raised our interest in serotonin system. Tryptophan hydroxylase 1 (TPH1) and monoamine oxidase (MAO), two important rate-limiting enzymes in serotonin synthesis and metabolic process respectively, were detected. Expressions of serotonin receptors including 5-HT1A, 2A, 2C receptors were measured. We demonstrated that chronic exposure to microwave (2.856GHz, with the average power density of 5, 10, 20 and 30mW/cm(2)) could induce dose-dependent deficit of spatial learning and memory in rats accompanied with inhibition of brain electrical activity, the degeneration of hippocampus neurons, and the disturbance of neurotransmitters, among which the increase of 5-HT occurred as the main long-term change that the decrease of its metabolism partly contributed to. Besides, the variations of 5-HT1AR and 5-HT2CR expressions were also indicated. The results suggested that in the long-term way, chronic microwave exposure could induce cognitive deficit and 5-HT system may be involved in it.

  17. Exposure to a PBDE/OH-BDE mixture alters juvenile zebrafish (Danio rerio) development.

    PubMed

    Macaulay, Laura J; Chernick, Melissa; Chen, Albert; Hinton, David E; Bailey, Jordan M; Kullman, Seth W; Levin, Edward D; Stapleton, Heather M

    2017-01-01

    Polybrominated diphenyl ethers (PBDEs) and their metabolites (e.g., hydroxylated BDEs [OH-BDEs]) are contaminants frequently detected together in human tissues and are structurally similar to thyroid hormones. Thyroid hormones partially mediate metamorphic transitions between life stages in zebrafish, making this a critical developmental window that may be vulnerable to chemicals disrupting thyroid signaling. In the present study, zebrafish were exposed to 6-OH-BDE-47 (30 nM; 15 μg/L) alone, or to a low-dose (30 μg/L) or high-dose (600 μg/L) mixture of PentaBDEs, 6-OH-BDE-47 (0.5-6 μg/L), and 2,4,6-tribromophenol (5-100 μg/L) during juvenile development (9-23 d postfertilization) and evaluated for developmental endpoints mediated by thyroid hormone signaling. Fish were sampled at 3 time points and examined for developmental and skeletal morphology, apical thyroid and skeletal gene markers, and modifications in swimming behavior (as adults). Exposure to the high-dose mixture resulted in >85% mortality within 1 wk of exposure, despite being below reported acute toxicity thresholds for individual congeners. The low-dose mixture and 6-OH-BDE-47 groups exhibited reductions in body length and delayed maturation, specifically relating to swim bladder, fin, and pigmentation development. Reduced skeletal ossification was also observed in 6-OH-BDE-47-treated fish. Assessment of thyroid and osteochondral gene regulatory networks demonstrated significantly increased expression of genes that regulate skeletal development and thyroid hormones. Overall, these results indicate that exposures to PBDE/OH-BDE mixtures adversely impact zebrafish maturation during metamorphosis. Environ Toxicol Chem 2017;36:36-48. © 2016 SETAC.

  18. Neurochemical alterations in lemon shark (Negaprion brevirostris) brains in association with brevetoxin exposure.

    PubMed

    Nam, Dong-Ha; Adams, Douglas H; Flewelling, Leanne J; Basu, Niladri

    2010-09-01

    Brevetoxins are persistent, bioaccumulative, lipophilic polyether neurotoxins synthesized by Karenia brevis, a harmful algal bloom (HAB) dinoflagellate. Although some marine organisms accumulate potentially harmful levels of brevetoxins, little is known about neurotoxic effects in wild populations. Here, tissue (i.e., liver, kidney, muscle, intestine, gill, brain) brevetoxin levels (as ng PbTx-3 eq/g) and four neurochemical biomarkers (monoamine oxidase, MAO; cholinesterase, ChE; muscarinic cholinergic receptor, mAChR; N-methyl-d-aspartic acid receptor, NMDAR) were compared between eleven lemon sharks collected during a K. brevis bloom and eighteen lemon sharks not exposed to a bloom (controls) in a case-control manner. Brevetoxin levels in tissues were significantly higher in HAB-exposed sharks when compared to controls, and tissue levels (e.g., 277-3112 ng/g in livers, 429-2833 ng/g in gills) in HAB-exposed sharks were comparable to levels detected in a shark (e.g., 1223 ng/g in liver, 930 ng/g in gill) that died presumably of toxin exposure. Further, there were significant correlations between brain brevetoxin levels and ChE activity (r=-0.41; p<0.05), MAO activity (r=-0.37; p<0.05), mAChR levels (r=0.55; p<0.01), and NMDAR levels (r=-0.49; p<0.01). There were no relationships between neurochemical biomarkers and metals (total mercury, methylmercury, selenium). Overall, these results in tissues from free-ranging lemon sharks indicate that ecologically relevant exposures to brevetoxins may cause significant changes in brain neurochemistry. As disruptions to neurochemistry precede structural and functional damage to the nervous system, these results suggest that relevant exposures to HABs may be causing sub-clinical effects in lemon sharks and raise further questions about the ecological and physiological impacts of HABs on marine biota.

  19. Postnatal development of rat pups is altered by prenatal methamphetamine exposure.

    PubMed

    Slamberová, Romana; Pometlová, Marie; Charousová, Petra

    2006-01-01

    There are studies showing that drug abuse during pregnancy may have impairing effect on progeny of drug-abusing mothers. Methamphetamine (MA) is one of the most common illicit drugs throughout the world. The purpose of the present study was to assess the effect of prenatal MA exposure on postnatal development of rat pups before the time of separation from their mothers. Female rats were injected with MA (5 mg/kg daily) for the duration of their pregnancy. Pups were then tested throughout the lactation period. They were weighed daily and the ano-genital distance was measured on postnatal day (PD) 1. Development of postural motor reaction was tested by righting reflex on surface between PD 1 and 12, and righting reflex in mid-air after PD 12 until successfully accomplished. On PD 15 homing test was examined as a test of pup acute learning. On PD 23 sensory-motor coordination was examined using the rotarod and bar-holding tests. Additionally, the markers of physical maturation, such as eye opening, testes descent in males and vaginal opening in females were also recorded. The birth weight in prenatally MA-exposed pups was lower than in controls or saline-exposed pups regardless of sex. There were no changes induced by prenatal MA exposure in weight gain or in sexual maturation. In righting reflexes, we demonstrated that pups exposed prenatally to MA were slower in righting reflex on surface and that they accomplished the test of righting reflex in mid-air later than controls or saline-exposed pups. The performance of homing test was not affected by prenatal drug exposure. The sensory-motor coordination was impaired in prenatally MA-exposed pups when testing in the rotarod test. Also, the number of falls in the bar-holding test was higher in MA-exposed pups than in controls. There were no sex differences in any measures. Thus, the present study demonstrated that prenatal MA exposure impairs development of postural motor movements of rat pups during the first 3 weeks

  20. Metabolic and feeding behavior alterations provoked by prenatal exposure to aspartame.

    PubMed

    von Poser Toigo, E; Huffell, A P; Mota, C S; Bertolini, D; Pettenuzzo, L F; Dalmaz, C

    2015-04-01

    The use of artificial sweeteners has increased together with the epidemic growth of obesity. In addition to their widespread use in sodas, artificial sweeteners are added to nearly 6000 other products sold in the US, including baby foods, frozen dinners and even yogurts. It has been suggested that the use of nonnutritive sweeteners can lead to body weight gain and an altered metabolic profile. However, very few studies have evaluated the effects of maternal consumption of artificial non-caloric sweeteners on body weight, feeding behavior or the metabolism of offspring in adult life. In this study, we found that animals exposed to aspartame during the prenatal period presented a higher consumption of sweet foods during adulthood and a greater susceptibility to alterations in metabolic parameters, such as increased glucose, LDL and triglycerides. These effects were observed in both males and females, although they were more pronounced in males. Despite the preliminary nature of this study, and the need for further confirmation of these effects, our data suggest that the consumption of sweeteners during gestation may have deleterious long-term effects and should be used with caution.

  1. Phosphatidylserine is polarized and required for proper Cdc42 localization and for development of cell polarity.

    PubMed

    Fairn, Gregory D; Hermansson, Martin; Somerharju, Pentti; Grinstein, Sergio

    2011-10-02

    Polarity is key to the function of eukaryotic cells. On the establishment of a polarity axis, cells can vectorially target secretion, generating an asymmetric distribution of plasma membrane proteins. From Saccharomyces cerevisiae to mammals, the small GTPase Cdc42 is a pivotal regulator of polarity. We used a fluorescent probe to visualize the distribution of phosphatidylserine in live S. cerevisiae. Remarkably, phosphatidylserine was polarized in the plasma membrane, accumulating in bud necks, the bud cortex and the tips of mating projections. Polarization required vectorial delivery of phosphatidylserine-containing secretory vesicles, and phosphatidylserine was largely excluded from endocytic vesicles, contributing to its polarized retention. Mutants lacking phosphatidylserine synthase had impaired polarization of the Cdc42 complex, leading to a delay in bud emergence, and defective mating. The addition of lysophosphatidylserine resulted in resynthesis and polarization of phosphatidylserine, as well as repolarization of Cdc42. The results indicate that phosphatidylserine--and presumably its polarization--are required for optimal Cdc42 targeting and activation during cell division and mating.

  2. Effect of Ion Binding in Palmitoyl-Oleoyl Phosphatidylserine Monolayers

    NASA Astrophysics Data System (ADS)

    Eckler, Matthew; Matysiak, Silvina

    2013-03-01

    Molecular dynamics simulations of palmitoyl-oleoyl phosphatidylserine (POPS) monolayers at the air-water interface were performed with different ionic strengths with the aim of determining the specific organization and dynamics of counterion binding events. Na + ions penetrated the monolayers into both the ester carbonyl and carboxylate regions of the phospholipids. The binding events increase with the addition of salt. Differences in lipid order parameter, headgroup orientation, and prevalence of inter- and intramolecular hydrogen bonding events between the amine group of the lipid and oxygen groups are observed depending on whether the Na + is binding near the carboxylate or ester region of the lipid. The observed changes are explained in terms of the salting-out effect.

  3. Can phosphatidylserine enhance atheroprotective activities of high-density lipoprotein?

    PubMed

    Darabi, Maryam; Kontush, Anatol

    2016-01-01

    Although high-density lipoprotein (HDL) is well known to be protective against atherosclerotic cardiovascular disease, therapeutic interventions to raise HDL-cholesterol levels do not translate into reduction in cardiovascular risk. Due to the compositional complexity of HDL particles, molecular determinants of their atheroprotective function still remain to be clarified. Recent structural and functional data identify phospholipid as a major bioactive component of HDL. Such a role has recently been specifically evidenced for phosphatidylserine (PS); indeed, HDL content of PS displayed positive correlations with all metrics of HDL functionality assessed. This review summarizes current knowledge about HDL-associated PS; possible mechanisms for its atheroprotective role are discussed and potential applications of PS to HDL-based therapies are highlighted.

  4. Short-duration exposure to radiofrequency electromagnetic radiation alters the chlorophyll fluorescence of duckweeds (Lemna minor).

    PubMed

    Senavirathna, Mudalige Don Hiranya Jayasanka; Takashi, Asaeda; Kimura, Yuichi

    2014-12-01

    Plants growing in natural environments are exposed to radiofrequency electromagnetic radiation (EMR) emitted by various communication network base stations. The environmental concentration of this radiation is increasing rapidly with the congested deployment of base stations. Although numerous scientific studies have been conducted to investigate the effects of EMR on the physiology of humans and animals, there have been few attempts to investigate the effects of EMR on plants. In this study, we attempted to evaluate the effects of EMR on photosynthesis by investigating the chlorophyll fluorescence (ChF) parameters of duckweed fronds. During the experiment, the fronds were tested with 2, 2.5, 3.5, 5.5 and 8 GHz EMR frequencies, which are not widely studied even though there is a potentially large concentration of these frequencies in the environment. The duckweed fronds were exposed to EMR for 30 min, 1 h and 24 h durations with electric field strength of 45-50 V/m for each frequency. The results indicated that exposure to EMR causes a change in the non-photochemical quenching of the duckweeds. The changes varied with the frequency of the EMR and were time-varying within a particular frequency. The temperature remained unchanged in the duckweed fronds upon exposure to EMR, which confirms that the effect is non-thermal.

  5. Maternal isobutyl-paraben exposure alters anxiety and passive avoidance test performance in adult male rats.

    PubMed

    Kawaguchi, Maiko; Irie, Kaoru; Morohoshi, Kaori; Watanabe, Gen; Taya, Kazuyoshi; Morita, Masatoshi; Kondo, Yasuhiko; Imai, Hideki; Himi, Toshiyuki

    2009-10-01

    Isobutyl-paraben (IBP), one of the most widely used preservatives, exhibits estrogenic activity. In this study, we analyzed the effects of maternal IBP treatment on the emotional behavior and learning performance in mature offspring. Pregnant female Sprague-Dawley rats were treated with IBP via a subcutaneous Silastic capsule. Consequently, the offspring were exposed to IBP during gestation through the placentae, and before weaning through the milk. Male and female offspring were tested for emotional behavior in an open field and in an elevated plus maze at five and six weeks old, respectively. IBP-exposed male (but not female) rats spent less time in the open arms of the elevated plus maze. At 11 weeks old, all females were gonadectomized and treated chronically with 17beta-estradiol or cholesterol by Silastic capsules; all males were kept intact. They were tested for learning performance in a passive avoidance test and a Morris water maze. IBP exposure impaired the performance of males in the passive avoidance test. These findings suggest that male rats are more affected by early exposure to IBP than female rats. IBP affects their adult behavior including anxiety and learning abilities.

  6. Alteration of oxygen consumption and energy metabolism during repetitive exposure of mice to hypoxia.

    PubMed

    Lu, G W; Cui, X Y; Zhao, B M

    1999-05-01

    Changes in oxygen consumption, body temperature and energy metabolism were studied while mice were repeatedly exposed to a sealed environment. The average tolerance limits of environmental oxygen level (vol%) and the average oxygen consumption rates (ml/g x min) were exponentially decreased and the average body rectal temperatures (degrees C) were linearly declined while the average tolerable times (min) to hypoxia were linearly increased as animals were repeatedly exposed to hypoxia for 5 runs. The average survival times (min) in sealed environments after administration of normal saline, iodoacetic acid, malonic acid, potassium cyanide, and potassium cyanide plus iodoacetic acid in group exposed repeatedly to hypoxia for three runs were, respectively, 3.1, 3.9, 1.4, 2.6, and 2.8 times those of the control groups that had corresponding administration of the different chemicals, but no exposure to hypoxia. The results indicate that progressive increase in hypoxia tolerance is related to progressively lower rate of oxygen consumption and heat production, and the lowered energy requirement during repetitive exposure to hypoxia is achieved mainly via pathways of the respiratory chain and glycolysis.

  7. Altered localization of choline transporter sites in the mouse hippocampus after prenatal heroin exposure.

    PubMed

    Vatury, Ori; Barg, Jacob; Slotkin, Theodore A; Yanai, Joseph

    2004-03-01

    Prenatal heroin exposure disrupts hippocampal cholinergic synaptic function and related behaviors. Biochemical studies indicate an increase in the number of presynaptic high-affinity choline transporter (HACT) sites, as assessed by [3H]hemicholinium-3 (HC-3) binding. The present study was designed to assess whether this effect involves global upregulation of the transporter, or whether disruption occurs with a specific tempero-spatial distribution. Pregnant mice were given 10mg/kg per day of heroin subcutaneously on gestational days (GD) 9-18. Autoradiographic distribution of HC-3 binding sites was evaluated in the hippocampus of the offspring at postnatal days 15, 25, and 53. These results, suggestive of hippocampal "miswiring," are likely to explain the net impairment of cholinergic synaptic function after prenatal heroin exposure, despite the simultaneous upregulation of both presynaptic cholinergic activity and postsynaptic receptors. Understanding the subregional selectivity of hippocampal defects can lead to the development of strategies that may potentially enable therapeutic interventions to offset or reverse the neurobehavioral defects.

  8. Exposure of salivary gland cells to low-frequency electromagnetic fields alters polypeptide synthesis.

    PubMed Central

    Goodman, R; Henderson, A S

    1988-01-01

    This study demonstrates that exposure of cells to extremely low-frequency electromagnetic fields can cause measurable changes in protein synthesis. Sciara coprophila salivary gland cells were exposed to five low-frequency (1.5-72 Hz) electromagnetic signals: three signals (1.5, 15, and 72 Hz) produced pulsed asymmetric electromagnetic fields and two signals (60 and 72 Hz) were sinusoidal. Subsequent analyses of two-dimensional gels showed that cell exposure to either type of low-frequency electromagnetic field resulted in both qualitative and quantitative changes in patterns of protein synthesis. Thus, signals producing diverse waveform characteristics induced previously undetectable polypeptides, some of which were signal specific and augmented or suppressed other polypeptides as compared with nonexposed cells. The pattern of polypeptide synthesis differed from that seen with heat shock: only five polypeptides in cells exposed to electromagnetic signals overlap those polypeptides exposed to heat shock, and the suppression of protein synthesis characteristic of heat shock does not occur. Images PMID:3375247

  9. Long-term cognitive, emotional and neurogenic alterations induced by alcohol and methamphetamine exposure in adolescent rats.

    PubMed

    Loxton, David; Canales, Juan J

    2017-03-06

    A high proportion of young methamphetamine (MA) users simultaneously consume alcohol. However, the potential neurological and behavioural alterations induced by such a drug combination have not been systematically examined. We studied in adolescent rats the long-term effects of alcohol, MA, and alcohol and MA combined on anxiety-like behaviour, memory, and neurogenesis in the adult hippocampus. Rats received saline, ethanol (ETOH, 1.5g/kg), MA (MA, 2mg/kg), or ethanol and MA combined (ETHOH-MA, 1.5g/kg ethanol plus 2mg/kg MA) via oral gavage, once daily for 5 consecutive days. Open field (OF), elevated plus maze (EPM) and radial arm maze (RAM) tests were conducted following a 15-day withdrawal period. The results showed alterations in exploratory behaviour in the OF in the MA and ETOH-MA groups, and anxiety-like effects in the EPM in all three drug treatment groups. All three drug groups exhibited reference memory deficits in the RAM, but only the combination treatment group displayed alterations in working memory. Both MA and ETOH-MA treatments increased the length of doublecortin (DCX)-void gaps in the dentate gyrus but only ETOH-MA treatment increased the number of such gaps. An increased number and length of DCX-void gaps correlated with decreased exploratory activity in the OF, and impaired working memory in the RAM was associated with an augmented number of gaps. These findings suggest that alterations in adult hippocampal neurogenesis are linked to the persistent cognitive and behavioural deficits produced by alcohol and MA exposure.

  10. Efficient thrombin generation requires molecular phosphatidylserine, not a membrane surface.

    PubMed

    Majumder, Rinku; Weinreb, Gabriel; Lentz, Barry R

    2005-12-27

    Activation of prothrombin to thrombin is catalyzed by a "prothrombinase" complex, traditionally viewed as factor X(a) (FX(a)) in complex with factor V(a) (FV(a)) on a phosphatidylserine (PS)-containing membrane surface, which is widely regarded as required for efficient activation. Activation involves cleavage of two peptide bonds and proceeds via one of two released intermediates or through "channeling" (activation without the release of an intermediate). We ask here whether the PS molecule itself and not the membrane surface is sufficient to produce the fully active human "prothrombinase" complex in solution. Both FX(a) and FV(a) bind soluble dicaproyl-phosphatidylserine (C6PS). In the presence of sufficient C6PS to saturate both FX(a) and FV(a2) (light isoform of FV(a)), these proteins form a tight (Kd = 0.6 +/- 0.09 nM at 37 degrees C) soluble complex. Complex assembly occurs well below the critical micelle concentration of C6PS, as established in the presence of the proteins by quasi-elastic light scattering and pyrene fluorescence. Ferguson analysis of native gels shows that the complex migrates with an apparent molecular mass only slightly larger than that expected for one FX(a) and one FV(a2), further ruling out complex assembly on C6PS micelles. Human prothrombin activation by this complex occurs at nearly the same overall rate (2.2 x 10(8) M(-1) s(-1)) and via the same reaction pathway (50-60% channeling, with the rest via the meizothrombin intermediate) as the activation catalyzed by a complex assembled on PS-containing membranes (4.4 x 10(8) M(-1) s(-1)). These results question the accepted role of PS membranes as providing "dimensionality reduction" and favor a regulatory role for platelet-membrane-exposed PS.

  11. Phosphatidylserine biosynthesis in cultured Chinese hamster ovary cells. III. Genetic evidence for utilization of phosphatidylcholine and phosphatidylethanolamine as precursors

    SciTech Connect

    Kuge, O.; Nishijima, M.; Akamatsu, Y.

    1986-05-05

    We reported that Chinese hamster ovary (CHO) cells contain two different serine-exchange enzymes (I and II) which catalyze the base-exchange reaction of phospholipid(s) with serine and that a phosphatidylserine-requiring mutant (strain PSA-3) of CHO cells is defective in serine-exchange enzyme I and lacks the ability to synthesize phosphatidylserine. In this study, we examined precursor phospholipids for phosphatidylserine biosynthesis in CHO cells. When mutant PSA-3 and parent (CHO-K1) cells were cultured with (/sup 32/P)phosphatidylcholine, phosphatidylserine in the parent accumulated radioactivity while that in the mutant was not labeled significantly. On the contrary, when cultured with (/sup 32/P)phosphatidylethanolamine, the mutant incorporated the label into phosphatidylserine more efficiently than the parent. Furthermore, we found that mutant PSA-3 grew normally in growth medium supplemented with 30 microM phosphatidylethanolamine as well as phosphatidylserine and that the biosynthesis of phosphatidylserine in the mutant was normal when cells were cultured in the presence of exogenous phosphatidylethanolamine. The simplest interpretation of these findings is that phosphatidylserine in CHO cells is biosynthesized through the following sequential reactions: phosphatidylcholine----phosphatidylserine----phosphatidylethanolamine--- - phosphatidylserine. The three reactions are catalyzed by serine-exchange enzyme I, phosphatidylserine decarboxylase, and serine-exchange enzyme II, respectively.

  12. SILAC-based quantitative proteomic analysis reveals widespread molecular alterations in human skin keratinocytes upon chronic arsenic exposure.

    PubMed

    Mir, Sartaj Ahmad; Pinto, Sneha M; Paul, Somnath; Raja, Remya; Nanjappa, Vishalakshi; Syed, Nazia; Advani, Jayshree; Renuse, Santosh; Sahasrabuddhe, Nandini A; Prasad, T S Keshava; Giri, Ashok K; Gowda, Harsha; Chatterjee, Aditi

    2017-03-01

    Chronic exposure to arsenic is associated with dermatological and nondermatological disorders. Consumption of arsenic-contaminated drinking water results in accumulation of arsenic in liver, spleen, kidneys, lungs, and gastrointestinal tract. Although arsenic is cleared from these sites, a substantial amount of residual arsenic is left in keratin-rich tissues including skin. Epidemiological studies suggest the association of skin cancer upon arsenic exposure, however, the mechanism of arsenic-induced carcinogenesis is not completely understood. We developed a cell line based model to understand the molecular mechanisms involved in arsenic-mediated toxicity and carcinogenicity. Human skin keratinocyte cell line, HaCaT, was chronically exposed to 100 nM sodium arsenite over a period of 6 months. We observed an increase in basal ROS levels in arsenic-exposed cells. SILAC-based quantitative proteomics approach resulted in identification of 2111 proteins of which 42 proteins were found to be overexpressed and 54 downregulated (twofold) upon chronic arsenic exposure. Our analysis revealed arsenic-induced overexpression of aldo-keto reductase family 1 member C2 (AKR1C2), aldo-keto reductase family 1 member C3 (AKR1C3), glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H dehydrogenase [quinone] 1 (NQO1) among others. We observed downregulation of several members of the plakin family including periplakin (PPL), envoplakin (EVPL), and involucrin (IVL) that are essential for terminal differentiation of keratinocytes. MRM and Western blot analysis confirmed differential expression of several candidate proteins. Our study provides insights into molecular alterations upon chronic arsenic exposure on skin.

  13. Adolescent Δ(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats.

    PubMed

    Scherma, Maria; Dessì, Christian; Muntoni, Anna Lisa; Lecca, Salvatore; Satta, Valentina; Luchicchi, Antonio; Pistis, Marco; Panlilio, Leigh V; Fattore, Liana; Goldberg, Steven R; Fratta, Walter; Fadda, Paola

    2016-04-01

    Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Δ(9)-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45-55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self-administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings-that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood-suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans.

  14. Sublethal exposure to azamethiphos causes neurotoxicity, altered energy allocation and high mortality during simulated live transport in American lobster.

    PubMed

    Couillard, C M; Burridge, L E

    2015-05-01

    In the Bay of Fundy, New Brunswick, sea lice outbreaks in caged salmon are treated with pesticides including Salmosan(®), applied as bath treatments and then released into the surrounding seawater. The effect of chronic exposure to low concentrations of this pesticide on neighboring lobster populations is a concern. Adult male lobsters were exposed to 61 ngL(-1) of azamethiphos (a.i. in Salmosan(®) formulation) continuously for 10 days. In addition to the direct effects of pesticide exposure, effects on the ability to cope with shipping conditions and the persistence of the effects after a 24h depuration period in clean seawater were assessed. Indicators of stress and hypoxia (serum total proteins, hemocyanin and lactate), oxidative damage (protein carbonyls in gills and serum) and altered energy allocation (hepatosomatic and gonadosomatic indices, hepatopancreas lipids) were assessed in addition to neurotoxicity (chlolinesterase activity in muscle). Directly after exposure, azamethiphos-treated lobsters had inhibition of muscle cholinesterase, reduced gonadosomatic index and enhanced hepatosomatic index and hepatopancreas lipid content. All these responses persisted after 24-h depuration, increasing the risk of cumulative impacts with further exposure to chemical or non-chemical stressors. In both control and treated lobsters exposed to simulated shipment conditions, concentrations of protein and lactate in serum, and protein carbonyls in gills increased. However, mortality rate was higher in azamethiphos-treated lobsters (33 ± 14%) than in controls (2.6 ± 4%). Shipment and azamethiphos had cumulative impacts on serum proteins. Both direct effects on neurological function and energy allocation and indirect effect on ability to cope with shipping stress could have significant impacts on lobster population and/or fisheries.

  15. Hepatic and intestine alterations in mice after prolonged exposure to low oral doses of Microcystin-LR.

    PubMed

    Sedan, Daniela; Laguens, Martín; Copparoni, Guido; Aranda, Jorge Oswaldo; Giannuzzi, Leda; Marra, Carlos Alberto; Andrinolo, Darío

    2015-09-15

    Oral intake of Microcystin-LR (MC-LR) is the principal route of exposure to this toxin, with prolonged exposure leading to liver damage of unspecific symptomatology. The aim of the present paper was therefore to investigate the liver and intestine damage generated by prolonged oral exposure to low MC-LR doses (50 and 100 μg MC-LR/kg body weight, administrated every 48 h during a month) in a murine model. We found alterations in TBARS, SOD activity and glutathione content in liver and intestine of mice exposed to both doses of MC-LR. Furthermore, the presence of MC-LR was detected in both organs. We also found hepatic steatosis (3.6 ± 0.6% and 15.3 ± 1.6%) and a decrease in intraepithelial lymphocytes (28.7 ± 5.0% and 44.2 ± 8.7%) in intestine of 50- and 100-μg MC-LR/kg treated animals, respectively. This result could have important implications for mucosal immunity, since intraepithelial lymphocytes are the principal effectors of this system. Our results indicate that prolonged oral exposure at 50 μg MC-LR/kg every 48 h generates significant damage not only in liver but also in intestine. This finding calls for a re-appraisal of the currently accepted NOAEL (No Observed Adverse Effect Level), 40 μg MC-LR/kg body weight, used to derive the guideline value for MC-LR in drinking water.

  16. Atrazine-induced reproductive tract alterations after transplacental and/or lactational exposure in male Long-Evans rats

    SciTech Connect

    Rayner, Jennifer L.; Enoch, Rolondo R.; Wolf, Douglas C.; Fenton, Suzanne E. . E-mail: fenton.suzanne@epa.gov

    2007-02-01

    Studies showed that early postnatal exposure to the herbicide atrazine (ATR) delayed preputial separation (PPS) and increased incidence of prostate inflammation in adult Wistar rats. A cross-fostering paradigm was used in this study to determine if gestational exposure to ATR would also result in altered puberty and reproductive tissue effects in the male rat. Timed-pregnant Long-Evans (LE) rats were dosed by gavage on gestational days (GD) 15-19 with 100 mg ATR/kg body weight (BW) or 1% methylcellulose (controls, C). On postnatal day (PND)1, half litters were cross-fostered, creating 4 treatment groups; C-C, ATR-C, C-ATR, and ATR-ATR (transplacental-milk as source, respectively). On PND4, male offspring in the ATR-ATR group weighed significantly less than the C-C males. ATR-ATR male pups had significantly delayed preputial separation (PPS). BWs at PPS for C-ATR and ATR-ATR males were reduced by 6% and 9%, respectively, from that of C-C. On PND120, lateral prostate weights of males in the ATR-ATR group were significantly increased over C-C. Histological examination of lateral and ventral prostates identified an increased distribution of inflammation in the lateral prostates of C-ATR males. By PND220, lateral prostate weights were significantly increased for ATR-C and ATR-ATR, but there were no significant changes in inflammation in either the lateral or ventral prostate. These results suggest that in LE rats, gestational ATR exposure delays PPS when male offspring suckle an ATR dam, but leads to increased lateral prostate weight via transplacental exposure alone. Inflammation present at PND120 does not increase in severity with time.

  17. Exposure to (12)C particles alters the normal dynamics of brain monoamine metabolism and behaviour in rats.

    PubMed

    Belov, Oleg V; Belokopytova, Ksenia V; Bazyan, Ara S; Kudrin, Vladimir S; Narkevich, Viktor B; Ivanov, Aleksandr A; Severiukhin, Yury S; Timoshenko, Gennady N; Krasavin, Eugene A

    2016-09-01

    Planning of the deep-space exploration missions raises a number of questions on the radiation protection of astronauts. One of the medical concerns is associated with exposure of a crew to highly energetic particles of galactic cosmic rays. Among many other health disorders, irradiation with these particles has a substantial impact on the central nervous system (CNS). Although radiation damage to CNS has been addressed extensively during the last years, the mechanisms underlying observed impairments remain mostly unknown. The present study reveals neurochemical and behavioural alterations induced in rats by 1Gy of 500MeV/u (12)C particles with a relatively moderate linear energy transfer (10.6keV/μm). It is found that exposure to carbon ions leads to significant modification of the normal monoamine metabolism dynamics as well as the locomotor, exploratory, and anxiety-like behaviours during a two-month period. The obtained results indicate an abnormal redistribution of monoamines and their metabolites in different brain regions after exposure. The most pronounced impairments are detected in the prefrontal cortex, nucleus accumbens, and hypothalamus that illustrate the sensitivity of these brain regions to densely ionizing radiations. It is also shown that exposure to (12)C particles enhances the anxiety in animals and accelerates the age-related reduction in their exploratory capability. The observed monoamine metabolism pattern may indicate the presence of certain compensatory mechanisms being induced in response to irradiation and capable of partial restoration of monoaminergic systems' functions. Overall, these findings support a possibility of CNS damage by space-born particles of a relatively moderate linear energy transfer.

  18. Acute fluoxetine exposure alters crab anxiety-like behaviour, but not aggressiveness

    PubMed Central

    Hamilton, Trevor James; Kwan, Garfield T.; Gallup, Joshua; Tresguerres, Martin

    2016-01-01

    Aggression and responsiveness to noxious stimuli are adaptable traits that are ubiquitous throughout the animal kingdom. Like vertebrate animals, some invertebrates have been shown to exhibit anxiety-like behaviour and altered levels of aggression that are modulated by the neurotransmitter serotonin. To investigate whether this influence of serotonin is conserved in crabs and whether these behaviours are sensitive to human antidepressant drugs; the striped shore crab, Pachygrapsus crassipes, was studied using anxiety (light/dark test) and aggression (mirror test) paradigms. Crabs were individually exposed to acute doses of the selective serotonin reuptake inhibitor, fluoxetine (5 or 25 mg/L), commonly known as Prozac®, followed by behavioural testing. The high dose of fluoxetine significantly decreased anxiety-like behaviour but had no impact on mobility or aggression. These results suggest that anxiety-like behaviour is more sensitive to modulation of serotonin than is aggressiveness in the shore crab. PMID:26806870

  19. Acute fluoxetine exposure alters crab anxiety-like behaviour, but not aggressiveness.

    PubMed

    Hamilton, Trevor James; Kwan, Garfield T; Gallup, Joshua; Tresguerres, Martin

    2016-01-25

    Aggression and responsiveness to noxious stimuli are adaptable traits that are ubiquitous throughout the animal kingdom. Like vertebrate animals, some invertebrates have been shown to exhibit anxiety-like behaviour and altered levels of aggression that are modulated by the neurotransmitter serotonin. To investigate whether this influence of serotonin is conserved in crabs and whether these behaviours are sensitive to human antidepressant drugs; the striped shore crab, Pachygrapsus crassipes, was studied using anxiety (light/dark test) and aggression (mirror test) paradigms. Crabs were individually exposed to acute doses of the selective serotonin reuptake inhibitor, fluoxetine (5 or 25 mg/L), commonly known as Prozac®, followed by behavioural testing. The high dose of fluoxetine significantly decreased anxiety-like behaviour but had no impact on mobility or aggression. These results suggest that anxiety-like behaviour is more sensitive to modulation of serotonin than is aggressiveness in the shore crab.

  20. Gene expression and pathologic alterations in juvenile rainbow trout due to chronic dietary TCDD exposure.

    PubMed

    Liu, Qing; Rise, Matthew L; Spitsbergen, Jan M; Hori, Tiago S; Mieritz, Mark; Geis, Steven; McGraw, Joseph E; Goetz, Giles; Larson, Jeremy; Hutz, Reinhold J; Carvan, Michael J

    2013-09-15

    The goal of this project was to use functional genomic methods to identify molecular biomarkers as indicators of the impact of TCDD exposure in rainbow trout. Specifically, we investigated the effects of chronic dietary TCDD exposure on whole juvenile rainbow trout global gene expression associated with histopathological analysis. Juvenile rainbow trout were fed Biodiet starter with TCDD added at 0, 0.1, 1, 10 and 100 ppb (ngTCDD/g food), and fish were sampled from each group at 7, 14, 28 and 42 days after initiation of feeding. 100 ppb TCDD caused 100% mortality at 39 days. Fish fed with 100 ppb TCDD food had TCDD accumulation of 47.37 ppb (ngTCDD/g fish) in whole fish at 28 days. Histological analysis from TCDD-treated trout sampled from 28 and 42 days revealed that obvious lesions were found in skin, oropharynx, liver, gas bladder, intestine, pancreas, nose and kidney. In addition, TCDD caused anemia in peripheral blood, decreases in abdominal fat, increases of remodeling of fin rays, edema in pericardium and retrobulbar hemorrhage in the 100 ppb TCDD-treated rainbow trout compared to the control group at 28 days. Dose- and time-dependent global gene expression analyses were performed using the cGRASP 16,000 (16K) cDNA microarray. TCDD-responsive whole body transcripts identified in the microarray experiments have putative functions involved in various biological processes including growth, cell proliferation, metabolic process, and immune system processes. Nine microarray-identified genes were selected for QPCR validation. CYP1A3 and CYP1A1 were common up-regulated genes and HBB1 was a common down-regulated gene among each group based on microarray data, and their QPCR validations are consistent with microarray data for the 10 and 100 ppb TCDD treatment groups after 28 days exposure (p<0.05). In addition, in the 100 ppb group at 28 days, expression of complement component C3-1 and trypsin-1 precursor have a more than 10-fold induction from the microarray

  1. Exposure and Figure Out of Climate Induced Alterations in the Wetlands of Banglades

    NASA Astrophysics Data System (ADS)

    Siddiquee, S. A.; Rahman, M. Z.

    2015-12-01

    Unique geographic location and geo-morphological conditions of Bangladesh have made the wetlands of this country one of the most vulnerable to climate change. Wetland plays a crucial role in maintaining the ecological balance of ecosystems and cultural figures and which occupy around 50% of the area. Drought, excessive temperature, mountain snowfields and glaciers melting, riverbank erosion, salinity intrusion, flashflood, storm surges, higher water temperatures, precipitation anomalies, coastal cyclones, seasonal anomalies and extremes are main threats to the wetland ecosystem. Enhanced UV-B radiation and increased summer precipitation will significantly increase dissolved organic carbon concentrations altering major biogeochemical cycles and also will result into the expansion of range for many invasive aquatic weeds. Generally, rising temperature will lower water quality through a fall in oxygen concentrations, release of phosphorus from sediments, increased thermal stability, and altered mixing patterns. As a result biodiversity is getting degraded, many species of flora and fauna are getting threatened, and wetland-based ecosystem is getting degenerated. At the same time, the living conditions of local people are deteriorating as livelihoods, socioeconomic institutions, and extensive cultural values as well. For conserving and managing wetlands technology, legislation, educational knowledge, action plan strategy and restoration practices are required. In order to address the human needs in the changing climate community-based adaptation approaches and wetland restoration, practices had been taken in almost every type of wetlands in Bangladesh. Therefore, Bangladesh now needs a comprehensive strategy and integrated system combining political, economic, social, technological approaches and institutional supports to address sustainable wetland restoration, conservation and the newly added crisis, climate change.

  2. Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects?

    PubMed

    Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu; Peterson, Lindsy M; Mai, Katherine; McHale, Quinn; Jenkins, Michael W; Linask, Kersti K; Rollins, Andrew M; Watanabe, Michiko

    2014-02-01

    Alcohol-induced congenital heart defects are frequently among the most life threatening and require surgical correction in newborns. The etiology of these defects, collectively known as fetal alcohol syndrome, has been the focus of much study, particularly involving cellular and molecular mechanisms. Few studies have addressed the influential role of altered cardiac function in early embryogenesis because of a lack of tools with the capability to assay tiny beating hearts. To overcome this gap in our understanding, we used optical coherence tomography (OCT), a nondestructive imaging modality capable of micrometer-scale resolution imaging, to rapidly and accurately map cardiovascular structure and hemodynamics in real time under physiological conditions. In this study, we exposed avian embryos to a single dose of alcohol/ethanol at gastrulation when the embryo is sensitive to the induction of birth defects. Late-stage hearts were analyzed using standard histological analysis with a focus on the atrio-ventricular valves. Early cardiac function was assayed using Doppler OCT, and structural analysis of the cardiac cushions was performed using OCT imaging. Our results indicated that ethanol-exposed embryos developed late-stage valvuloseptal defects. At early stages, they exhibited increased regurgitant flow and developed smaller atrio-ventricular cardiac cushions, compared with controls (uninjected and saline-injected embryos). The embryos also exhibited abnormal flexion/torsion of the body. Our evidence suggests that ethanol-induced alterations in early cardiac function have the potential to contribute to late-stage valve and septal defects, thus demonstrating that functional parameters may serve as early and sensitive gauges of cardiac normalcy and abnormalities.

  3. Identification of the Atlantic cod L-amino acid oxidase and its alterations following bacterial exposure.

    PubMed

    Kitani, Yoichiro; Fernandes, Jorge M O; Kiron, Viswanath

    2015-06-01

    Antibacterial factors that are present in epidermal mucus of fish have a potential role in the first line of host defence to bacterial pathogens. This study reports the identification of L-amino acid oxidase (LAO) in Atlantic cod (GmLao) and the changes in the molecule following bacterial exposure. The gmlao transcripts and LAO activity were present on both the body surface and in the internal organs of the fish. Relative mRNA level of gmlao increased significantly in the gills, the spleen and the head kidney (up to 8-fold) of fish that were challenged with the pathogen Vibrio anguillarum. The gmlao expression in skin was 4-fold higher in challenged fish. Our data indicate that LAO may be an important effector of antibacterial defence in Atlantic cod.

  4. Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function

    PubMed Central

    Chen, Yichang; Qiu, Zhiqun; Lee, Dong Yeon; Telesca, Donatello; Yang, Xia; Allard, Patrick

    2016-01-01

    Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures. PMID:27472198

  5. Altered miRNA expression in the cervix during pregnancy associated with lead and mercury exposure

    PubMed Central

    Sanders, Alison P; Burris, Heather H; Just, Allan C; Motta, Valeria; Amarasiriwardena, Chitra; Svensson, Katherine; Oken, Emily; Solano-Gonzalez, Maritsa; Mercado-Garcia, Adriana; Pantic, Ivan; Schwartz, Joel; Tellez-Rojo, Martha M; Baccarelli, Andrea A; Wright, Robert O

    2015-01-01

    Aim: Toxic metals including lead and mercury are associated with adverse pregnancy outcomes. This study aimed to assess the association between miRNA expression in the cervix during pregnancy with lead and mercury levels. Materials & methods: We obtained cervical swabs from pregnant women (n = 60) and quantified cervical miRNA expression. Women's blood lead, bone lead and toenail mercury levels were analyzed. We performed linear regression to examine the association between metal levels and expression of 74 miRNAs adjusting for covariates. Results: Seventeen miRNAs were negatively associated with toenail mercury levels, and tibial bone lead levels were associated with decreased expression of miR-575 and miR-4286. Conclusion: The findings highlight miRNAs in the human cervix as novel responders to maternal chemical exposure during pregnancy. PMID:26418635

  6. Prenatal exposure to SKF-38393 alters the response to light of adult rats.

    PubMed

    Ferguson, S A; Kennaway, D J

    2000-05-15

    The current study examined the consequences of prenatal SKF-38393