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1.
Crit Rev Toxicol ; 41(4): 339-68, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21345153

RESUMO

The development and use of nanoparticles have alerted toxicologists and regulators to issues of safety testing. By analogy with ambient air particles, it can be expected that small doses are associated with a small increase in risk of cardiovascular diseases, possibly through oxidative stress and inflammatory pathways. We have assessed the effect of exposure to particulate matter on progression of atherosclerosis and vasomotor function in humans, animals, and ex vivo experimental systems. The type of particles that have been tested in these systems encompass TiO(2), carbon black, fullerene C(60), single-walled carbon nanotubes, ambient air particles, and diesel exhaust particles. Exposure to ambient air particles is associated with accelerated progression of atherosclerosis and vasomotor dysfunction in both healthy and susceptible animal models and humans at risk of developing cardiovascular diseases. The vasomotor dysfunction includes increased vasoconstriction as well as reduced endothelium-dependent vasodilatation; endothelium-independent vasodilatation is often unaffected indicating mainly endothelial dysfunction. Pulmonary exposure to TiO(2), carbon black, and engineered nanoparticles generate vasomotor dysfunction; the effect size is similar to that generated by combustion-derived particles, although the effect could depend on the exposure period and the administered dose, route, and mode. The relative risk associated with exposure to nanoparticles may be small compared to some traditional risk factors for cardiovascular diseases, but superimposed on these and possible exposure to large parts of the population it is a significant public health concern. Overall, assessment of vasomotor dysfunction and progression of atherosclerosis are promising tools for understanding the effects of particulate matter.


Assuntos
Poluentes Atmosféricos/toxicidade , Aterosclerose/epidemiologia , Material Particulado/toxicidade , Sistema Vasomotor/efeitos dos fármacos , Animais , Aterosclerose/patologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Progressão da Doença , Humanos , Nanopartículas/toxicidade , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Sistema Vasomotor/patologia
2.
Cancer Lett ; 266(1): 84-97, 2008 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-18367322

RESUMO

There is growing concern that air pollution exposure increases the risk of lung cancer. The mechanism of action is related to particle-induced oxidative stress and oxidation of DNA. Humans exposed to urban air with vehicle emissions have elevated levels of oxidized guanine bases in blood cells and urine. Animal experimental studies show that pulmonary and gastrointestinal exposure is associated with elevated levels of oxidized guanines in the lung and other organs. Collectively, there is evidence indicating that exposure to traffic-related air pollution particles is associated with oxidative damage to DNA and this might be associated with increased risk of cancer.


Assuntos
Poluição do Ar/efeitos adversos , Carcinógenos/toxicidade , Dano ao DNA , Neoplasias/induzido quimicamente , Estresse Oxidativo , Animais , Transformação Celular Neoplásica , Cobaias , Humanos , Camundongos , Oxirredução , Material Particulado/toxicidade , Ratos , Emissões de Veículos/toxicidade
3.
Mutagenesis ; 23(3): 223-31, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18326868

RESUMO

The comet assay is popular for assessments of genotoxicity, but the comparison of results between studies is challenging because of differences in experimental procedures and reports of DNA damage in different units. We investigated the variation of DNA damage in mononuclear blood cells (MNBCs) measured by the comet assay with focus on the variation related to alkaline unwinding and electrophoresis time, number of cells scored, as well as the putative benefits of transforming the primary end points to common units by the use of reference standards and calibration curves. Eight experienced investigators scored pre-made slides of nuclei differently, but each investigator scored constantly over time. Scoring of 200 nuclei per treatment was associated with the lowest residual variation. Alkaline unwinding for 20 or 40 min and electrophoresis for 20 or 30 min yielded different dose-response relationships of cells exposed to gamma-radiation and it was possible to reduce the variation in oxidized purines in MNBCs from humans by adjusting the level of lesions with protocol-specific calibration curves. However, there was a difference in the level of DNA damage measured by different investigators and this variation could not be reduced by use of investigator-specific calibration curves. The mean numbers of lesions per 10(6) bp in MNBCs from seven humans were 0.23 [95% confidence interval (CI): 0.14-0.33] and 0.31 (95% CI: 0.20-0.55) for strand breaks (SBs) and oxidized guanines, respectively. In conclusion, our results indicate that inter-investigator difference in scoring is a strong determinant of DNA damage levels measured by the comet assay.


Assuntos
Ensaio Cometa/estatística & dados numéricos , Ensaio Cometa/normas , Dano ao DNA , DNA/análise , Estresse Oxidativo , Núcleo Celular/química , Núcleo Celular/ultraestrutura , Interpretação Estatística de Dados , Humanos , Leucócitos Mononucleares/química , Leucócitos Mononucleares/ultraestrutura , Variações Dependentes do Observador
4.
Toxicology ; 237(1-3): 134-144, 2007 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-17602821

RESUMO

Epidemiological studies have shown that exposure to air pollution particles is associated with cardiovascular diseases, whereas the role in the initiation of atherosclerosis is unresolved. Atherosclerosis is considered to be an inflammatory disease that also involves oxidative stress. Here we investigated effects of oxidative stress elicited by diesel exhaust particles (DEP) in the aorta, liver, and lung of dyslipidemic ApoE(-/-) mice at the age when visual plaques appear in the aorta (11-13 weeks). DEP was administrated by intraperitoneal injection (0, 50, 500 and 5,000 microg DEP/kg bodyweight) in order to omit vascular effects secondary to pulmonary inflammation. The mice were killed either 6 or 24h after the administration. Inflammation was measured as the expression of inducible nitric oxide synthase (iNOS) and serum nitric oxide and DNA damage was measured by the comet assay. The expression of iNOS mRNA was increased in the liver 6h after the administration. The level of oxidized purine bases, determined as formamidopyrimidine DNA glycosylase sites was increased by 67% (95% CI: 11-124%) in the liver after 24h in the mice administrated with only 50 microg/kg bodyweight. However, there was no indication of systemic inflammation determined as the serum concentration of nitric oxide and iNOS expression, and DNA damage was not increased in the aorta. These observations indicate that intraperitoneal DEP injection does not induce inflammation or oxidatively damaged DNA in the lung and aorta, whereas a direct effect in terms of inflammation and oxidized DNA was observed in the liver of dyslipidemic ApoE(-/-) mice.


Assuntos
Apolipoproteínas E/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Dano ao DNA , Dislipidemias/genética , Fígado , Material Particulado/toxicidade , Emissões de Veículos/toxicidade , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Aorta/metabolismo , Aterosclerose/complicações , Aterosclerose/genética , Doença Hepática Induzida por Substâncias e Drogas/complicações , Ensaio Cometa , Dislipidemias/complicações , Feminino , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Estresse Oxidativo/genética , Material Particulado/farmacocinética
5.
Toxicol Sci ; 129(1): 98-107, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22610611

RESUMO

Exposure to nanosized particles may increase the risk of cardiovascular diseases by endothelial dysfunction, particularly in susceptible subjects with metabolic syndrome. We investigated vasomotor dysfunction in aorta from obese and lean Zucker rats after oral exposure to nanosized carbon black (CB). Rats were exposed to 1 or 10 weekly doses of 0, 0.064, 0.64 or 6.4 mg/kg bodyweight and sacrificed 24 h or 13 weeks later. The exposure to 10 doses of 0.064 or 0.64 mg/kg reduced the acetylcholine-induced vasorelaxation in the lean and obese rats. The half maximal effect concentration values increased by twofold (95% CI: 1.1-3.5-fold) and fourfold (95% CI: 2.3-6.9-fold) in the rats exposed to 0.064 and 0.64 mg/kg compared with the controls, respectively. The rats exposed to 10 doses of 0.64 mg/kg had also 20% (95% CI: 10-29%) lower maximal effect value compared with the controls. However, the nitroglycerin-induced vasorelaxation and phenylephrine-induced vasocontraction was not affected in rats exposed to CB. The endothelial dysfunction was not observed in rats sacrificed 13 weeks after the last CB exposure. There was unaltered expression of Chrm3, Nos3, Nos2, Ccl2, and Hmox1 in aorta tissue of CB-exposed rats. In conclusion, repeated oral exposure to CB was associated with endothelial dysfunction in rats, further aggravating the effect of metabolic syndrome.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Síndrome Metabólica/fisiopatologia , Nanopartículas/toxicidade , Estado Pré-Diabético/fisiopatologia , Fuligem/toxicidade , Administração Oral , Animais , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiopatologia , Feminino , Ratos , Ratos Zucker
6.
Mutagenesis ; 22(2): 105-10, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17234687

RESUMO

The free radical theory of aging depicts an accumulation of cellular oxidatively damaged DNA. In this study, we investigated this theory in mice with knocked-out apolipoprotein E gene (ApoE(-/-)), which develops atherosclerosis and wild-type counterparts. The level of oxidatively damaged DNA was investigated as strand breaks, endonuclease III- and formamidopyrimidine DNA glycosylase-sensitive sites by the comet assay. The level of DNA damage was mainly increased with age in the liver of ApoE(-/-) mice, whereas no increase was observed in the aorta or lung of the mice. This suggests that the accumulation of oxidized DNA in the liver of dyslipidemic ApoE(-/-) mice could be secondary to dysfunction of the lipid metabolism. Visually, the aortas of the ApoE(-/-) mice were clearly atherosclerotic as indicated by rigid texture and yellowish in color. However, the unaltered levels of oxidized DNA in severely atherosclerotic aortas of old ( approximately 70 weeks) ApoE(-/-) mice indicate that oxidative stress may not be a generalized phenomenon, but rather related locally to the individual plaques. In conclusion, the results of this study suggest that dyslipidemic ApoE(-/-) mice suffer from hepatic oxidative stress in terms of oxidized DNA, and this effect could be due to the dysfunction of lipid metabolism.


Assuntos
Envelhecimento/genética , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Dano ao DNA , Dislipidemias/genética , Estresse Oxidativo , Animais , Aorta/metabolismo , DNA Glicosilases/metabolismo , Endonucleases/metabolismo , Feminino , Fígado/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
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