Naphthenic acids are the most significant environmental contaminants resulting from petroleum extraction from oil sands deposits. In this study, a mixture of naphthenic acids isolated from Athabasca oil sands (AOS) tailings pond water was used in acute and subchronic toxicity tests with rodents, in order to assess potential risks posed to terrestrial wildlife. Dosages were chosen to bracket worst-case environmental exposure scenarios. In acute tests, adult female Wistar rats were given single po dosages of naphthenic acids at either 3, 30, or 300 mg per kg body weight (mg/kg), while adult male rats received 300 mg/kg. Food consumption was temporarily suppressed in the high-dose groups of both sexes. Following euthanasia 14 days later, histopathology revealed a significant incidence of pericholangitis in the high-dose group of both sexes, suggesting hepatotoxicity as an acute effect. Other histological lesions included brain hemorrhage in high-dose males, and cardiac periarteriolar necrosis and fibrosis in female rats. In subchronic tests, naphthenic acids were po administered to female Wistar rats at 0.6, 6, or 60 mg/kg, 5 days per week for 90 days. Results again suggested the liver as a potential target organ. The relative liver weight in the high-dose group was 35% higher than in controls. Biochemical analysis revealed elevated blood amylase (30% above controls) and hypocholesterolemia (43% below controls) in high-dose rats. Excessive hepatic glycogen accumulation was observed in 42% of animals in this group. These results indicate that, under worst-case exposure conditions, acute toxicity is unlikely in wild mammals exposed to naphthenic acids in AOS tailings pond water, but repeated exposure may have adverse health effects.
Microcystin-LR (MCLR) is a cyanobacterial hepatotoxin that inhibits intracellular serine/threonine protein phosphatases causing disruption of actin microfilaments (MFs) and intermediate filaments (IFs) in hepatocytes. This study compared the effects of MCLR on the organization of MFs, IFs, and microtubules (MTs) in hepatocytes and nonhepatocyte cell lines and determined the sequence of toxin-induced changes in these cytoskeletal components. Rat renal epithelial cells and fibroblasts were incubated with MCLR at 100 or 200 microM for 6-18 hr. Rat hepatocytes in primary culture were exposed to the toxin at 1 or 10 microM for 2-64 min. Cells were fixed and incubated with primary antibodies against beta-tubulin, actin, and vimentin or cytokeratin IFs, followed by gold-labeled secondary antibodies with silver enhancement of the gold probe. The fraction of fibroblasts and hepatocytes with altered cytoskeletal morphology was evaluated as a function of MCLR dose and exposure time to assess the sequence of changes in cytoskeletal components. Changes in fibroblasts and some hepatocytes were characterized initially by disorganization of IFs, followed rapidly by disorganization of MTs, with the progressive collapse of both cytoskeletal components around cell nuclei. Many hepatocytes exhibited MT changes prior to effects on IF structure. Alterations in MFs occurred later and included initial aggregation of actin under the plasma membrane, followed by condensation into rosette-like structures and eventual complete collapse into a dense perinuclear bundle. The similarity of effects among different cell types suggests a common mechanism of action, but the independent kinetics of IF and MT disruption in hepatocytes suggests that there may be at least 2 sites of phosphorylation that lead to cytoskeletal alterations.
In vitro digestors can be used to provide bioaccessibility values to help assess the risk from incidental human ingestion of contaminated soils. It has been suggested that these digestors may need to include a lipid sink to mimic human uptake processes. We compare the correspondence between in vivo polycyclic aromatic hydrocarbon (PAH) uptake for eight different PAH contaminated soils with PAH release in in vitro digestors in the presence and absence of a lipid sink. Lipid sinks were essential to the success of the in vitro digestors in predicting juvenile swine PAH uptake. In the presence of the lipid sink, results of the In Vitro Digestion model (IVD) closely corresponded with a slope of 0.85 (r(2) = 0.45, P < 0.07) to the in vivo results. The Relative Bioaccessibility Leaching Procedure (RBALP) results did not correspond to the in vivo study but did tightly reflect total soil PAH concentration. We conclude that the basis of this difference between digestors is that the RBALP used an aggressive extraction technique that maximized PAH release from soil. Systemic uptake in juvenile swine was not linked to soil PAH concentration but rather to the thermodynamic properties of the soil.
The cyanobacterial toxin microcystin-LR (MCLR) is a potent inhibitor of protein phosphatases 1 and 2A, and is selectively toxic to the liver in vivo and to isolated hepatocytes in vitro. This selectivity is believed to be due to toxin uptake via bile acid carriers. We investigated at the light and ultrastructural levels the effects of high concentrations of MCLR and long incubation times to determine in vitro whether fibroblasts and kidney cells (non-target cells) respond in the same manner as do hepatocytes (target cells) at low concentrations and short incubation times. Cultured rat skin fibroblasts (ATCC 1213) and rat kidney epithelial cells (ATCC 1571) were incubated with with MCLR at 133 microM for 1-24 hr. Lesions in these cells were compared with those in cultured hepatocytes incubated MCLR at 13.3 microM from 1 to 32 min. Lesions in hepatocytes, kidney cells, and fibroblasts were noted at 4 min, 1 hr, and 8 hr, respectively, after initial exposure to MCLR. Lesions in all three cell types progressed and included plasma membrane blebbing, loss of cell-to-cell contact, clumping and rounding of cells, cytoplasmic vacuolization, and redistribution of cytoplasmic organelles. Loss of microvilli, whorling of rough endoplasmic reticulum, dense staining and dilated cristae in mitochondria, and pinching off of membrane blebs were noted only in hepatocytes. Nuclear changes typical of apoptosis were observed only in fibroblasts and kidney cells. Similarities in responses of different cell types to MCLR exposure probably reflect a common biochemical mechanism of action, i.e., inhibition of protein phosphatases 1 and 2A as described by others.(ABSTRACT TRUNCATED AT 250 WORDS)
Microcystin-LR (MCLR) is a commonly encountered blue-green algal hepatotoxin and a known inhibitor of cellular protein phosphatase types 1 and 2A. The toxin causes alterations in, and redistribution of, intermediate filaments, microtubules, and actin microfilaments (MFs) in affected cells. In this study, the effect of MCLR on the sequence of alterations in MFs and actin-associated proteins (AAPs) of isolated hepatocytes was examined in an effort to determine whether morphologic changes induced in MFs by microcystins are a result of prior dislocation of AAPs. We studied the effects of MCLR exposure on alpha-actinin and talin, two AAPs that play a role in the orientation of the MFs. Primary hepatocytes were incubated with 10 microns MCLR for 0-64 min. The distribution of actin, alpha-actinin, and talin were examined using fluorescence microscopy. MCLR induced similar changes in the distribution of actin and the AAPs. Actin filament redistribution was first observed after 12 min of MCLR exposure, and was characterized by detachment of MFs from the cell periphery, followed by condensation at distinct focal points and progressive collapse into the interior of affected cells. Changes in alpha-actinin and talin distribution were first observed after 20 min of toxin exposure. The AAPs appeared to detach from focal contacts on the cytoplasmic surface of the plasma membrane, condense into cytoplasmic aggregates, and ultimately collapse into a juxtanuclear bundle. The results of this study indicate that, in hepatocytes exposed to MCLR, the collapse of actin MFs occurs prior to the dislocation of alpha-actinin and talin. Changes in these actin associated proteins are not likely to account for the initial changes in actin MFs.
Sodium chloride (NaCl) is widely used as a deicing agent on roadways. There are numerous anecdotal reports of poisoning of passerine birds by road salt in the United States and Canada, but little is known about the toxicity of NaCl to songbirds. The objectives of this study were to determine the lethal dose range for NaCl in a representative passerine species (house sparrow [Passer domesticus]); to determine the clinical, physiologic, and pathologic effects of sublethal and lethal oral NaCl exposure; and to assess the potential for recovery after exposure to granular salt or highly concentrated salt solutions. The up-and-down method was used in a pilot study to estimate the lethal oral dose of granular NaCl in wild caught house sparrows. The toxicity of highly concentrated NaCl solution also was investigated. This was followed by an acute dose response study in which house sparrows were dosed orally with granular NaCl at 0, 500, 1,500, 2,500, or 3,500 mg/kg. Sparrows were deprived of water for 6 hr postexposure (PE) in an attempt to mimic specific winter conditions. Groups of three birds at each dose were euthanized at 1, 3, 6, and 12 hr PE, and samples were collected for histopathology and brain and plasma electrolyte analyses. Results indicated an approximate mean lethal dose (LD 50 ) of 3,000-3,500 mg/kg in water-deprived birds, which is similar to mammalian values. House sparrows dosed with a concentrated solution of NaCl generally died at doses of 8,000 mg/kg. Clinical signs observed at Ն1,500 mg/kg included rapid onset (Ͻ30 min) of depression (indicated by reduced activity and reduced response to visual and auditory stimuli), ataxia, inability to fly or perch, and death in as little as 45 min. Birds that survived for 6 hr usually recovered. Plasma Na concentrations Ͼ200 mmol/l were consistently associated with clinical signs. Pathologic lesions consisted of edema and distension of the caudoventral thin muscled region of the gizzard and were observed 1 hr PE in most birds dosed with Ն500 mg/kg. Brain Na concentrations in clinically ill sparrows and those that died of NaCl toxicity ranged from 1,297 to 1,615 (meanϭ1,450; SDϭ115) ppm wet weight or 5,603 to 6,958 (meanϭ6,367; SDϭ454) ppm dry weight, which differed significantly from control birds. No histologic lesions were observed in brain sections of exposed birds, likely reflecting the acute nature of the exposure. However, fluid accumulation beneath the koilin layer of the gizzard was observed in the majority of birds at high dosage levels. These results indicate that passerines ingesting relatively small numbers of road salt granules or small quantities of highly concentrated NaCl solutions are at risk of sodium poisoning.
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