Enhanced lung toxicity of paraquat in selenium-deficient rats

doi:10.1016/0041-008X(78)90003-0

Toxicology and Applied Pharmacology

Volume 43, Issue 2, February 1978, Pages 237-247

https://doi.org/10.1016/0041-008X(78)90003-0 Get rights and content

Abstract

In an attempt to further clarify the mechanisms of paraquat lung injury, paraquat toxicity was studied in selenium (Se)-deficient rats. Chronic respiratory disease-free rats fed a basal Se-deficient diet or a basal diet supplemented with 0.5 or 2.0 ppm of Se for 40 days after weaning were injected with 25 mg/kg of paraquat dichloride (ip). Within 4 hr after paraquat injection, 50% of the rats fed the Sedeficient regimen died, exhibiting neurological and respiratory signs of distress prior to death, whereas all rats fed Se-supplemented diets survived for this short time span. Excised lungs from surviving Se-deficient rats injected with paraquat showed extensive lung damage, as evidenced by gross examination, increased lung weights, and increases in cystosolic lung lysosomal enzymes, and exhibited a significant increase of thiobarbituric acid (TBA)-reactive products. Excised lungs from Se-supplemented rats failed to show similar increases in these indices of paraquat-induced lung injury. Our data confirms and extends previous findings of others that paraquat toxicity is enhanced in Se-deficient animals and suggests that lipid peroxide formations may play a role in the enhanced susceptibility.

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Selenium reduces bradykinesia and DNA damage in a rat model of Parkinson's disease
2015, Nutrition
Citation Excerpt :
This indicates a homogeneous cellular injury affecting all the cells rather than strong aggression directed at only a few cells. Studies conducted in earlier decades reported that dietary Se can act as a shield against the toxic effects of PQ [39], as well as increased pulmonary toxicity caused by PQ in rats with Se deficiency [40]. In our study, the reduction of DNA damage in the Se + PQ group (Fig. 3) is an interesting and important result because it reinforces the mineral's ability to protect the integrity of DNA, as shown in recent studies [16,41].
The aim of this study was to explore the effects of selenium (Se) on locomotor activity and DNA damage in a rat model of Parkinson's disease (PD) induced by paraquat (PQ).
Forty-eight male Wistar rats were divided into four groups: control group (n = 12), Se group (n = 12), PQ group (n = 12), and Se + PQ group (n = 12). PQ was administered intraperitoneally (10 mg/kg). Se was offered in the drinking water at a concentration of 11.18 μg/L. Locomotor activity was evaluated weekly using the narrow beam test. The comet assay was performed to assess the level of DNA damage in leukocytes and in brain cells.
As expected, increased DNA damage was found in the PQ group compared with the control and Se groups (P < 0.001). Interestingly, coadministration of Se and PQ effectively prevented the harmful effects of the toxin in locomotor activity and at the molecular level, reducing bradykinesia (P < 0.01) and DNA damage in leukocytes compared with the PQ-only group (P < 0.001), whereas the levels of DNA damage were comparable to those found in the control and Se groups (P > 0.05). Using the comet assay to analyze brain cells, no differences were found between the groups with regard to damage index (P = 0.774), damage frequency (P = 0.817), or non-detectable cell nuclei (P = 0.481).
In this experimental model of PQ-induced PD, the use of Se could contribute to the maintenance of locomotor activity and the integrity of leukocytes DNA. No changes in the levels of DNA damage in brain cells were observed between the experimental groups.
Paraquat
2010, Hayes' Handbook of Pesticide Toxicology
This chapter explores the chemical identity, toxicity, and usage of paraquat. Paraquat is usually formulated as the dichloride salt also known as methyl viologen. Code designations for the material are PP148 for the dichloride salt and PP910 for the bis salt. Paraquat dichloride forms colorless, hygroscopic crystals, which decompose at 300 °C. It is practically non-volatile with a vapor pressure of < 0.1 mPa. It is very soluble in water (700 g/l at 20 °C) and practically insoluble in most other organic solvents. It is mainly formulated as an aqueous solution with surface-active agents. It is used for broad-spectrum control of broad-leaved weeds and grasses in fruit orchards and plantations and for inter-row weed control in many crops. It is also used for general weed control on non-crop land, as a defoliant on cotton and hops, for destruction of potato haulms, as a desiccant, and for control of aquatic weeds. Paraquat is rapidly deactivated upon contact with the soil and does not leach. Following a lethal dose of paraquat to rats mortality is first seen on days 2–5 after dosing but deaths can also occur around days 10–12, indicating there is considerable inter-individual animal response to the chemical. The major cause of death after a median lethal dose (MLD) is due to lung damage. The MLD of pure paraquat dichloride expressed as the cation was about 150 mg/kg to female rats and ranged from 100–143 mg/kg in a number of different strains from a number of different laboratories. As in experimental animals, paraquat is not metabolized in humans, but is reduced to an unstable free radical, which is then re-oxidized to produce a superoxide radical. The therapy of paraquat intoxication has focused on three main areas: prevention of absorption from the gastrointestinal tract, enhancement of elimination of paraquat from the body, and therapy directed against the mechanisms of toxicity.
Paraquat
2010, Hayes' Handbook of Pesticide Toxicology, Third Edition: Volume 1
This chapter explores the chemical identity, toxicity, and usage of paraquat. Paraquat is usually formulated as the dichloride salt also known as methyl viologen. Code designations for the material are PP148 for the dichloride salt and PP910 for the bis salt. Paraquat dichloride forms colorless, hygroscopic crystals, which decompose at 300 °C. It is practically non-volatile with a vapor pressure of < 0.1 mPa. It is very soluble in water (700 g/l at 20 °C) and practically insoluble in most other organic solvents. It is mainly formulated as an aqueous solution with surface-active agents. It is used for broad-spectrum control of broad-leaved weeds and grasses in fruit orchards and plantations and for inter-row weed control in many crops. It is also used for general weed control on non-crop land, as a defoliant on cotton and hops, for destruction of potato haulms, as a desiccant, and for control of aquatic weeds. Paraquat is rapidly deactivated upon contact with the soil and does not leach. Following a lethal dose of paraquat to rats mortality is first seen on days 2–5 after dosing but deaths can also occur around days 10–12, indicating there is considerable inter-individual animal response to the chemical. The major cause of death after a median lethal dose (MLD) is due to lung damage. The MLD of pure paraquat dichloride expressed as the cation was about 150 mg/kg to female rats and ranged from 100–143 mg/kg in a number of different strains from a number of different laboratories. As in experimental animals, paraquat is not metabolized in humans, but is reduced to an unstable free radical, which is then re-oxidized to produce a superoxide radical. The therapy of paraquat intoxication has focused on three main areas: prevention of absorption from the gastrointestinal tract, enhancement of elimination of paraquat from the body, and therapy directed against the mechanisms of toxicity.
Biochemical changes in mouse lung after subcutaneous injection of the sulfur mustard 2-chloroethyl 4-chlorobutyl sulfide
2004, Toxicology
Sulfur mustard (HD) is a vesicant-type chemical warfare agent (CWA) introduced in World War I which continues to be produced, stockpiled, and occasionally deployed by some countries, and could be used potentially by terrorists. Exposure to HD can cause erythema, blisters, corneal opacity, and airway damage. We have reported previously that subcutaneous (SC) injection of immunodeficient athymic nude mice with the half mustard butyl 2-chloroethyl sulfide (BCS) causes systemic biochemical changes in several organs distal to the exposure site. In the present study, we examined the response of non-immunodeficient Swiss Webster mice to the mustard, 2-chloroethyl 4-chlorobutyl sulfide (CECBS). In a pilot study, we found that a single SC injection of 20–25 μl/mouse causes death within 24 h. Consequently, we used 5 μl/mouse (approx. 0.017 mg/kg body weight) of neat CECBS or an equal volume of saline as control. We examined the lungs after 1, 24, and 48 h for biochemical changes including total and oxidized glutathione, protein, DNA, and lipid peroxidation contents in tissue homogenate, and superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, and glutathione S-transferases activities in the cytosol. After 1 h and/or 24 h, we found statistically significant changes that were resolved by 48 h. These changes mimicked those of HD and BCS and were generally consistent with free radical-mediated oxidative stress. The implications of these observations are two-fold. First, dermal exposure to low-dose mustard gas could elicit systemic changes impacting distal organs such as the lungs. It also suggests that antioxidants could potentially modulate the response and reduce the damage. Second, although the use of known CWAs such as HD is prohibited, analogs that are not recognized as agents are as toxic and could be dangerous if acquired and used by potential terrorists.
Lung function and airway inflammation in rats following exposure to combustion products of carbon-graphite/epoxy composite material: Comparison to a rodent model of acute lung injury
2003, Toxicology
Pulmonary function and inflammation in the lungs of rodents exposed by inhalation to carbon/graphite/epoxy advanced composite material (ACM) combustion products were compared to that of a rodent model of acute lung injury (ALI) produced by pneumotoxic paraquat dichloride. This investigation was undertaken to determine if short-term exposure to ACM smoke induces ALI; and to determine if smoke-related responses were similar to the pathogenic mechanisms of a model of lung vascular injury. We examined the time-course for mechanical lung function, infiltration of inflammatory cells into the lung, and the expression of three inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein-2 (MIP-2) and interferon-gamma (IFN-γ). Male Fischer-344 rats were either exposed to 26.8–29.8 g/m³ nominal concentrations of smoke or were given i.p. injections of paraquat dichloride. Measurements were determined at 1, 2, 3, and 7 days post exposure. In the smoke-challenged rats, there were no changes in lung function indicative of ALI throughout the 7-day observation period, despite the acute lethality of the smoke atmosphere. However, the animals showed signs of pulmonary inflammation. The expression of TNF-α was significantly increased in the lavage fluid 1 day following exposure, which preceded the maximum leukocyte infiltration. MIP-2 levels were significantly increased in lavage fluid at days 2, 3, and 7. This followed the leukocyte infiltration. IFN-γ was significantly increased in the lung tissue at day 7, which occurred during the resolution of the inflammatory response. The paraquat, which was also lethal to a small percentage of the animals, caused several physiologic changes characteristic of ALI, including significant decreases in lung compliance, lung volumes/capacities, distribution of ventilation, and gas exchange capacity. The expression of TNF-α and MIP-2 increased significantly in the lung tissue as well as in the lavage fluid. Increased MIP-2 levels also preceded the maximum neutrophil infiltration. The differences in the time-course and primary site of TNF-α, MIP-2, and IFN-γ expression; and the differences in the temporal relationship between their expression and infiltration of inflammatory cells may have accounted for the differences in lung function between paraquat treated and ACM smoke exposed animals.
Role of antioxidants in paraquat toxicity
2002, Toxicology
Paraquat, a quarternary nitrogen herbicide, is a highly toxic compound for humans and animals and many cases of acute poisoning and death have been reported over the past few decades. The mechanisms of paraquat toxicity involve: the generation of the superoxide anion, which can lead to the formation of more toxic reactive oxygen species, such as hydrogen peroxide and hydroxyl radical; and the oxidation of the cellular NADPH, the major source of reducing equivalents for the intracellular reduction of paraquat, which results in the disruption of important NADPH-requiring biochemical processes. The major cause of death in paraquat poisoning is respiratory failure due to an oxidative insult to the alveolar epithelium with subsequent obliterating fibrosis. Management of paraquat poisoning has remained mostly supportive and has been directed towards the modification of the toxicokinetics of the poison. Currently, there are no true pharmacological antagonists for paraquat and there are no chelating agents capable of binding the poison in the blood or other tissues. Recognizing the fact that paraquat induces its toxic effects via oxidative stress-mediated mechanisms, innovations in the management of paraquat poisoning are directed towards the use of antioxidants. In this review, the status of antioxidants in ameliorating or treating the toxic effects produced by paraquat is presented.

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¹: Present address: Biochemistry Division, Letterman Army Institute of Research, Presidio of San Francisco, California 94129.

²: Present address: Stanford Research Institute, Arlington, Virginia 22209.

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Enhanced lung toxicity of paraquat in selenium-deficient rats

Abstract

Life Sci.

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Toxicol. Appl. Pharmacol.

J. Nutr.

J. Biol. Chem.

FEBS Lett.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

J. Nutr.

Anal. Biochem.

Biochem. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Prevention of acute paraquat toxicity in rats by superoxide dismutase (SOD)

Amer. Rev. Resp. Dis.

Lipid peroxidation: A possible mechanism for paraquat toxicity

Res. Commun. Chem. Pathol. Pharmacol.

An enzymatic protective mechanism against lipid peroxidation damage to lungs of ozone-exposed rats

Lipids