The inappropriate utilisation of the agricultural insecticide lambda-cyhalothrin (LCT) has the potential to result in residues that compromise food safety and human health. Respiratory exposure represents a major route of LCT contact in humans. Nevertheless, its deleterious effects on the respiratory system remain inadequately characterized. It is imperative to elucidate the potential relationship and mechanisms by which lung cancer, a significant malignant neoplasm of the respiratory system, is associated with exposure to LCT. The objective of this study is to utilise bioinformatics methodologies to screen and analyse the key target molecules affected by LCT in the occurrence of lung cancer, and their mechanisms of action. Specifically, network toxicology methods were employed to identify core targets of LCT-induced lung cancer. Subsequently, functional annotation to delineate associated cellular pathways, and finally, molecular docking to simulate binding modes between LCT and shared core targets. Core target screening identified 50 targets for large cell lung cancer, 54 for small cell lung cancer, 29 for lung squamous cell carcinoma, and 28 for lung adenocarcinoma, with EGFR, HSP90AA1, JUN, CCL2, MYC, CXCL8, and HSPA4 shared in all subtypes. Functional annotation revealed that LCT-triggered oncogenic pathways predominantly involved ubiquitination, chemotaxis, and tumor immune signaling. Molecular docking demonstrated spontaneous binding of LCT to core targets mediated by hydrogen bonds and π-cation interactions. These results establish a theoretical framework for evaluating LCT-associated risks of lung cancer and respiratory system damage.
Lung Neoplasms/metabolism* ; Pyrethrins/toxicity* ; Humans ; Insecticides/toxicity* ; Nitriles/toxicity* ; Molecular Docking Simulation

OBJECTIVETo investigate whether fenvalerate can induce mouse hippocampal nerve cell damage by interfering with estrogen (E2) effect.

METHODSHippocampus were dissected and cultured from Embryo 18 d ICR mice, the cells were cultured for 7 days. Fenvalerate (FEN, 0, 1, 10, 50 µg/ml), FEN (10, 50 µg/ml) and estrogen receptor antagonist ICI 182, 780 (1 µmol/L), FEN (0, 10, 50 µg/ml) and E2 (10 nmol/L) were applied to the cultured cells for 48h. Immunocytochemically stained with neurons and astrocytes to evaluate the levels respectively, and the growth of neurite. Result 1µg/ml FEN have no effect on neurons, neurites and protoplasmic astrocytes, 10 and 50 µg/ml FEN can significantly decrease the neuron viability and the length of neurite as well as increase the level of protoplasmic astrocytes (P < 0.05 vs. control group). ICI 182, 780 alone have no effect on neurons, neurites and protoplasmic astrocytes; ICI+10 µg/ml FEN significantly increase the cell viability and extend neurite length as well as decrease protoplasmic astrocytes (P < 0.05 vs. 10 µg/ml FEN alone group); ICI+50 µg/ml FEN significantly increase the cell viability and decrease protoplasmic astrocytes (P < 0.05 vs. 50 µg/ml FEN alone group). E2 alone have no effect on protoplasmic astrocytes, while can promote neuronal survival and neurite growth; E2+10 µg/ml FEN and E2+50 µg/ml FEN significantly decrease neuronal survival and neurite growth, as well as increase protoplasmic astrocytes (P < 0.05 vs. E2 alone group).

CONCLUSIONFenvalerate can induce the loss of hippocampal neurons through disrupting estrogen nuclear receptor signaling, and inhibit the length of neurite through disrupting estrogen nuclear receptor and membrane receptor signaling. The effect of estrogen disruption play an important role in developmental neurotoxicity by fenvalerate.

Animals ; Astrocytes ; drug effects ; Cells, Cultured ; Estrogens ; pharmacology ; Hippocampus ; drug effects ; pathology ; Mice ; Mice, Inbred ICR ; Neurons ; drug effects ; pathology ; Nitriles ; toxicity ; Pyrethrins ; toxicity

OBJECTIVETo investigate the estrogen interference property of fenvalerate in neurodevelopmental toxicity.

METHODSThirty 4-week-old healthy female ICR mice were randomly divided into 6 groups: sham operation group, ovariectomized control group, ovariectomized with estrogen (10 µg/g) group, ovariectomized with fenvalerate (5 µg/g) group, sham operation with fenvalerate group, and ovariectomized with estrogen and fenvalerate group, with 5 mice in each group. Fenvalerate was injected intraperitoneally once a day for 7 consecutive days. Mice were sacrificed at 24 h after the last exposure to separate the hippocampus. Immunofluorescence was used to detect neuron marker (NeuN) and astrocyte marker (GFAP) in hippocampal CA1, CA3, and DG regions.

RESULTSCompared with the sham operation group (numbers of NeuN-positive cells: CA1 (54.00±1.73), CA3 (59.00 ± 1.73), DG (100.00 ± 4.58)), the sham operation with fenvalerate group (CA1 (37.67 ± 2.08), CA3 (41.33 ± 1.15), DG (80.67±0.58)) and ovariectomized control group (CA1 (44.00 ± 3.00), CA3 (51.00 ± 3.00), DG (83.00 ± 1.72)) showed significant decreases in number of neurons (NeuN-positive cells) in the hippocampus (P < 0.05). Compared with the ovariectomized control group, the ovariectomized with fenvalerate group (CA1 (47.67 ± 3.21), CA3 (49.00 ± 1.73), DG (87.33 ± 4.04)) showed no significant change in number of hippocampal NeuN-positive cells. Compared with the ovariectomized with fenvalerate group (CA1 (47.67 ± 3.21), DG (87.33 ± 4.04)), the sham operation with fenvalerate group and ovariectomized with estrogen and fenvalerate group (CA1 (40.00 ± 1.00), DG (78.67 ± 2.31)) experienced significant decreases in NeuN-positive cells (P < 0.05). Compared with the sham operation group (CA3 (11.00 ± 1.12), DG (10.67 ± 1.15)), the sham operation with fenvalerate group (CA3 (18.67 ± 2.07), DG (16.33 ± 1.53)) showed significant increase in number of astrocytes (GFAP-positive) cells (P < 0.05). Compared with the sham operation with fenvalerate group, the ovariectomized with fenvalerate group (CA3 (12.00 ± 1.00), DG (11.68 ± 1.16)) showed significant decrease in GFAP-positive cells (P < 0.05). Compared with the ovariectomized with fenvalerate group, the sham operation with fenvalerate group and ovariectomized with estrogen and fenvalerate group (CA3 (16.67 ± 2.13), DG (15.38 ± 1.42)) showed significant increases in GFAP-positive cells (P < 0.05).

CONCLUSIONThe interference with circulating estrogen is an important mechanism underlying the neurodevelopmental toxicity of fenvalerate.

Animals ; Estrogens ; pharmacology ; Female ; Hippocampus ; drug effects ; pathology ; Mice ; Mice, Inbred ICR ; Neurons ; drug effects ; pathology ; Nitriles ; toxicity ; Ovariectomy ; Pyrethrins ; toxicity

OBJECTIVETo investigate the cytotoxicity of bromoxynil on SH-SY5Y cells and its effect on the expression of nuclear factor-kappa B (NF-κB) and I kappa B alpha (IκBα) in SH-SY5Y cells.

METHODSSH-SY5Y cells were exposed to bromoxynil (10, 50, or 100 µmol/L) for 24 and 48 h, and other SH-SY5Y cells, which were used as a control, were exposed only to dimethyl sulfoxide. After 24 and 48 h of exposure, the morphological changes of these cells were observed under an inverted microscope, and the cytotoxicity of bromoxynil was measured by MTT assay. The cellular proliferation was examined by cell counting after 12, 24, 48, 72, and 96 h of exposure. After 24 h of exposure, the expression of NF-κB was evaluated by Western blot and immunocytochemistry, and the expression of IκBα was evaluated by Western blot.

RESULTSThe cellular proliferation inhibition rates (CPIRs) of 50 and 100 µmol/L groups were significantly higher than that of the control group after 24 and 48 h of exposure (P < 0.05); the CPIR was significantly higher after 48 h than after 24 h in the two groups (P < 0.05). The growth curve revealed that these groups began to show differences in cell count at the 24th of exposure and that the differences were even more marked as the exposure went on (F = 17.15, P < 0.05). The control group had a significantly increased cell count at the 48th, 72nd, and 96th h of exposure (P < 0.05); the 10 and 50 µmol/L groups had a significantly increased cell count at the 72nd and 96th h of exposure (P < 0.05); the 100 µmol/L group showed no significant change in cell count during 96h of exposure. The 50 and 100 µmol/L groups hada significantly longer cell doubling time than the control group (P < 0.05). The immunocytochemistry showed that as the dose of bromoxynil increased, the brownish yellow particles in the cytoplasm and nuclei became darker, the expression of NF-κB was upregulated, and the nuclear translocation of NF-κB was increased. The Western blot showed that the 100 µmol/L group had significantly higher expression of NF-κB in the nuclei than the control group (P < 0.05) and that the 50 and 100 µmol/L groups had significantly lower expression of IκBα in total proteins than the control group (P < 0.05).

CONCLUSIONBromoxynil can inhibit the proliferation of SH-SY5Y cells under this experimental condition, which may be related to activation of NF-κB.

Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; I-kappa B Proteins ; metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B ; metabolism ; Nitriles ; toxicity

OBJECTIVETo evaluate histopathological alterations of the liver and kidney of female rats exposed to low doses of DM and its potential genotoxic activity.

METHODSFemale Wistar rats were randomly assigned to control (3 groups, 6 rats in each) and treatment groups (3 groups, 6 rats in each). They were subjected to subcutaneous injections of DM (at doses of 0.003, 0.03, and 0.3 mg/kg bw/d) after 30, 45, and 60 d, respectively.

RESULTSSignificant alterations were recorded in liver parenchyma induced by hepatic vacuolization, fragmented chromatin in nuclei, dilatation of sinusoids and congestions. Lesions within proximal and distal tubules were observed in the kidneys. Tissue congestions and severe alterations within glomeruli were visible. DM as a pyrethroid insecticide induced significant increase (P≤0.05) of plasma MDA concentrations after 45 d. A significant increase (P≤0.05) in plasma ALT (after 45 and 60 d) and AST (after 60 d) concentrations was recorded as compared to controls. During the whole experimental period the toxic agent provoked significant DNA damages (P≤0.05), especially in the dominance of classes 3 and 4 of obtained comet.

CONCLUSIONDM even at a very low dose displays harmful effects by disrupting hepatic and renal function and causing DNA damages in puberscent female rats. Low doses of DM are hepatotoxic and nephrotoxic.

Animals ; Aspartate Aminotransferases ; metabolism ; Behavior, Animal ; drug effects ; Chemical and Drug Induced Liver Injury ; metabolism ; pathology ; Creatinine ; blood ; Dose-Response Relationship, Drug ; Female ; Insecticides ; administration & dosage ; chemistry ; toxicity ; Kidney ; drug effects ; Kidney Diseases ; chemically induced ; pathology ; Liver ; drug effects ; Malondialdehyde ; Molecular Structure ; Nitriles ; administration & dosage ; chemistry ; toxicity ; Organ Size ; Oxidative Stress ; drug effects ; Pyrethrins ; administration & dosage ; chemistry ; toxicity ; Random Allocation ; Rats ; Urea ; blood ; Weight Gain ; drug effects

Adverse drug reactions constitute a major public health problem. In recent years, serious safety issues arose with marketed drugs, and public outcry demanded better safety surveillance. Now regulatory focus is shifting to the active post-marketing safety surveillance. This paper provides an overview of the recent international initiatives of drug safety management especially focused on the US and Europe. The US Food and Drug Administration's (FDA) Sentinel Initiative is a long-term program designed to build and implement a national electronic system for monitoring the safety of FDA-approved drugs and other medical products. The Sentinel System will enable FDA to monitor the safety of medical products with the assistance of a wide array of collaborating institutions throughout the nation. The European Network of Centers for Pharmacoepidemiology and Pharmacovigilance is a collaborative scientific network coordinated by the European Medicines Agency and developed in collaboration with European experts in the fields of pharmacoepidemiology and pharmacovigilance. Its goal is to further strengthen the post-marketing monitoring of medicinal products in Europe by facilitating the conduct of multi-center, independent, post-authorization studies focusing on safety and on benefit-risk. Medicine is a global enterprise that demands worldwide standards for good drug safety practices. In the near future, we have to establish a Korean Sentinel System for active post-marketing safety surveillance to ensure the safety and effectiveness of drugs used in medical practice.
Cooperative Behavior ; Dietary Sucrose ; Drug Toxicity ; Electronics ; Electrons ; Europe ; Nitriles ; Organothiophosphorus Compounds ; Pharmacoepidemiology ; Pharmacovigilance ; Public Health ; Pyrethrins ; Safety Management

OBJECTIVETo explore the effects of rat maternal exposure to fenvalerate during lactation on behaviors development in rat pubertal female offspring.

METHODSTwelve ICR maternal mice were randomly divided into 7.5 and 30.0 mg/kg fenvalerate exposure groups and control group (four dams each group, ten pups each dam, half male half female, twenty female pups each group). The exposure groups were orally exposed to fenvalerate at the doses of 7.5 and 30 mg/kg a day from postnatal day 1 (PND1) to PND21. The control group was exposed to corn oil. The effects of maternal fenvalerate exposure during lactation on motor and species-typical behaviors in female offspring were observed on the PND 35.

RESULTSThe peripheral time and standing frequency of 30.0 mg/kg exposure group were (263.4 ± 54.8) s and (47.3 ± 16.2) times, which were significantly higher than those [(203.4 ± 53.0) s and (30.9 ± 17.3) times] of control group (P < 0.05). The scores in 7.5 mg/kg and 30.0 mg/kg exposure groups were 56.50 ± 50.79 and 54.73 ± 53.91, respectively, which were significantly lower than that (114.53 ± 53.87) in control group (P < 0.05). However, no significant differences in beam walking scores, food hoarding quantity, food digging quantity, and nest construction scores between two exposure groups were found (P > 0.05).

CONCLUSIONThe rat maternal exposure to fenvalerate during lactation could decrease the ability of exploration and motor condition and increase the anxiety but not affect life habit in rat pubertal female offspring.

Animals ; Behavior, Animal ; Female ; Male ; Maternal Exposure ; Mice ; Mice, Inbred ICR ; Nitriles ; toxicity ; Pregnancy ; Prenatal Exposure Delayed Effects ; Pyrethrins ; toxicity

OBJECTIVETo evaluate the influence on the synaptic protein expression in different brain regions of ICR mice after lambda-cyhalothrin (LCT) exposure during postnatal period.

METHODSTwo male and 4 female healthy ICR mice were put in one cage. It was set as pregnancy if vaginal plug was founded. Offspring were divided into 5 groups randomly, and exposed to LCT (0.01% DMSO solution) at the doses of 0.1, 1.0 and 10.0 mg/kg by intragastric rout every other day from postnatal days (PND) 5 to PND13, control animals were treated with normal saline or DMSO by the same route. The brains were removed from pups on PND 14, the synaptic protein expression levels in cortex, hippocampus and striatum were measured by western blot.

RESULTSGFAP levels of cortex and hippocampus in the LCT exposure group increased with doses, as compared with control group (P < 0.05), while Tuj protein expression did not change significantly in the various brain regions of ICR mice. GAP-43 protein expression levels in the LCT exposed mouse hippocampus and in female ICR mouse cortex increased with doses, as compared with control group (P < 0.05). Presynaptic protein (Synapsin I) expression levels did not change obviously in various brain regions. However, postsynaptic density protein 95 (PSD95) expression levels of the hippocampus and striatum in male offspring of 10.0 mg/kg LCT group, of cortex of female LCT groups, and of female offspring in all exposure groups, of striatum, in 1.0 or 10.0 mg/kg LCT exposure groups significantly decreased (P < 0.05).

CONCLUSIONSEarly postnatal exposure to LCT affects synaptic protein expression. These effects may ultimately affect the construction of synaptic connections.

Animals ; Animals, Newborn ; Brain ; drug effects ; metabolism ; Corpus Striatum ; drug effects ; metabolism ; Female ; Hippocampus ; drug effects ; metabolism ; Male ; Mice ; Mice, Inbred ICR ; Nitriles ; toxicity ; Pyrethrins ; toxicity ; Synapsins ; metabolism

OBJECTIVEto investigate the changes of γ-aminobutyric acid (GABA) and glutamate (Glu) in the cerebral cortex following acute bromoxynil intoxication in mice and the protective effect of sodium dimercaptopropane sulfonate (Na-DMPS).

METHODS30 ICR mice were randomly divided into blank control group (10), exposure group (10) and Na-DMPS protection group (10). The levels of GABA and Glu in the cerebral cortex were measured by RP-HPLC. The glutamine (Gln) level and the glutamine synthetase (GS), glutamate decarboxylation enzyme (GAD), γ-aminobutyric acid transaminase (GABA-T) activity in the cerebral cortex were determined by UV colorimetric.

RESULTScompared with the control group [GABA: (3.41 ± 0.12) micromol/g, Glu (14.00 ± 0.16) micromol/g, Gln (1.25 ± 0.19) micromol/g, GAD (13.50 ± 0.25) micromol × g(-1) × h(-1), GABA-T (25.51 ± 0.21) micromol × g(-1) × h(-1), GS(142.19 ± 1.31) U/mg pro], the level of GABA [(3.14 ± 0.14) micromol/g] was decreased (P < 0.05), whereas the level of Glu [(17.54 ± 0.40) micromol/g] and Gln [(3.35 ± 0.27) micromol/g] were increased (P < 0.05), the activity of GAD [(11.93 ± 0.15 micromol × g(-1) × h(-1)], GABA-T [(24.15 ± 0.22) micromol × g(-1) × h(-1)], GS [(140.75 ± 1.01) U/mg pro] was decreased (P < 0.05) in acute intoxication group; Compared with the acute intoxication group, the level of GABA [(3.52 ± 0.30) micromol/g] was increased (P < 0.05), whereas the level of Glu [(14.20 ± 0.32) micromol/g] and Gln [(1.32 ± 0.17) micromol/g] were decreased (P < 0.05), the activity of GAD [(13.01 ± 0.45 micromol × g(-1) × h(-1)], GABA-T [(25.19 ± 0.26) micromol × g(-1) × h(-1), GS [(142.35 ± 1.20) U/mg pro] was increased (P < 0.05); In contrast, the levels of GABA, Glu, Gln and the activity of GAD, GABA-T, and GS in Na-DMPS protection group were not significantly different in comparison with control group (P > 0.05).

CONCLUSIONthe central toxic effects of mice with acute bromoxynil intoxication may be related to the changes of GABA and Glu content in the cerebral cortex;Na-DMPS can protect mice from bromoxynil-induced central toxic effects and GABA and Glu abnormal change in the cerebral cortex.

Animals ; Cerebral Cortex ; drug effects ; metabolism ; Female ; Glutamic Acid ; metabolism ; Male ; Mice ; Mice, Inbred ICR ; Nitriles ; poisoning ; Toxicity Tests, Acute ; Unithiol ; pharmacology ; gamma-Aminobutyric Acid ; metabolism

OBJECTIVETo study the protective effect of MG-132 on hippocampus cells apoptosis induced by deltamethrin (DM), one kind of pyrethroid pesticide.

METHODS40 Male wistar rats were randomly divided into four groups: olive oil control, DM treated alone (12.5 mg/kg), MG-132 (0.5 mg/kg) plus DM group, MG-132 treated 2h plus olive oil. After 24h treatment of DM, the hippocampus was taken out to detect the apoptotic cell rate, the level of bcl-2 and Caspase-3 activity.

RESULTSCompared with DM treated alone group (27.29% +/- 2.41%), the apoptotic cell rate in MG-132 + DM group (19.94% +/- 2.07%) was increased (P < 0.05), bcl-2 expression was enhanced [(0.43 +/- 0.06) vs. (2.01 +/- 0.23)] (P < 0.05) and the activity of Caspase-3 was decreased significantly (P < 0.05) in MG-132 treated 2h plus DM group [(4.55 +/- 0.46) vs.(3.73 +/- 0.35)].

CONCLUSIONMG-132 can protect hippocampus cells against apoptosis induced by deltamethrin.

Animals ; Apoptosis ; drug effects ; Hippocampus ; cytology ; drug effects ; Insecticides ; toxicity ; Leupeptins ; pharmacology ; Male ; Neurons ; drug effects ; Nitriles ; toxicity ; Pyrethrins ; toxicity ; Rats ; Rats, Wistar