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The Journal of Pharmacology and... Oct 2015P-glycoprotein (P-gp) has been associated with a number of neurodegenerative diseases, including Parkinson's disease, although the mechanisms remain unclear. Altered...
P-glycoprotein (P-gp) has been associated with a number of neurodegenerative diseases, including Parkinson's disease, although the mechanisms remain unclear. Altered transport of neurotoxic pesticides has been proposed in Parkinson's disease, but it is unknown whether these pesticides are P-gp substrates. We used three in vitro transport models, stimulation of ATPase activity, xenobiotic-induced cytotoxicity, and inhibition of rhodamine-123 efflux, to evaluate P-gp transport of diazinon, dieldrin, endosulfan, ivermectin, maneb, 1-methyl-4-phenyl-4-phenylpyridinium ion (MPP(+)), and rotenone. Diazinon and rotenone stimulated ATPase activity in P-gp-expressing membranes, with Vmax values of 22.4 ± 2.1 and 16.8 ± 1.0 nmol inorganic phosphate/min per mg protein, respectively, and Km values of 9.72 ± 3.91 and 1.62 ± 0.51 µM, respectively, compared with the P-gp substrate verapamil, with a Vmax of 20.8 ± 0.7 nmol inorganic phosphate/min per mg protein and Km of 0.871 ± 0.172 μM. None of the other pesticides stimulated ATPase activity. We observed an increased resistance to MPP(+) and rotenone in LLC-MDR1-WT cells compared with LLC-vector cells, with 15.4- and 2.2-fold increases in EC50 values, respectively. The resistance was reversed in the presence of the P-gp inhibitor verapamil. None of the other pesticides displayed differential cytotoxicity. Ivermectin was the only pesticide to inhibit P-gp transport of rhodamine-123, with an IC50 of 0.249 ± 0.048 μM. Our data demonstrate that dieldrin, endosulfan, and maneb are not P-gp substrates or inhibitors. We identified diazinon, MPP(+), and rotenone as P-gp substrates, although further investigation is needed to understand the role of P-gp transport in their disposition in vivo and associations with Parkinson's disease.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Line; Cell Membrane; Neurotoxins; Parkinson Disease; Pesticides
PubMed: 26272936
DOI: 10.1124/jpet.115.226373 -
Toxicology May 2013Paraoxonase (PON1) is an A-esterase capable of hydrolyzing the active metabolites (oxons) of a number of organophosphorus (OP) insecticides such as parathion, diazinon... (Review)
Review
Paraoxonase (PON1) is an A-esterase capable of hydrolyzing the active metabolites (oxons) of a number of organophosphorus (OP) insecticides such as parathion, diazinon and chlorpyrifos. PON1 activity is highest in liver and in plasma. Human PON1 displays two polymorphisms in the coding region (Q192R and L55M) and several polymorphisms in the promoter and the 3'-UTR regions. The Q192R polymorphism imparts differential catalytic activity toward some OP substrates, while the polymorphism at position -108 (C/T) is the major contributor of differences in the levels of PON1 expression. Both contribute to determining an individual's PON1 "status". Animal studies have shown that PON1 is an important determinant of OP toxicity. Administration of exogenous PON1 to rats or mice protects them from the toxicity of specific OPs. PON1 knockout mice display a high sensitivity to the toxicity of diazoxon and chlorpyrifos oxon, but not of paraoxon. In vitro catalytic efficiencies of purified PON192 alloforms for hydrolysis of specific oxon substrates accurately predict the degree of in vivo protection afforded by each isoform. Evidence is slowly emerging that a low PON1 status may increase susceptibility to OP toxicity in humans. Low PON1 activity may also contribute to the developmental toxicity and neurotoxicity of OPs, as shown by animal and human studies.
Topics: Animals; Aryldialkylphosphatase; Genetic Predisposition to Disease; Humans; Mice; Organophosphate Poisoning; Polymorphism, Single Nucleotide; Rats
PubMed: 22884923
DOI: 10.1016/j.tox.2012.07.011 -
Current Medical Mycology Jun 2019is an important pathogen in immunodeficient patients. Due to the abundance of this fungus in nature, fungicides are commonly used to preserve and maintain agricultural...
BACKGROUND AND PURPOSE
is an important pathogen in immunodeficient patients. Due to the abundance of this fungus in nature, fungicides are commonly used to preserve and maintain agricultural products. Long-term exposure to these pesticides can lead to the induction of drug resistance in this fungus.
MATERIALS AND METHODS
For the purpose of the study, 10 strains of ATCC 204304 were cultured in benomyl and diazinon pesticides at the concentrations of 62.5, 125, 250.500, 750, 1000, 1500, 2000, and 2500 mg/L in nine steps. Morphological changes and resistance to voriconazole, itraconazole, and amphotericin B were evaluated at the end of each step. Subsequently, changes in the expression of and genes were studied in the strains showing drug resistance.
RESULTS
The results showed that during the nine stages of the adjacency of strains with benomyl and diazinon at different concentrations, resistance to voriconazole, itraconazole, and amphotericin B in these toxins increased by 30% and 10%, respectively. In addition, the microscopic examination of resistant strains revealed the absence of sporulation, and only mycelium was found. Macroscopically, the color of the colonies changed from green to white. Furthermore, the investigation of the expression of and genes in these strains showed a decrease and increase in adjacency with diazinon and benomyl, respectively.
CONCLUSION
As the findings indicated, exposure to agricultural pesticides can lead to the incidence of morphological changes and resistance to amphotericin B, itraconazole, and voriconazole in the sensitive species of by altering the expression of genes involved in drug resistance.
PubMed: 31321335
DOI: 10.18502/cmm.5.2.1158 -
Arhiv Za Higijenu Rada I Toksikologiju Jun 2009Hyperglycaemia has been observed with exposure to organophosphate insecticides. This study was designed to compare the effects of calcium channel blockers,... (Comparative Study)
Comparative Study
Comparative effects of calcium channel blockers, autonomic nervous system blockers, and free radical scavengers on diazinon-induced hyposecretion of insulin from isolated islets of Langerhans in rats.
Hyperglycaemia has been observed with exposure to organophosphate insecticides. This study was designed to compare the effects of calcium channel blockers, alpha-adrenergic, beta-adrenergic, and muscarinic receptor blockers, and of free radical scavengers on insulin secretion from diazinon-treated islets of Langerhans isolated from the pancreas of rats using standard collagenase digestion, separation by centrifugation, and hand-picking technique. The islets were then cultured in an incubator at 37 degrees C and 5 % CO2. In each experimental set 1 mL of 8 mmol L(-1) glucose plus 125 microg mL(-1) or 625 microg mL(-1) of diazinon were added, except for the control group, which received 8 mmol L(-1) glucose alone. The cultures were then treated with one of the following: 30 micromol L(-1) atropine, 100 micromol L(-1) ACh + 10 micromol L(-1) neostigmine, 0.1 micromol L(-1) propranolol, 2 micromol L(-1) nifedipine, 50 micromol L(-1) phenoxybenzamine, or 10 micromol L(-1) alphatocopherol. In all experiments, diazinon significantly reduced glucose-stimulated insulin secretion at both doses, showing no dose dependency, as the average inhibition for the lower dose was 62.20 % and for the higher dose 64.38 %. Acetylcholine and alpha-tocopherol restored, whereas atropine potentiated diazinon-induced hyposecretion of insulin. Alpha-, beta- and calcium channel blockers did not change diazinon-induced effects. These findings suggest that diazinon affects insulin secretion mainly by disturbing the balance between free radicals and antioxidants in the islets of Langerhans and by inducing toxic stress.
Topics: Adrenergic Antagonists; Animals; Calcium Channel Blockers; Cholinesterase Inhibitors; Diazinon; Dose-Response Relationship, Drug; Free Radical Scavengers; Glucose; In Vitro Techniques; Insecticides; Insulin; Insulin Secretion; Islets of Langerhans; Male; Muscarinic Antagonists; Rats; Rats, Wistar
PubMed: 19581208
DOI: 10.2478/10004-1254-60-2009-1917 -
Iranian Red Crescent Medical Journal Apr 2015Diazinon (0,0-Diethyl 0-(1-6-methyl-2-isoprophyl 4 pyrimidinyl) phosphorothioate) (DI) is a very effective organophosphate pesticide, used widely in agriculture....
BACKGROUND
Diazinon (0,0-Diethyl 0-(1-6-methyl-2-isoprophyl 4 pyrimidinyl) phosphorothioate) (DI) is a very effective organophosphate pesticide, used widely in agriculture. Consequently, data on poisoning cases secondary to DI exposure are important. The DI may affect a variety of tissues, including liver. Silibinin is a pharmacologically active constitute of Silybum marianum, with documented antioxidant activity.
OBJECTIVES
The aim of our study was to evaluate both histopathologically and biochemically whether silibinin is protective in DI induced liver damage.
MATERIALS AND METHODS
Thirty two Wistar albino rats were divided into four groups, as follows: 1) control group - oral corn oil was given; 2) DI group - rats were administered orally 335 mg/kg in the corn oil solution; 3) Silibinin group - 100 mg/kg/day silibinin was given alone orally, every 24 hours for 7 days; 4) Silibinin + DI group - DI plus silibinin was given. All rats were sacrificed at the end of experiment. Superoxide dismutases (SOD), glutathione peroxidase (GPX), nitric oxide (NO) and myeloperoxidase (MPO) were investigated in serum and liver tissue. In addition, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme activities were evaluated. The liver tissue was evaluated histopathologically with Hematoxilin & Eosin dye.
RESULTS
Biochemically, ALT, AST, NO, MPO in serum and NO, MPO in liver tissue were found to be significantly higher in DI group, compared to control group (P < 0.001). In Group Silibinin + DI, serum AST, ALT, NO, MPO levels were significantly lower (P < 0.01), and both serum and tissue SOD activities were significantly higher, compared to DI group (P < 0.001). Diazinon induced histopathological changes in liver tissue were: severe sinusoidal dilatation, moderate disruption of the radial alignment of hepatocytes around the central vein, severe vacuolization in the hepatocyte cytoplasm, inflammation around central vein and portal region. In rats receiving both DI and silibinin, the DI induced changes accounted for less sinusoidal dilatation, vacuolization in the hepatocyte cytoplasm and the inflammation around central vein and portal region (P < 0.05).
CONCLUSIONS
The DI was found to induce liver damage by oxidative stress mechanisms. Silibinin reduced the oxidative stress by inducing antioxidant mechanisms, thereby showing protective effect against DI induced liver damage. Further studies with silibinin should be performed regarding DI toxicity.
PubMed: 26023342
DOI: 10.5812/ircmj.17(4)2015.25310 -
International Journal of Environmental... May 2022Endometriosis is a disease characterized by the presence of the uterine endometrium outside of its normal location. As the etiology of endometriosis is not well known... (Review)
Review
Endometriosis is a disease characterized by the presence of the uterine endometrium outside of its normal location. As the etiology of endometriosis is not well known and hormonal imbalance is central to disease pathogenesis, the potential contribution of exposure to endocrine-disrupting chemicals (EDCs) has been hypothesized in endometriosis. A systematic search of the literature was carried out to identify relevant studies using: PubMed, Scopus, Elsevier, Springer; EBSCO, and Web of Science. A total of 22 studies were considered. Most of the studies reviewed in this paper showed an association between exposure to BPA and phthalates and endometriosis. In the case of phthalate exposure, the reviewed studies found an association between the concentration of at least one phthalate metabolite and endometriosis. Only one study was performed to assess the exposure to parabens and a significant relationship with endometriosis was found. Additionally, only one study assessed the relationship of non-persistent pesticide exposure with endometriosis, observing a significant association between endometriosis and the urinary concentration of diazinon, chlorpyrifos, and chlorpyrifos-methyl. Studies struggled to provide a conclusion on the effect of exposure to benzophenones on endometriosis. Despite the numerous limitations of the results, the reviewed studies suggest that exposure to non-persistent endocrine disruptors, especially bisphenol A and phthalates may affect endometriosis. The results of the studies on exposure to parabens, benzophenones, and non-persistent insecticides are inconclusive.
Topics: Benzophenones; Endocrine Disruptors; Endometriosis; Environmental Exposure; Environmental Pollutants; Female; Humans; Parabens; Phthalic Acids
PubMed: 35565013
DOI: 10.3390/ijerph19095608 -
Ticks and Tick-borne Diseases Mar 2022In the present study, the acaricide susceptibility status of Hyalomma marginatum in Morocco was investigated in the Rabat-Sale-Kenitra region using the Larval Packet...
In the present study, the acaricide susceptibility status of Hyalomma marginatum in Morocco was investigated in the Rabat-Sale-Kenitra region using the Larval Packet Test. The overall LC value for diazinon and amitraz was 115 ppm (95% CI: [104; 125]) and 22 ppm (95% CI: [21; 23]), respectively. The LC values varied significantly between the nine sampled locations (P<0.001) ranging from 75 ppm (95% CI: [65; 84]) in Ouelmes to 179 ppm (95% CI: [139; 201]) in Jorf El Melha for diazinon and from 18 ppm (95% CI: [15; 21]) in Skhirat to 28 ppm (95% CI: [24; 31]) in Ouelmes for amitraz. Sequencing of the target-site of diazinon, acetylcholinesterase 1 (AChE1), indicated that previously reported resistance mutations in AChE1 were absent in ticks from Jorf El Melha surviving 500 ppm diazinon. This study is the first report on the H. marginatum susceptibilty status to the most frequently used acaricides in Morocco and indicates that acaricide tick resistance is emerging.
Topics: Acetylcholinesterase; Animals; Diazinon; Ixodidae; Morocco; Tick Infestations; Toluidines
PubMed: 34894524
DOI: 10.1016/j.ttbdis.2021.101883 -
Arhiv Za Higijenu Rada I Toksikologiju Dec 2011Formulation components of organophosphate insecticidal preparations might affect their toxic action in animals. The objective of this study was to examine and compare...
Formulation components of organophosphate insecticidal preparations might affect their toxic action in animals. The objective of this study was to examine and compare the acute toxicity and cholinesterase inhibition in seven to 14-day-old chicks dosed orally with dichlorvos and diazinon in standard veterinary and agricultural formulations. The acute (24 h) oral median lethal doses (LD50) of the formulations were determined using the up-and-down method. Respective LD50 of dichlorvos of the veterinary and agricultural formulations in chicks were 11.1 mg kg(-1) and 6.51 mg kg(-1) and those of diazinon 6.4 mg kg(-1) and 6.7 mg kg(-1). Plasma and brain cholinesterase activities were measured by electrometry after in vivo and in vitro exposure to organophosphates. The chicks showed signs of cholinergic toxicosis within one hour of dosing. Dichlorvos (8 mg kg(-1)) and diazinon (4 mg kg(-1)) in the veterinary and agricultural formulation significantly reduced both plasma and brain cholinesterase activities in the chicks. The veterinary formulation of dichlorvos reduced plasma ChE by 60% and agricultural by 40% and brain ChE by 93% and 87%, respectively. In contrast, ChE inhibition by diazinon in the agricultural formulation of diazinon was stronger than by the veterinary formulation; 72% vs. 64% in plasma and 97% vs. 80% in the brain, respectively. The highest in vitro inhibitions were observed with dichlorvos in the agricultural formulation (50%) in the brain samples and with diazinon in the agricultural formulation (52%) in the plasma samples. While they exist, differences between formulations cannot be taken as a rule and further investigations should inventory the toxicity of standard veterinary and agricultural organophosphate formulations in addition to the known data for pure forms.
Topics: Agrochemicals; Animals; Chickens; Cholinesterase Inhibitors; Diazinon; Dichlorvos; Insecticides; Organophosphorus Compounds; Poultry Diseases
PubMed: 22202465
DOI: 10.2478/10004-1254-62-2011-2139 -
Frontiers in Veterinary Science 2022An epidemiological (cross-sectional) and therapeutic (randomized controlled field trial) study was conducted on sheep lice in Sayint district, South Wollo, Northeast...
An epidemiological (cross-sectional) and therapeutic (randomized controlled field trial) study was conducted on sheep lice in Sayint district, South Wollo, Northeast Ethiopia. The aim of the study was to (i) quantify the magnitude of sheep lice burden and the prevailing lice species, (ii) identify and quantify risk factors affecting lice infestation in sheep, and (iii) evaluate the efficacy of commonly used acaricides (diazinon and ivermectin) against sheep lice infestation. A total of 232 randomly selected sheep, 15 naturally infested sheep, and 80 viable lice were used for epidemiological, , and based therapeutic studies, respectively. Three naturally infested treatment groups each with five sheep (Group I-treated with diazinon, Group II-treated with ivermectin, and Group III-untreated/control) were used for therapeutic study. Lice count for the corresponding treatment groups was conducted on weekly basis using clinical and parasitological examinations. We used logistic regression to quantify the association between different putative risk factors and lice infestation, and the independent -test and one-way ANOVA to compare the within and between treatment group mean lice count variations. The overall prevalence of sheep lice in the study area was 48.3%, where (83%) was the dominant lice species. Hair length, body condition, agroecology, and season were significantly ( < 0.05) associated with sheep lice infestation. Analysis of variance revealed that mean lice count significantly ( < 0.05) varies between treatment groups. A significant ( < 0.05) low mean lice cunt was recorded in diazinon- and ivermectin-treated groups when compared to untreated group. The efficacy of ivermectin (81%) was lower than diazinon (99%) when compared to the efficacy standard limit (98-100%). However, no significant mean lice count variation was recorded between the two groups. (99%) and (95%) assay evidence revealed that diazinon was highly effective for the treatment of sheep lice. According to this study, it can be concluded that the magnitude of sheep lice burden in Sayint district was found to be high and this could have a potential negative impact on sheep productivity and health performances. Thus, applying an appropriate intervention measure including the right choice of effective acaricides could help to control sheep lice in the study area.
PubMed: 36406066
DOI: 10.3389/fvets.2022.1008455 -
Proceedings of the National Academy of... Oct 2019Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such...
Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.
Topics: Acetylcholinesterase; Animals; Aphids; Carboxylic Ester Hydrolases; Cell Line; Diazinon; Female; HEK293 Cells; Humans; Insecticide Resistance; Insecticides; Malathion; Mice; Mice, Inbred C57BL; Organophosphates
PubMed: 31575743
DOI: 10.1073/pnas.1909130116