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| 2. |
- Brittebo, Eva, 1951-, et al.
(författare)
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Bioactivation and effects of environmental pollutants in human and rodent blood vessel endothelial cells
- 2012
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Ingår i: Organohalogen compound database (http://www.dioxin20xx.org/ohc_database_search.htm).
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Konferensbidrag (refereegranskat)abstract
- IntroductionRecent epidemiological studies reveal associations between exposure to environmental pollutants and cardiovascular disorders in humans. Elevated serum concentrations of polychlorinated biphenyls (PCBs) have for instance been associated with cardiovascular risk factors such as hypertension (1-3). Exposure to the carbonate plastic monomer bisphenol A (BPA) has been associated with an increased incidence of cardiovascular disease and atherogenic changes in the vascular wall (4-6). The contention that the human cardiovascular system is a sensitive target for toxic chemicals gain support from our earlier and recent experimental studies in rodents, birds and fish, as well as in cultured human primary endothelial cells. It is also compatible with earlier observations that certain polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens that may also contribute to atherosclerosis in mice and birds (7,8).In this presentation we will briefly discuss effects of Ah receptor (AhR) agonists (e.g. the coplanar PCB126 or BNF, ß-naphthoflavone) on the expression of cytochrome P450 (CYP)1 enzymes in various endothelia in rodents in vivo or ex vivo, as well as in cultured human umbilical vein endothelial cells (HUVEC). The CYP1-dependent bioactivation and irreversible binding of prototype polyaromatic hydrocarbons (PAH) and heterocyclic amines such as benzo(a)pyrene (BaP), 7,12-dimethyl- benz(a)anthracene (DMBA) and 3-amino-1,4-dimethyl-5H-pyrido- [4,3-b]indole (Trp-P1) in these endothelia will be reviewed. We will also report how PCB126 affects vasoactive factors in HUVEC, and how these effects are modulated by physiological 17ß-oestradiol concentrations. Some effects of PCB126, 1-nitropyrene (1-NP) and bisphenol A (BPA) on biomarkers for endothelial dysfunction, cell stress and DNA damage in HUVEC will finally be presented.Material and methodsHuman umbilical vein endothelial cells (HUVEC) were purchased from Science Cell Research laboratories, Carlsbad, CA. C57Bl mice and Wistar or Sprague Dawley rats were purchased from various suppliers. All animal experiments were approved by the Local Ethical Committee for Research on Animals in Uppsala and the studies followed the guidelines laid down by the Swedish and European Union legislation on animal experimentation. Rodents, tissue-slices and cultured cells were treated with model chemicals as previously described. Tape section and light microscopy autoradiographic imaging using 3H-labelled BaP, DMBA and Trp-P-1 and immunohistochemistry was performed as previously described (9-19). Precision-cut tissue slices for in vitro autoradiography were prepared as described in (14) and the slices were incubated with various 3H-labelled chemicals. HUVEC were exposed to various compounds and the detection of biomarkers of endothelial dysfunction, DNA damage were performed as described (20-22). Finally, female Fischer rats were exposed to BPA (0.025, 0.25 and 2.5 mg/l) and fructose (50 g/l) in the drinking water from 5 to 15 weeks of age to mimic human exposure (unpublished data).Results and discussionCo-localization of CYP1A1 expression and BaP, DMBA and Trp-P-1 adduct formation in endothelial linings As demonstrated by immunohistochemistry, a high CYP1A immunoreactivity occurred in capillaries of the heart, skeletal muscle, uterus and in blood-brain interfaces such as the leptomeninges and plexus choroideus, whereas no expression was observed for instance in cerebral capillary endothelial cells of mice treated with AhR agonists (9-11). No, or very low constitutive immunoreactivities were observed in these endothelia in vehicle-treated animals. No basal or induced CYP1B1 expression was observed in endothelial cells, while a weak CYP1B1 immunostaining was detected in the muscle layer of small arteries. It should be noted that in subcellular preparations of whole organs, e.g. heart and brain, the CYP1A1 in endothelial cells is diluted due to cells that do not express high levels of CYP1A1, for examples myocytes or neurons, in excess. A cell-specific metabolism in endothelial cells may therefore remain undetected due to the presence of metabolically inactive cells. In order to detect minor sites of bioactivation such as endothelial linings we employed light microscopic autoradiographic imaging to examine the bioactivation and subsequent irreversible binding of the radiolabelled prototype toxicants in tissues of animals pretreated with AhR-agonists. As determined by light microscopic autoradiography of AhR-agonist-treated mice exposed to 3H-labelled BaP, DMBA or Trp-P-1 and birds exposed to 3H-Trp-P-1 a significant accumulation of non-extractable radioactivity occurred in endothelial linings (9-18). The bound radioactivity occurred in the nuclei and the perinuclear cytoplasm, suggesting that the autoradiograms depict both DNA- and protein-bound adducts. Since the binding sites of 3H-labelled BaP, DMBA or Trp-P-1 corresponded with the sites of CYP1A1 induction, we concluded that rodents express a constitutively low but highly inducible and functional CYP1A1 in endothelial cells. The binding of reactive metabolites in endothelial cells exceeded the binding in all other cell types in AhR-agonist treated mice and was abolished by pretreatment with the CYP1A1 inhibitor ellipticine, supporting a CYP1A1-catalysed metabolic activation in situ to a reactive species (9, 10,12). These findings imply that there is a preferential CYP1A1-catalysed formation of reactive metabolites from all three carcinogens in endothelial cells expressing high CYP1A1 levels. Interestingly, however, carcinogenesis in endothelial cells is a relative rare finding, suggesting that degenerative lesions and cell death may be more prevalent responses to metabolism-activated carcinogens/mutagens in these cells. Experiments with 3H-DMBA and 3H-Trp-P-1 in HUVEC confirmed that AhR-agonists induced an increased bioactivation, suggesting that also human endothelial cells should be targets for toxicity of reactive intermediates formed from CYP1A1- activated carcinogens/mutagens (17-18). This conclusion is supported by immunohistochemical studies on the heavily vascularized human endometrium demonstrating an expression of CYP1A1 and CYP1B1 protein in and around human endometrial blood vessels, although a large interindividualvariation was observed (19). None of the endometrial biopsy samples displayed vascular expression of CYP2A6, CYP2B6, CYP2C8/2C9/2C19, CYP2D6, or CYP3A4/5 protein.Effects of PCB 126, 1-NP, and BPA on biomarkers of endothelial dysfunction and cell stress in endothelial cells In vitro studies demonstrated that PCB126 increased the levels of vasoconstriction factors and decreased the levels of vasodilating factors in cultured HUVEC in a fashion that is characteristic for endothelial dysfunction related to human hypertension. The study showed that the co-planar PCB126 induced expression of the endothelium-derived vasoconstriction factor COX-2 and stimulated formation of the vasoconstrictor prostaglandin PGF2 via the AhR in HUVEC (20). COX-2 is known to play a role in hypertension by catalysing the formation of vasoconstriction prostaglandins and by stimulating reactive oxygen species (ROS) production. Further studies demonstrated that PCB126 increased the production of the vasoconstriction prostaglandin PGF2 and ROS in HUVEC. The relationship between increased ROS production and human hypertension is well established, ROS promotes vasoconstriction by stimulating the production of vasoconstriction prostaglandins and by reducing bioavailability of the vasorelaxing factor NO. Indeed, exposure to PCB126 slightly reduced the production of NO in HUVEC. Furthermore, the PCB126-induced mRNA expressions of CYP1A1, CYP1B1 and COX-2 in HUVEC were enhanced in the presence of physiological levels of 17- estradiol. This suggests that increased levels of oestrogen stimulate AhR-dependent transcription of genes previously associated with endothelial dysfunction and hypertension.In another study we have examined the effects of a nitrated PAH, 1-nitropyrene, that is abundant in diesel exhausts (21). The results revealed that 1-NP induced DNA damage, increased levels of ROS and increased protein expression of the endoplasmic reticulum stress chaperone GRP78 in cultured HUVEC. Induction of CYP1A1 by PCB126 as well as inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction and not by CYP1-dependent bioactivation to reactive intermediates.Recent in vitro studies demonstrated that bisphenol A increased the mRNA expression of genes that regulate vasoconstriction and angiogenesis in HUVEC (eNOS, VEGF, VEGFR2, connexin 43 and ACE1) and in human cardiomyocytes (eNOS and ACE1) (22). The results also showed that BPA increased the expression of P-eNOS(ser1177) and the production of NO in HUVEC. NO is the main effector molecule in angiogenesis downstream of VEGF. Based on the findings that BPA increase the expression of proangiogenic factors we investigated whether BPA could stimulate in vitro angiogenesis in HUVEC using the endothelial tube formation assay. The results demonstrated that BPA increased HUVEC tube formation suggesting that BPA can act directly on the endothelium and stimulate angiogenesis. Long-term exposure in rats revealed that environmentally relevant levels of BPA, increased the cardiac mRNA expression of genes that regulate vasoconstriction and angiogenesis. Ten weeks exposure of rats from preadolescence to adulthood to BPA in the drinking water increased theexpression of eNOS, VEGF, VEGFR2 and ACE1 in the heart. Taken together, the genes that were upregulated in rat cardiac tissues in vivo were also upregulated in human endothelial cells and cardiomyocytes in vitro. The heart is a heavily vascularized t
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| 3. |
- Egard, Mikael, et al.
(författare)
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Frequency Modulation in mm-Wave InGaAs MOSFET/RTD Wavelet Generators
- 2013
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Ingår i: 2013 International Conference on Indium Phosphide and Related Materials (IPRM). - 1092-8669. ; , s. 1-2
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Konferensbidrag (refereegranskat)abstract
- Co-integration of an InGaAs MOSFET and an RTD is performed to realize a wavelet generator. The large transconductance of the MOSFET (1.9 mS/mu m) is used to switch the current in an oscillator circuit and coherent wavelets down to 41 ps are generated in the frequency domain of 50 to 100 GHz. The lowest power consumption measured is 1.9 pJ/pulse. It is found that the supply bias can be used to modulate the center frequency of the wavelets.
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| 4. |
- Egard, Mikael, et al.
(författare)
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High Transconductance Self-Aligned Gate-Last Surface Channel In0.53Ga0.47As MOSFET
- 2011
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Ingår i: 2011 IEEE International Electron Devices Meeting (IEDM). - 9781457705052
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Konferensbidrag (refereegranskat)abstract
- In this paper we present a 55 nm gate length In0.53Ga0.47As MOSFET with extrinsic transconductance of 1.9 mS/mu m and on-resistance of 199 Omega mu m. T he self-aligned MOSFET is formed using metalorganic chemical vapor deposition regrowth of highly doped source and drain access regions. The fabricated 140 nm gate length devices shows a low subthreshold swing of 79 mV/decade, which is attributed to the described low temperature gate-last process scheme.
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| 5. |
- Egard, Mikael, et al.
(författare)
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Self-aligned gate-last surface channel In0.53Ga0.47As MOSFET with selectively regrown source and drain contact layers
- 2011
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Ingår i: 69th Device Research Conference, DRC 2011 - Conference Digest. - 9781612842417
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Konferensbidrag (refereegranskat)abstract
- III-V MOSFETs are currently being considered as a candidate for future high performance transistors [1]. In particular, In1-xGaxAs compounds are investigated for application in digital logic due to their advantageous electronic properties [2]. III-V technologies may be introduced beyond the 22 nm node, which will require a self aligned III/V device architecture as well as integration of high-¿ gate oxides.
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| 6. |
- Ohlsson, Lars, et al.
(författare)
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Admittance Matching of 60 GHz Rectangular Dielectric Resonator Antennas for Integrated Impulse Radio
- 2010
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Ingår i: [Host publication title missing]. ; , s. 253-256
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Konferensbidrag (refereegranskat)abstract
- Methods to achieve admittance matching of rectangular dielectric resonator antennas intended for 60~GHz impulse radio are reported. The motivation is to find a suitable antenna that may be integrated in the V-band gated tunnel diode wavelet generator, replacing its tank circuit and forming a low complexity transmitter. Probed one- and two-port scattering parameter measurements have been performed to characterise the fabricated antennas. Changing the feed structure from a tapered dipole to an offset fed and tapered slot, a change from capacitive to inductive characteristics is observed, and the matching to the gated tunnel diode is improved. Deembedded admittance resonance frequencies of fabricated antennas were found at 53.6 and 52.2~GHz for dipole and slot fed antennas, respectively. Characterising the transmission link between dipole fed antennas, a maximum antenna gain of 10.5~dBi and a 3~dB power bandwidth of 1.5~GHz were found at 53.3~GHz.
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| 7. |
- Roll, Guntrade, et al.
(författare)
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RF reliability of gate last InGaAs nMOSFETs with high-k dielectric
- 2013
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Ingår i: 2013 IEEE International Integrated Reliability Workshop Final Report, IIRW 2013. - 9781479903504 ; , s. 38-41
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Konferensbidrag (refereegranskat)abstract
- A complete reliability study of the high-frequency characteristics for nMOSFETs on InGaAs channel with Al2O3/HfO2 gate dielectric is presented. DC gate voltage stress causes an increase in the transconductance frequency dispersion. Stress induced border traps degrade the maximum DC-transconductance, but do not react at high frequencies. The main degradation characteristics of the high-frequency measurements can be modeled by the threshold voltage related transconductance shift. The maximum of the cut-off frequency is shifted with stress to higher or lower gate biases, but not decreased.
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| 8. |
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| 9. |
- Ärlelid, Mats, et al.
(författare)
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60 GHz impulse radio measurements
- 2011
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Ingår i: 2011 IEEE International Conference on Ultra-Wideband (ICUWB). - 2162-6588. - 9781457717635 ; , s. 536-540
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Konferensbidrag (refereegranskat)abstract
- The bit-error rate of a 60 GHz wireless impulse radio link is investigated at a bit-rate of 4 Gbps using on-off keying. The measurement results show that it is possible to have a BER below 10(-12), and the measured BER vs. E-b/N-o is approximately 1 dB from the theoretical value. The reliability of the wideband 60 GHz wavelet generator is furthermore confirmed by studying the number of faulty wavelets generated, and the circuit performance is characterized. The wavelet generator consumes 30 mW and may generate signals with bandwidth exceeding 25 GHz, which may be used to investigate the channel properties at 60 GHz.
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| 10. |
- Astromskas, Gvidas, et al.
(författare)
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Temperature and frequency characterization of InAs nanowire and HfO2 interface using capacitance-voltage method
- 2011
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Ingår i: Microelectronic Engineering. - : Elsevier BV. - 1873-5568 .- 0167-9317. ; 88:4, s. 444-447
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Konferensbidrag (refereegranskat)abstract
- InAs/HfO2 nanowire capacitors using capacitance-voltage (CV) measurements are investigated in the range of 10 kHz to 10 MHz. The capacitors are based on vertical nanowire arrays that are coated with an 8 nm-thick HfO2 layer by atomic layer deposition. CV characteristics are measured at temperatures in the range between -140 and 40 degrees C and the CV characteristics for nanowires with different Sn and Se n-type doping levels are compared. The comparison of the data at various doping levels points towards large number of traps for highly doped samples, caused by the preferential dopant precursor incorporation at the nanowire surface. We also evaluate the frequency dispersion of the accumulation capacitance and determine values below 2% with weak temperature dependence, indicating the existence of border traps in these nanowire capacitors. (C) 2010 Elsevier B.V. All rights reserved.
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