Chlorfenapyr is a widely used, moderately hazardous pesticide. Previous reports have indicated that chlorfenapyr intoxication can be fatal in humans. We reported the first non-fatal case of chlorfenapyr-induced toxic leukoencephalopathy in a 44-year-old female with resolution of extensive and abnormal signal intensities in white matter tracts throughout the brain, brain stem, and spinal cord on serial magnetic resonance imaging.
Adult ; Brain/*radiography ; Brain Stem/radiography ; Female ; Humans ; Insecticides/*toxicity ; Leukoencephalopathies/*etiology/radiography ; *Magnetic Resonance Imaging ; Pyrethrins/*toxicity ; Spinal Cord/*radiography ; White Matter/radiography

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 mechanism of di-2-ethylhexyl phthalate (DEHP) and cypermethrin (CYP) inducing gonadal dysgenesis in prepubertal male rats.

METHODSA total of 40 healthy 3-week-old specific pathogen-free male Sprague-Dawley rats were randomly and equally divided into four groups: control group (corn oil), DEHP group (500 mg/kg, dissolved in corn oil), CYP group (80 mg/kg, dissolved in corn oil), and combined exposure group (exposed to 500 mg/kg DEHP and 80 mg/kg CYP, dissolved in corn oil). Rats were treated by gavage administration once a day for 30 days. Twenty-four hours after the last exposure, the animals were sacrificed. The body weight and the wet weight of testis were determined, and the weight coefficient of testis was calculated. Radioimmunoassay was used to determine serum testosterone level. Ultrastructural-level histopathological changes of the testis were examined by transmission electron microscopy. The mRNA and protein expression of follicle stimulating hormone receptor (FSHR), androgen binding protein (ABP), inhibin beta-B (INHBB) and vimentin (VIM) were analyzed by real-time PCR and Western blot, respectively. Factorial design analysis of variance was used to compare differences between groups; interaction diagrams were used to determine the interaction between DEHP and CYP.

RESULTSCompared with those of the control group, the testis weights and testis coefficients of the DEHP, CYP, and combined exposure groups significantly decreased by 39.3-59.2%and 19.7-58.6%, respectively, and all exposure groups showed significant reductions in serum level of testosterone, ranging from 49.1% to 62.7% (P < 0.05 or P < 0.01). And all the exposure groups showed different levels of ultrastructural damages in the testes. Compared with that in the control group, the mRNA expression of FSHR, ABP, INHBB, and VIMin the DEHP group was down-regulated by 1.72, 2.64, 2.83 and 1.79 times, and their protein levels were significantly reduced by 65.2%, 53.7%, 70.1%, and 51.9% (P < 0.05 or P < 0.01). Significant decreases in mRNA expression of ABP (down 1.72 times) and INHBB (down 2.06 times) were observed in the CYP group, and their protein levels decreased by 38.3% and 49.7%, respectively (P < 0.05). The combined exposure to both DEHP and CYP resulted in big decreases in the mRNA levels of FSHR (down 1.62 times), ABP (down 2.00 times), INHBB (down 2.35 times), and VIM (down 1.54 times) and protein levels of FSHR (down 52.1%), INHBB (down 53.9%), and VIM (down 58.8%) (P < 0.05). Factorial design analysis of variance showed that the combination of two substances had an antagonistic effect on the expression of ABP and INHBB (P < 0.05).

CONCLUSIONDEHP and CYP, alone or combined, can lead to gonadal dysgenesis in prepubertal male rats. Both of them can disrupt functional mRNA and protein expression in Sertoli cells to certain levels. The combination of DEHP and CYP shows antagonistic effects, and DEHP has a stronger reproductive toxicity than CYP.

Animals ; Diethylhexyl Phthalate ; toxicity ; Gonadal Dysgenesis ; chemically induced ; Male ; Pyrethrins ; toxicity ; Rats ; Rats, Sprague-Dawley ; Sertoli Cells ; metabolism ; Testis ; cytology ; drug effects

OBJECTIVETo explore the effect of maternal cypermethrin exposure during lactation on learning and memory ability in adult female offspring, as well as the possible mechanism.

METHODSTwelve maternal mice were randomly divided into 6.25 mg/kg cypermethrin, 25.0 mg/kg cypermethrin and control groups (four dams each group, ten pups each dam, half male half female, twenty female pups each group). Maternal mice were orally administered with different doses of cypermethrin (6.25 and 25 mg/kg/d) once daily from postnatal day1 (PND1) to PND21. Maternal mice in control group were treated with corn oil. The learning and memory ability of female offspring were observed by using water labyrinth task for continuously seven days on PND60. All the female offspring were killed and the brain and hippocampus were detached after the test. The expression level of NMDA receptor NR1 protein in hippocampus was detected by Western-blotting.

RESULTSThere were no statistically significant in the difference in weight of body and brain among three groups (P > 0.05). Through the Repeated one way ANOVA, the learning time of latency in the 25.0 mg/kg cypermethrin group [(31.3 ± 17.0) s] were significantly longer than that in the control group [(21.0 ± 14.0) s] (P < 0.05). The memory time of latency in the 25.0 mg/kg cypermethrin group [(24.6 ± 21.1) s] were significantly longer than that in the control group [(14.1 ± 16.3) s] (P < 0.05). However, the difference of the wrong number among groups was not statistically significant in the test (P > 0.05).

CONCLUSIONMaternal cypermethrin exposure during lactation disturbs learning and memory ability in adult female offspring in a degree, which maybe caused by the reduction of protein level of hippocampus NR1.

Animals ; Animals, Newborn ; Female ; Male ; Maternal Exposure ; Maze Learning ; Memory ; Mice ; Mice, Inbred ICR ; Pregnancy ; Pyrethrins ; 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

Animals ; Humans ; Neurotoxins ; toxicity ; Pesticides ; toxicity ; Pyrethrins ; toxicity ; Toxicology

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

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 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