Toxicología ambiental : evaluación de riesgos y restauración ambiental

Contiene: introducción, toxicología ambiental, evaluación de riesgos ambientales, restauración ambiental y prevención de la contaminación.

Arsenic and cigarette smoke synergistically increase DNA oxidation in the lung.

Epidemiological evidence has indicated that arsenic and cigarette smoking exposure act synergistically to increase the incidence of lung cancer. Since oxidative damage of DNA has been linked to cancer, our hypothesis is that aerosolized arsenic and cigarette smoke work synergistically to increase oxidative stress and increase DNA oxidation in the lung. To test this hypothesis male Syrian golden hamsters were exposed to room air (control), aerosolized arsenic compounds (3.2 mg/m3 for 30 minutes), cigarette smoke (5 mg/m3 for 30 minutes), or both smoke and arsenic. Exposures were for 5 days/week for 5 or 28-days. Animals were sacrificed one day after the last exposure. In the 28-day group, glutathione levels and DNA oxidation (8-oxo-2'-deoxyguanosine (8-oxo-dG)) were determined. Our results show that in the 28-day arsenic/smoke group there was a significant decrease in both the reduced and total glutathione levels compared with arsenic or smoke alone. This correlated with a 5-fold increase in DNA oxidation as shown by HPLC. Immunohistochemical localization of 8-oxo-dG showed increase staining in nuclei of airway epithelium and subadjacent interstitial cells. These results show that dual exposure of arsenic and cigarette smoke at environmentally relevant levels can act synergistically to cause DNA damage.

Morphological and functional alterations in human proximal tubular cell line induced by low level inorganic arsenic: evidence for targeting of mitochondria and initiated apoptosis.

The kidney is a known target organ for arsenic and is critical for both arsenic biotransformation and elimination. Previous studies have demonstrated that at high doses (ppm) inorganic arsenic is toxic to mitochondria primarily by affecting cellular respiration. However, the effect of inorganic arsenic on mitochondria after low level exposures is not known, particularly in the kidney. Thus the functional and morphological effects of low level inorganic arsenic were investigated in a human proximal tubular cell line, HK-2. Mitochondrial function was assessed at subcytotoxic concentrations of arsenite (< or = 10 microm) by examining the alteration of the mitochondrial membrane potential using MitoTracker Red, a mitochondrion selective dye. In a subset of cells, subcytotoxic arsenite led to mitochondrial membrane depolarization, which could subsequently lead to permeability transition and apoptosis. Subcytotoxic arsenite also induced translocation of phosphatidylserine, indicative of early-stage apoptosis. To confirm whether subcytotoxic arsenite induces cellular and/or mitochondrial morphological alterations consistent with initiated apoptosis, HK-2 cells were evaluated with transmission electron microscopy. Classic morphology of apoptosis was not observed with subcytotoxic arsenite exposures; however, evidence of necrotic changes in the cytoplasmic structure and mitochondrial morphology were apparent. Therefore, based on depolarization of mitochondria and the externalization of phosphatidylserine, HK-2 cells appear to initiate apoptosis following subcytotoxic arsenite insult, but morphological changes indicate that HK-2 cells fail to complete apoptosis and ultimately undergo necrosis. Therefore, subcytotoxic arsenite can be sufficiently toxic to mitochondria that they lose their ability to keep the cell on course for apoptotic cell death.

Interaction of arsine with hemoglobin in arsine-induced hemolysis.

The mechanism of arsine (AsH3) toxicity is not completely understood, but hemoglobin (Hb) has long been recognized as a necessary component of the overall mechanism of AsH3-induced hemolysis. In this study, the role of Hb in AsH3-induced hemolysis was investigated. The purpose was to determine whether exposure to AsH3 altered the structure of the heme or globin constituents of Hb. Arsine was incubated with isolated, human oxyhemoglobin (oxyHb) and carboxyhemoglobin (carboxyHb), and the release of heme and formation of AsH3-induced hemoglobin modifications were examined. Arsine increased the amount of heme released from oxyHb by 18%. When carboxyHb was incubated with AsH3, there was no change in heme release, suggesting that the sixth ligand position on the heme iron may be critical in the interaction with AsH3. Arsine-Hb interactions were studied by mass spectral analysis of heme, alpha-chain globin, and beta-chain globin. Arsine had no significant effect on the alpha- or beta-chain LCMS spectra in oxyHb and carboxyHb, but in oxyHb, arsine consistently increased the frequency of methyl acetate ion fragment (.CH2OOH, m/z = 59) loss from heme in the matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) spectra. The formation of Hb-protein crosslinks was investigated by Western blotting using an anti-Hb antibody in isolated membranes from AsH3-treated erythrocytes, but no Hb-membrane adducts were found. These results suggest that the interaction between AsH3 and hemoglobin result in an increase in heme release which may contribute to the hemolytic mechanism of AsH3.

The metabolism of inorganic arsenic oxides, gallium arsenide, and arsine: a toxicochemical review.

The aim of this review is to compare the metabolism, chemistry, and biological effects to determine if either of the industrial arsenicals (arsine and gallium arsenide) act like the environmental arsenic oxides (arsenite and arsenate). The metabolism of the arsenic oxides has been extensively investigated in the past 4 years and the differences between the arsenic metabolites in the oxidation states +III versus +V and with one or two methyl groups added have shown increased importance. The arsenic oxide metabolism has been compared with arsine (oxidation state -III) and arsenide (oxidation state between 0 to -III). The different metabolites appear to have different strengths of reaction for binding arsenic (III) to thiol groups, their oxidation-reduction reactions and their forming an arsenic-carbon bond. It is unclear if the differences in parameters such as the presence or absence of methyl metabolites, the rates of AsV reduction compared to the rates of AsIII oxidation, or the competition of phosphate and arsenate for cellular uptake are large enough to change biological effects. The arsine rate of decomposition, products of metabolism, target organ of toxic action, and protein binding appeared to support an oxidized arsenic metabolite. This arsine metabolite was very different from anything made by the arsenic oxides. The gallium arsenide had a lower solubility than any other arsenic compound and it had a disproportionate intensity of lung damage to suggest that the GaAs had a site of contact interaction and that oxidation reactions were important in its toxicity. The urinary metabolites after GaAs exposure were the same as excreted by arsenic oxides but the chemical compounds responsible for the toxic effects of GaAs are different from the arsenic oxides. The review concludes that there is insufficient evidence to equate the different arsenic compounds. There are several differences in the toxicity of the arsenic compounds that will require substantial research.