Ziqiang Meng

Oxidative damage of sulfur dioxide on various organs of mice: sulfur dioxide is a systemic oxidative damage agent.

Cu,Zn-superoxide dismutase (SOD), Se-dependent glutathione peroxidase (GSH-Px), catalase (CAT), and glutathione (GSH) play an important role in attenuating free radical-induced oxidative damage. The purpose of this research was to determine (1) whether sulfur dioxide (SO 2) increases levels of lipid peroxidation and alters intracellular redox status in multiple organs of mice, and (2) whether SO 2 is a systemic toxic agent. The effect of SO 2 on levels of thiobarbituric acid-reactive substances (TBARS) and GSH and activities of SOD, GSH-Px, and CAT were investigated in nine organs (brain, lung, heart, liver, stomach, intestine, spleen, kidney, and testis) of Kunming albino mice of both sexes. SO 2 at 20 ppm (56 mg/m 3) was administrated to the animals of SO 2 groups in an exposure chamber for 6 h/day for 7 days while control groups were exposed to filtered air in the same condition. Results show that SO 2 inhalation decreased significantly activities of SOD and GSH-Px in all organs tested in all SO 2 groups, with respect to their corresponding control groups; CAT activities in all organs tested of both sexual mice were significantly unaltered, except CAT activities in livers were significantly lowered by SO 2; SO 2 exposure decreased significantly GSH contents and significantly increased TBARS levels of all organs tested, in comparison with their respective control groups. These results lead to two conclusions: (1) SO 2 is a systemic oxidative damage agent. It results in a significant increase in the lipid peroxidation process in all organs tested of mice of both sexes, which is accompanied by changes of antioxidant status in these organs. (2) SO 2 may cause toxicological damage to multiple organs of animals, and it is suggested that the oxidative damage produced by SO 2 inhalation may influence or promote the progression or occurrence of some disease states of various organs, not only to respiratory system. Further work is required to understand the toxicological role of SO 2 on multiple or even all organs in mammals.

Sulfur dioxide upregulates the aortic nitric oxide pathway in rats

Sulfur dioxide (SO(2)) is a common gaseous pollutant. It is also, however, endogenously generated from sulfur-containing amino acids. Recent studies have demonstrated that rat blood pressure can be lowered by SO(2)-exposure in vivo and that vasodilation caused by SO(2) at low concentrations (<450 microM) is endothelium-dependent in rat aorta. However, effects of SO(2) on nitric oxide synthase (NOS) and nitric oxide (NO) production have not been previously studied in rat aorta. The objective of the present study is to assess the effects of acute (10 min) and prolonged (2h) stimulation with different concentrations of SO(2) on NO/cGMP pathway in isolated rat aorta. The results show that: (1) the acute and prolonged pretreatments with SO(2) produced an inhibition of vasoconstrictions induced by norepinephrine. (2) SO(2) potentiated activity of endothelial nitric oxide synthase (eNOS), but not of induced NOS (iNOS). (3) SO(2) could increase expression of eNOS gene on the transcription and translation levels in rat aorta. (4) SO(2) enhanced NO formation in aortic tissue. (5) The level of cGMP in rat aorta was increased by SO(2) and no change of cAMP. These findings led to the conclusion: there were acute and prolonged effects of SO(2) on the NO/cGMP signalling pathway; and SO(2) could upregulate the eNOS-NO-cGMP pathway and at least partly by which the SO(2) might cause vasodilation and inhibition to vasoconstriction.

BLOOD PRESSURE OF RATS LOWERED BY SULFUR DIOXIDE AND ITS DERIVATIVES

This study was designed to investigate effects of sulfur dioxide (SO 2) and its derivatives (bisulfite and sulfite) on the rat blood pressure. The blood pressures of male Wistar rats exposed to SO 2 and its derivatives at various doses were measured. Findings were that: (1) with acute-one time exposure to SO 2 for 6 h, the rat blood pressures were lowered in contrast to their controls and their background levels in a dose-dependent manner. (2) There were both a dose-response relationship and a time-response relationship between subchronic SO 2 exposure and the rat blood pressure. For SO 2 exposure at 10 ppm, first the blood pressures decreased significantly with exposure days in contrast to their controls and their background levels, and then these decreases became not significant, suggesting an adaption mechanism might be induced. However, SO 2 exposures at 40 ppm caused significant decreases of the blood pressures during the whole experiment, and no adaptation process was found. (3) SO 2 derivatives (bisulfite and sulfite) also caused the decreases of rat blood pressures in a dose-dependent manner. There are two conclusions: (1) Short-time, even acute one-time, exposure to SO 2 or its derivatives may cause a decrease of blood pressure of the animals in both dose-dependent and time-dependent manners. (2) SO 2 is a systemic toxic agent, not only to the respiratory system. SO 2 can cause at least functional damage to the cardiovascular system.

Oxidative damage of sulfur dioxide inhalation on lungs and hearts of mice

Effects of sulfur dioxide (SO2) on concentrations of thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH), activities of Cu,Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were investigated in lungs and hearts of Kunming albino mice of both sexes. The mice of SO2 groups were exposed to various concentrations (22, 56, and 112 mg/m3) of SO2 in separate exposure chambers for 6 h/day for 7 days, whereas control groups were exposed to filtered air under otherwise the same conditions. Our results show that SO2 caused lipid peroxidation and changes of antioxidative status in both lungs and hearts of mice. Exposure to SO2 at all concentrations tested caused a significant increase of TBARS and a significant decrease in GSH content in lungs and hearts of mice, with the exception of GSH content in the hearts of female mice. For lungs, SO2 at low concentrations significantly increased SOD and GPx activities, whereas at high concentrations it significantly decreased these same activities in mice of both sexes. For hearts, SO2 at all tested concentrations significantly decreased activities of SOD from mice of both sexes, as well as that of GPx from male mice, but the decrease of GPx activities in hearts from female mice was statistically insignificant. SO2 inhalation tended to decrease activities of CAT in lungs and hearts from mice of both sexes, whereas only the decrease of CAT activities caused by SO2 in lungs from male mice was statistically significant, at 112 mg/m3. The results also show a gender difference in oxidative stress and antioxidation status caused by SO2 exposure. These results lead us to conclude that SO2 exposure can cause oxidative damage to lungs and hearts of mice, and SO2 is toxic not only to the respiratory system, but to the heart as well. Additional work is required to understand the toxicological role of SO2 on many or even all mammalian organs.

The Vasodilator Effect and Its Mechanism of Sulfur Dioxide-Derivatives on Isolated Aortic Rings of Rats

The vasodilator effect of exogenous sulfur dioxide (SO2) derivatives (mixture of sodium bisulfite and sodium sulfite, 3:1 M/M in neutral solution) on rat vascular system was studied in order to explore the mechanism of blood pressure lowered by SO2 and its derivatives. Isolated rat aortic rings were perfused in bath tubes containing various chemicals and their tensions were recorded. The results showed: (1) The SO2 derivatives could relax isolated aorta precontracted by norepinephrine (NE) or potassium chloride (KCl) in a dose-dependent manner. (2) This vasodilator effect was attenuated after preincubation with indomethacin, but was not affected by N-L-nitro-arginine, methylene blue, and propranolol, and was independent of the aorta endothelium. (3) The vasoconstriction responses induced by NE, KCl, or Ca2+ were antagonized by SO2 derivatives in a noncompetitive manner. (4) The vasoconstrictions of two components (initial fast vasoconstriction induced by intracellular Ca2+ release and sustained vasoconstriction evoked by extracellular Ca2+ influx) were also inhibited by SO2 derivatives. These results led to the conclusions: The SO2 derivatives could cause vasorelaxation by a direct role of the chemicals on aortic smooth muscle cells. It was not dependent on vascular endothelium and was independent of nitric oxide (NO). It is suggested that SO2 and its derivatives might be also vasoactive substances that modulate changes of blood pressure, like other gasotransmitters. The vasorelaxation might be related to the inhibition effects of SO2 derivatives on Ca2+ entry through both potential-dependent calcium channels and receptor-operating calcium channels, and also to the inhibition of intracellular Ca2+ release. The vasorelaxation was at partly related to the increase of prostacyclin (PGI2) induced by SO2 derivatives.

Cell morphological ultrastructural changes in various organs from mice exposed by inhalation to sulfur dioxide.

Sulfur dioxide (SO2) is a common air pollutant, present in low concentrations in the community air as well as in higher concentrations in some workplaces. Our previous studies demonstrated that SO2 can cause oxidative stress and DNA damage to multiple organs of mice. However, there was no direct proof if and how the morphological changes are caused by SO2. In this study, the ultrastructural morphologies of lungs, livers, spleens, testis, brains, hearts, and kidneys from mice exposed by inhalation to SO2 at 28.00 ± 1.98 and 56.00 ± 3.11 mg/m3 were observed with electron microscopy. Our results show that (1) type II alveolar cells of lungs in SO2-exposure groups had obvious pathological changes including vacuolation of osmiophilic multilamellar bodies, a decrease in microvilli content and mitochondrial pyknosis or swelling, as well as various changes in the structure of the nucleus and chromatin. Meanwhile obvious changes in the mitochondrial and nuclear compartments, in type II alveolar cells were also observed. (2) A series of pathological changes was discovered in hepatic cells in SO2-exposure groups, such as swelling of the nucleus, dispersion of lipid droplets, degenerated mitochondria, and dilatation of rough endoplasmic reticulum. For mice exposed to SO2 at 56 mg/m3, necrosis of hepatocytes with unclear karyotheca or nearly dissolved karyotheca and decreases in organelles were observed. (3) The numbers of apoptotic splenocytes from mice exposed to SO2 were increased by SO2 inhalation in a dose-dependent manner. (4) In SO2-exposure groups, some of the cerebral cortex neurons, many glial cells and nerve fibers were damaged. (5) Mitochondrial swelling, decrease or disappearance of mitochondria crista, myocardial myofibril disorder, various changes of nucleus and chromatin, intercalated discs dissociation, and endothelium edema caused by SO2 exposure in heart tissues were found. In addition, other effects, such as myofibrillar fragmentation and dissolution, some myocardial cell membranes breach, and inflammatory cell infiltration, were observed in groups exposed to SO2 at 56 mg/m3. (6) SO2 exposure induced serious ultrastructural lesions in renal proximal tubular lining cells; moreover glomeruli and distal tubular lining cells were damaged in a dose-dependent manner. (7) Compared with the control group, the basement membranes, various seminiferous cells, as well as spermatozoa, and Sertoli cells of testes were altered in the SO2-exposure groups in a dose-dependent manner. In the aggregate, these results lead to a conclusion that inhalation of SO2 can cause the ultrastructure cellular damage of multiple organs in mice. Thus, inhalation of sulfur dioxide appears to be not only toxic to the respiratory system, but also a systemic toxin as well.

Effect of Sulfur Dioxide Inhalation on Cytokine Levels in Lungs and Serum of Mice

Abstract In order to elucidate the immunotoxic mechanism exerted by sulfur dioxide (SO2), we investigated the effect of SO2, a major air pollutant, on the cytokine levels in lungs and serum of male mice. Levels of interlukin-6(IL-6), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1) in lungs and serum from male mice exposed to SO2 at various concentrations were measured by the enzyme-linked immunosorbent assay. Sixty Kunming albino male mice were divided randomly into six equal groups: three groups exposed to SO2 (14.00 ± 1.25, 28.00 ± 1.98, and 56.00 ± 3.11 mg/m3, which are 5 ± 0.45, 10 ± 0.71, and 20 ± 1.11 ppm) and their respective control groups. The results were as follows: (1) For lung tissues of male mice, exposure to SO2 at 14 mg/m3 (5 ppm) caused statistically significant increase of levels of IL-6 and TNF-α (p < .05) compared with the control group; exposure at 28 mg/m3 (10 ppm) caused a statistically highly significant increase of level of IL-6 (p < .01) and a significant increase of TNF-α (p < .05); and exposure at 56 mg/m3 (20 ppm) caused no any significant increase of levels of IL-6 and TNF-α. SO2 at all concentrations tested could not cause significant change of level of TGF-β1 in lungs. (2) For serum from male mice, after exposure to SO2 at 14 mg/m3 (5 ppm), the level of TNF-α was significantly increased (p < .05) compared with the control group, but the changes of levels of IL-6 and TGF-β1 were not significant. After exposure to SO2 at 28 mg/m3 (10 ppm) and 56 mg/m3 (20 ppm), levels of IL-6 and TNF-α were increased nonsignificantly, but the level of TGF-β1 was decreased nonsignificantly. These results imply that inflammation reaction could be induced in lung tissue by SO2 inhalation and the inflammation reaction might relate to these cytokines. And determination of cytokines in lung may be more valuable than in serum when lung injury caused by SO2.

The vasorelaxant effect and its mechanisms of sodium bisulfite as a sulfur dioxide donor

To study the biological role of bisulfite on vascular contractility and its underlying cellular and molecular mechanisms, to explore whether bisulfite can be used as a sulfur dioxide (SO(2)) donor in the biological experiments, the vasorelaxant effects of sodium bisulfite and sodium sulfite on isolated rat thoracic aortic rings were compared; and the signal transduction pathways and the ion channels involved in the vascular effects of bisulfite were investigated. The results show that: (1) Sodium bisulfite relaxed rat thoracic aortic rings in a concentration-dependent manner (from 100 to 4000 μM); however, sodium sulfite at 500 and 1000 μM caused vasoconstriction, and only at higher concentrations (from 2000 to 4000 μM) it caused vasorelaxation in a concentration-dependent manner. (2) The vasorelaxation caused by the bisulfite at low concentrations (≤500 μM) was endothelium-dependent, but at high concentrations (≥1000 μM) it was endothelium-independent. (3) The vasorelaxation by the bisulfite at the low concentrations was partially mediated by the cGMP pathway and the vasorelaxation was related to big-conductance Ca(2+)-activated K(+) (BK(Ca)) channel, but not due to prostaglandin, protein kinase C (PKC) and cAMP pathways. (4) The vasorelaxation by the bisulfite at high concentrations was partially inhibited by tetraethylammonium (TEA) and glibenclamide, suggesting that the vasorelaxation was related to ATP-sensitive K(+) channel (K(ATP)) and L-type calcium-channel. These results led to the conclusion that bisulfite (HSO(3)(-)) might be a vasoactive factor and sodium bisulfite can be used as a SO(2) donor for the study of SO(2) biology.

Vasodilator effect of gaseous sulfur dioxide and regulation of its level by Ach in rat vascular tissues

To explore the toxicological and physiological role of gaseous SO2 on vascular contractility and its level in vascular tissues, a vasodilation study of isolated rat thoracic aortic rings by gaseous SO2 was carried out. The level of SO2 in vascular tissue was assayed using a modified high-performance liquid chromatographic method with fluorescence detection (HPLC-FD). The results show that gaseous SO2 (from 1 μM to 2000 μM) relaxed rat thoracic aortic rings in a dose-dependent manner. The physiological concentrations of SO2 in thoracic aortic tissues and plasma in rats were 127.76 ± 31.34 μM and 16.77±8.24 μM, respectively; The vasorelaxant effect of gaseous SO2 at physiological and low concentrations (<450 μM) was endothelium dependent, and at high concentrations (>500 μM) was endothelium independent. The results also show that SO2 could be endogenously generated in vascular tissues, and mainly in vascular endothelial cells; acetylcholine (Ach) increased the SO2 level in vascular tissue, and noradrenaline (NE) decreased the SO2 level. These findings demonstrate that gaseous SO2 is a vasorelaxant substance, and the vasorelaxant effect of gaseous SO2 is much stronger than that of its derivatives sulfite and bisulfite, which result from the inactivation process of SO2 gas transmitter by which SO2 is hydrated to form sulfite, and the latter is enzymatically oxidized to form sulfate. These findings also demonstrate that endogenous SO2 level in vascular tissue may be regulated by Ach and NE.

Effects of arsenic on blast transformation and DNA synthesis of human blood lymphocytes.

Effects of inorganic arsenicals on DNA synthesis in unsensitized human blood lymphocytes were biphasic: the chemicals at very low concentrations enhanced blast transformation and DNA synthesis, whereas higher concentrations inhibited the transformation and DNA synthesis. The concentrations of arsenicals at which the maximum stimulating effect was found were 1 x 10(-5) M, 1 x 10(-6) M or 2 x 10(-6) M, and 0.8 x 10(-6) M or 1 x 10(-6) M for sodium arsenite exposure of 1 h, 3 days and 6 days, respectively; for sodium arsenate, 1 x 10(-5) M, 1 x 10(-5) M, and 2 x 10(-6) M or 5 x 10(-6) M, respectively. Arsenicals must be present for the entire 6 days culture period to produce maximum stimulation of blast transformation of human lymphocytes. The longer exposure of the lymphocytes to arsenicals, the lower the concentrations of arsenicals at which the maximum stimulating effect was found. The stimulating effect of trivalent arsenic (sodium arsenite) was stronger than pentavalent arsenic (sodium arsenate).