Exposure to humidifier disinfectants was identified in 2011 as the potential cause of an outbreak of lung disease in Korea. It is estimated that over 8 million people have been exposed to humidifier disinfectants—chemicals added to the water used in humidifiers to prevent the growth of microorganisms—since their commercial introduction. The primary component of humidifier disinfectant products involved was polyhexamethylene guanidine phosphate (PHMG-P), a guanidine-based antimicrobial agent. Lesions observed in the lungs of patients were similar to those observed in laboratory animals exposed to PHMG-P. In this review, we outline the physicochemical and toxicological properties of PHMG-P, and introduce a putative mechanism for its lung toxicity based in large part on research findings to date.
Potential health risks for humans from dietary exposure to acrylamide (AA) and its reactive epoxide metabolite, glycidamide (GA), exist because substantial amounts of AA are found in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of studies indicate that AA is genotoxic in multiple organs of mice and rats. Although AA is neurotoxic, there are no reports on AA-induced gene mutations in the mouse brain. Therefore, to investigate if gene mutation can be induced by AA or its metabolite GA, we screened brains for cII mutant frequency (MF) and scored for mutation types in previously treated male and female Big Blue mice with 0, 1.4 mM, and 7.0 mM AA or GA in drinking water for up to 4 weeks. High doses of AA and GA induced similar cII MFs in males and females but only the induced cII MF in males was significantly higher than the corresponding male control MF (p < 0.05). Molecular analysis of the cII mutants from males showed that AA and GA each induced at least a 2.5-fold increase in the incidence of G:C → T:A, A:T → T:A, and A:T → C:G transversions compared to the vehicle controls, with similar mutational spectra observed when comparing AA with GA treatment. These results suggest that the MFs and types of mutations induced by AA and GA in the brain are consistent with AA exerting its genotoxicity via metabolism to GA.
Trifloxystrobin is a strobilurin class fungicide, the mode of action of which is to block the mitochondrial electron transport chain and inhibit energy production in fungi. Although adverse effects have been reported by occupational or environmental exposure of fungicides, the pathophysiological mechanism in human cells remains poorly understood. In the present study, we investigated the impact of trifloxystrobin on exposed skin at the cellular organelle level using HaCaT, the human skin keratinocyte cell line. Cells were treated with trifloxystrobin for 48 hr and trifloxystrobin showed detrimental effects on mitochondria evidenced by altered mitochondrial membrane potential and morphology. To identify autophagic degradation of the damaged mitochondria, confocal imaging and Western blotting were performed. Trifloxystrobin induced autophagy-related proteins in HaCaT cells. The mitochondrial reactive oxygen species scavenger mitoTEMPO was applied to further explore the mechanism of trifloxystrobin-mediated mitophagy in human skin cells. PINK1 and Parkin were overexpressed by trifloxystrobin, and mitoTEMPO alleviated the effects on mitophagy induction. Taken together, our findings indicated that mitochondrial damage and mitophagy may play a role in trifloxystrobin-induced toxicity in human keratinocytes and this could be suggested as a mechanism of cutaneous diseases developed by exposure.
Sildenafil is a phosphodiesterase type-5 inhibitor. We evaluated the effects of sildenafil on the sinoatrial rate, developed tension of the papillary muscle and coronary blood flow by using the canine isolated, blood-perfused sinoatrial node and papillary muscle preparations. The former preparation had a regular automaticity rate of 106 ± 1 beats/min (n = 4), whereas the latter showed a developed tension of 22 ± 4 mN (n = 4) and a coronary blood flow of 3.9 ± 0.1 mL/min (n = 4). Intracoronary injection of 10, 30 and 100 µg of sildenafil, which would provide about 20 to 200 times higher plasma drug concentrations than its therapeutic level, increased the automaticity rate by 4, 12 and 22%, the developed tension by 19, 55 and 118% and the coronary blood flow by 42, 95 and 142%, respectively. These results indicate that supratherapeutic concentration of sildenafil possesses direct positive chronotropic and inotropic effects together with a coronary vasodilator action, confirming that caution has to be paid on the use of sildenafil for patients with ischemic heart diseases, obstructive hypertrophic cardiomyopathy and/or ventricular arrhythmias. The information on sildenafil reported in this study may help establish a guidance on cardiac safety assessment of newer phosphodiesterase type-5 inhibitors.
2,4-Dichlorophenol (2,4-DCP) is an environmental pollutant exhibiting a wide spectrum of toxic effects. We investigated the toxic effects and potential mechanisms underlying 2,4-DCP-induced hepatotoxicity. In vitro, 2,4-DCP caused hepatotoxicity manifested by a decrease in cell viability and inhibition of colony formation. Bip and CHOP expression was up-regulated at the mRNA and protein levels. Moreover, 2,4-DCP induced eIF2α phosphorylation and Xbp1 mRNA splicing, indicating that endoplasmic reticulum (ER) stress was activated after exposure of HL7702 cells to 2,4-DCP for 12 hr. Furthermore, the mitochondrial membrane potential collapsed and apoptosis was triggered after exposure to 2,4-DCP for 24 hr. In vivo, 2,4-DCP caused histological changes in the liver, and dramatically elevated the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels of mice. ER stress was also triggered in the liver of mice on days 1 and 3. The ER stress inhibitor TUDCA could partly relieve the liver damage, as indicated by the restoration of serum ALT and AST levels. Taken together, our results demonstrated that ER stress may serve as an early warning mechanism against 2,4-DCP-induced hepatotoxicity, and severe ER stress may lead to apoptosis.
About forty certified patients aged around 50 years old existed as living witnesses to fetal-type Minamata disease (methylmercury poisoning due to in utero exposure) in Minamata, Japan in 2006. Computerized hand tremor and postural sway tests with spectral analysis were conducted for 24 of them and in matched control subjects to examine the pathophysiological feature of neuromotor function. The tremor intensities of the patients with fetal-type Minamata disease were significantly larger than those of the 67 controls at every frequency band for both hands. In the patients, proportions for intensity at 1-6 Hz of both hands were larger, but those of the intensity at 6-10 Hz were smaller compared with the controls. The center frequency of a tremor was significantly lower in the patients than in the controls. Only eight males of the 24 patients were examined to evaluate postural sway because of extremely low scores in activities of daily living in the remaining. Most of the postural sway parameters obtained with eyes open and closed were significantly larger in the patients than in the male controls. Likewise, Romberg quotients of postural sway in anterior-posterior direction were significantly higher in the patients. In conclusion, the patients with fetal-type Minamata disease of our study showed a larger tremor of low frequency at less than 6 Hz and postural instability. Spectral analyses of computerized hand tremor and postural sway are suggested to be useful for assessing the pathophysiological change, related to a lesion of the cerebellum, resulting from prenatal methylmercury exposure.
OBJECTIVE: The purpose of this study was to identify the clinical aspects leading to overdose of multiple psychotropic drugs, in order to determine areas which need attention in the proper treatment of overdose patients. METHODS: Patients who were treated for overdose of psychotropic drugs at our emergency and critical center over two years were targeted. The clinical data was gathered from the medical records and database of all patients, including age, gender, vital signs, and laboratory data, drugs, and medical complications during hospital stay. In addition primary patient care at the emergency department was examined. RESULTS: Among the 277 patients treated during this study period, 255 (74.0%) used two or more types of psychotropic drugs. Risk factors associated with endotracheal intubation and aspiration pneumonitis included the use of antipsychotics and/or barbiturates as types of overdose drugs. The mean number of days in the ICU was 3.4 days. Seventy-four patients (26.7%) stayed 4 days or more in the ICU of which 16 patients (5.8%) still had suicidal thoughts. A significantly higher incidence of extended ICU stay or endotracheal intubation and aspiration pneumonitis was observed in the group who overdosed on more than 50 or 60 tablets of psychotropic drugs, respectively. CONCLUSIONS: Patients who ingested an overdose of more than 60 tablets of psychotropic drugs should be considered a high-risk group requiring intensive care with extended ICU stay. In case of including antipsychotics and/or barbiturates, the patient should be observed carefully due to a higher risk of medical complications.
While it has long been believed that benzenes and naphthalenes are unable to activate the aryl hydrocarbon receptor (AhR) because they are poor ligands, we recently reported that these quinoid metabolites upregulated cytochrome P450 1A1 (CYP1A1) in Hepa1c1c7 cells (Abiko et al., 2015). In the current study, AhR activation, measured with a bioluminescence-based cell free assay, was induced by 1,2-naphthoquinone (1,2-NQ), a metabolite of naphthalene. Consistent with this, 1,4-benzoquinone (1,4-BQ), tert-butyl-1,4-BQ, and 1,4-NQ, as well as 1,2-NQ, all electrophilic mono- and bi-cyclic quinones, upregulated CYP1A1 mRNA and protein in HepG2 cells, whereas their parent aromatic hydrocarbons had little effect. Furthermore, immunofluorescence analysis confirmed that these quinones enhanced translocation of AhR to the nucleus.
Antimony cytotoxicity was assessed in human embryonic kidney cells (HEK-293). Uptake, mitochondrial respiratory activity, ROS generation and diffusional kinetics were measured using fluorescence recovery after photobleaching (FRAP). Furthermore, the toxic effect induced by Sb was compared with As toxicity in regard to ROS generation and diffusional kinetics, which provides information on the protein aggregation process. Our results show a favored uptake of Sb(III) and a more severe effect, decreasing the mitochondrial activity more than in the presence of Sb(V). In comparison with As, the Sb species did not generate a significant increase in ROS generation, which was observed with As(III) and As(V). FRAP analysis yielded important information on the diffusion and binding dynamics of live cells in presence of these metalloids. The mobile fraction showed a strong decrease with the As species and Sb(III). The diffusion rate and the koff-rate were significantly decreased for the As and Sb species but were more strong in the presence of As(III).
The present study aimed to evaluate the acute locally injurious property of our most current hydroxyl radical generation system by hydrogen peroxide (H2O2) photolysis. This system, which releases 3% H2O2 with a 405-nm laser, was developed in our laboratory for the treatment of dental and periodontal infectious diseases. First, the hydroxyl radical yield generated by H2O2 photolysis was examined by applying an electron spin resonance-spin trapping technique. Second, the bactericidal effect of the device was examined under a simulant condition in which Streptococcus mutans, a pathogenic bacterial species that causes caries, was irrigated with running 3% H2O2 concomitantly with laser irradiation. Finally, the acute topical effect of the model apparatus on rat palatal mucosa was evaluated by histological examination. We found that the hydroxyl radical yield was dependent upon laser output power. The bacterial count was substantially reduced within as little as 3 min. No abnormal findings were observed in the palatal mucosa, even when rats received three treatments of 3% H2O2 with laser irradiation at an output power of 40 mW. These results suggest that our apparatus has the ability to kill bacteria via hydroxyl radical generation and is safe to use at the lesion site of dental and periodontal infectious diseases.
To clarify the major pathway of liver tumor development induced by imazalil (IMA), an imidazole fungicide, male constitutive androstane receptor (CAR)-knockout (CARKO) and wild-type (WT) mice were treated with IMA at 500 ppm in the diet up to 27 weeks after initiation by diethylnitrosamine. After 27 weeks of treatment, neither altered foci nor adenomas were significantly increased in CARKO mice, whereas both eosinophilic altered foci and adenomas were increased in WT mice. After 4 or 13 weeks of IMA treatment, liver hypertrophy was observed at the tumor-inducible dose without differences among genotypes or durations. Analysis of hepatic drug metabolite enzymes, performed after administration of multiple doses during a 1-week period, indicated that pregnane X receptor might be involved in liver hypertrophy because IMA markedly elevated Cyp3a11 and Cyp2b10 expression levels in a dose-dependent manner in both genotypes. Our results demonstrated that the CAR pathway was the main mechanism of liver tumor development induced by IMA. The carcinogenic pathway was different from that of liver hypertrophy.
N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-3-methyl-D-valine methyl ester (5F-ADB) is one of the most potent synthetic cannabinoids and elicits severe psychotic symptoms in humans, sometimes causing death. To investigate the neuronal mechanisms underlying its toxicity, we examined the effects of 5F-ADB on midbrain dopaminergic and serotonergic systems, which modulate various basic brain functions such as those in reward-related behavior. 5F-ADB-induced changes in spontaneous firing activity of dopaminergic and serotonergic neurons were recorded by ex vivo electrophysiological techniques. In dopaminergic neurons, 5F-ADB (1 μM) significantly increased the spontaneous firing rate, while 5F-ADB failed to activate dopaminergic neurons in the presence of the CB1 antagonist AM251 (1 μM). However, the same concentration of 5F-ADB did not affect serotonergic-neuron activity. These results suggest that 5F-ADB activates local CB1 receptors and potentiates midbrain dopaminergic systems with no direct effects on midbrain serotonergic systems.