Ilseob Shim

Aluminum Nanoparticles Induce ERK and p38MAPK Activation in Rat Brain

Aluminum nanoparticles (Al-NPs) are one of the most widely used nanomaterial in cosmetics and medical materials. For this reason, Al-NP exposure is very likely to occur via inhalation in the environment and the workplace. Nevertheless, little is known about the mechanism of Al-NP neurotoxicity via inhalation exposure. In this study, we investigated the effect AL-NPs on the brain. Rats were exposed to Al-NPs by nasal instillation at 1 mg/kg body weight (low exposure group), 20 mg/kg body weight (moderate exposure group), and 40 mg/kg body weight (high exposure group), for a total of 3 times, with a 24-hr interval after each exposure. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated that the presence of aluminum was increased in a dose-dependent manner in the olfactory bulb (OFB) and the brain. In microarray analysis, the regulation of mitogen-activated protein kinases (MAPK) activity (GO: 0043405), including Ptprc, P2rx7, Map2k4, Trib3, Trib1, and Fgd4 was significantly over-expressed in the treated mice than in the controls (p = 0.0027). Moreover, Al-NPs induced the activation of ERK1 and p38 MAPK protein expression in the brain, but did not alter the protein expression of JNK, when compared to the control. These data demonstrate that the nasal exposure of Al-NPs can permeate the brain via the olfactory bulb and modulate the gene and protein expression of MAPK and its activity.

Evaluation of toxicity to triclosan in rats following 28 days of exposure to aerosol inhalation

The present study was conducted to investigate the potential subchronic toxicity of triclosan (TCS) in rats following 28 days of exposure by repeated inhalation. Four groups of six rats of each sex were exposed to TCS-containing aerosols by nose-only inhalation of 0, 0.04, 0.13, or 0.40 mg/L for 6 h/day, 5 days/week over a 28-day period. During the study period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. At 0.40 mg/L, rats of both sexes exhibited an increase in the incidence of postdosing salivation and a decrease in body weight. Histopathological alterations were found in the nasal septum and larynx. There were no treatment-related effects in rats of either sex at ⩽0.13 mg/L. Under the present experimental conditions, the target organs in rats were determined to be the nasal cavity and larynx. The no-observed-adverse-effect concentration in rats was determined to be 0.13 mg/L.

Investigation of disinfectants for foot-and-mouth disease in the Republic of Korea

Disinfectants for foot-and-mouth disease were sprayed on livestock barns and roads from early February to May 2011. Although 90% of the disinfectant was concentrated on the roads, 10% was sprayed on cattle sheds and other sites where foot-and-mouth disease occurred. Since the outbreak of foot-and-mouth disease in November 2010, there has been a steady increase in disinfectant use. Consequently, its adverse environmental effects have prompted government officials to take preventive measures. The major chemical components of the disinfectants are citric acid, potassium sulfate base complex, quaternary ammonium compound, malic acid, and glutaraldehyde, ranging in amounts from tons to hundreds of tons. The exact amount of each component of the disinfectants could not be identified because the types of components used in the different commercial formulations overlapped. In this review, we obtained information on disinfectants that are widely used nationwide, including the types of major chemical components and their respective toxicities (both human and ecological).

Analysis of microRNA and gene expression profiling in triazole fungicide-treated HepG2 cell line.

MicroRNA (miRNA) plays an important role in various diseases and in cellular and molecular responses to toxicants. In the present study, we investigated differential expression of miRNAs in response to three triazole fungicides (myclobutanil, propiconazole, and triadimefon). The human hepatoma cell line (HepG2) was treated with the above triazoles for 3 h or 48 h. miRNA-based microarray experiments were carried out using the Agilent human miRNA v13 array. At early exposure (3h), six miRNAs were differentially expressed and at late exposure (48 h), three miRNAs were significantly expressed. Overall, this study provides an array of potential biomarkers for the above triazole fungicides. Furthermore, these miRNAs induced by triazoles could be the foundation for the development of a miRNA-based toxic biomarker library that can predict environmental toxicity.

Evaluation of comparative cytotoxicity of spray-type chemicals used in household products

Chemicals are widely used in our daily lives for various purposes such as disinfectant, air fresher, paints and hair spray. However, their pulmonary toxicity has less studied compared with oral and dermal toxicity. Therefore, the purpose of this study was to examine comparative cytotoxicity of triclosan (TCS), benzisothiazolinone (BIT), dichlorophene (DCP) and citral (CTR) major using spray-type chemicals used in household products (CHPs) in Korea. TCS, DCP and BIT induced more severe mitochondria injury and cell membrane damage than CTR in lung epithelial cell during 24 hrs exposure. Furthermore, the result of clonogenic assay revealed that exposure of CHPs significantly decreased colony size and that BIT reduced cell growth at most compared with TCS, DCP and CTR. In summary, results of comparative cytotoxicity demonstrated that inhalation of TCS, DCP and BIT may cause pulmonary toxicity. Therefore, our results suggest that TCS, BIT and DCP are requiring inhalation toxicity assessment for maintaining a high quality of life.

Oxidative stress and cytotoxic effects of silver ion in mouse lung macrophages J774.1 cells

Silver is commonly used as a disinfectant, and chronic exposure to silver may cause argyria, resulting in a gray–blue discoloration of human skin. However, the mechanism for cellular toxicity of silver has not been well explained. We studied the mode of cell death, the ratio of glutathione disulfide/glutathione, induction of metallothionein and activation of mitogen‐activated protein kinases in J774.1 cells together with activation of antioxidant responsive element and nuclear factor‐κB in CHO cells following exposure to silver ion (Ag+) to investigate the mechanism by which Ag+ causes lethal effects. Ag+ increased phosphorylation levels of extracellular signal‐regulated, c‐Jun N‐terminal and p38 mitogen‐activated protein kinases and remarkably increased the ratio of glutathione disulfide/glutathione in both a time‐ and concentration‐dependent manner. Luciferase reporter gene assays revealed that antioxidant responsive element and nuclear factor‐κB were activated following exposure to Ag+. In addition, exposure to Ag+ increased the mRNA and protein levels of metallothionein. We investigated whether or not Ag+ killed J774.1 cells by inducing apoptosis. Ag+ increased the activity of caspase‐3/7 which was abrogated by caspase 3 and pan‐caspase inhibitors. However, these inhibitors did not ameliorate the cytotoxic effects of Ag+, suggesting that Ag+ causes oxidative stress, which leads to necrotic rather than apoptotic cell death in J774.1 cells by decreasing functional sulfhydryl groups including glutathione in the cells. Copyright

Pulmonary Toxicity Assessment of Aluminum Oxide Nanoparticles via Nasal Instillation Exposure

Objective: The use of nanoparticle products is expected to present a potential harmful effect on consumers. Also, the lack of information regarding inhaled nanoparticles may pose a serious problem. In this study, we addressed this issue by studying pulmonary toxicity after nasal instillation of Al-NPs in SD rats. Methods: The animals were exposed to Al-NPs at 1 mg/kg body weight (low dose), 20 mg/kg body weight (medium dose) and 40 mg/kg body weight (high dose). To determine pulmonary toxicity, bronchoalveolar lavage (ts.AnBAL) fluid analysis and histopathological examination were conducted in rats. In addition, cell viability was investigated at 24 hours after the treatment with Al-NPs. Results: BAL fluid analysis showed that total cells (TC) count and total protein (TP) concentrations increased significantly in all treatment groups, approximately two to three times. Also, lactate dehydrogenase (LDH) and cytokines such as TNF-alpha and IL-6 dose-dependently increased following nasal instillation of Al-NPs. However, polymorphonuclear leukocytes (PMNs) levels showed no significant changes in a dose dependant manner in BAL fluid. In the cytotoxicity analysis, the treatment of Al-NPs significantly and dose-dependently induced cell viability loss (20 to 30%) and damage of cell membrane (5 to 10%) in rat normal lung epithelial cells (L2). Conclusions: Our results suggest that inhaled Al-NPs in the lungs may be removed quickly by alveolar macrophages with minimal inflammatory reaction, but Al-NPs have the potential to affect lung permeability. Therefore, extensive toxicity evaluations of Al-NPs are required prior to their practical application as consumer products.

Inhalation Toxicity of Ethylene Glycol in Rat

Several air fresheners and deodorants that contain ethylene glycol were found (1-2% (w/v)) in commercially available products. Ethylene glycol is a liquid used as a surfactant or an emulsifier in household products. The aim of this study is to determine the inhalation toxicity of ethylene glycol. The effect of whole-body inhalation to EG was performed for an inhalation study of rat. Specific pathogen-free male Sprague-Dawley rats (7 weeks old) were exposed to ethylene glycol in a stainless steel whole body inhalation chamber with a capacity of 1 m3 (Sibata Model VT3-X15 Japan). For acute and sub-acute rat inhalation toxicities, the differences of body weights were not statistically significant comparing with those of control rats. In sub-acute rat inhalation toxicity, the relative kidney weights were significantly higher in high-exposure group (500 mg/m3) than those of the other groups. In blood biochemistry the values of TG (triglyceride) and BUN (urea nitrogen) were significantly decreased. Other hematological changes with toxicological relevance were not observed in exposed male rats when compared with the control animals. The histopathological findings were not observed in the lung and kidney tissues exposed to chemicals comparing with those of control tissues. The No Observed Adverse Effect Level (NOAEL) of EG in 28 day’s inhalation test was evaluated to be over 100 mg/m3.

Inhalation of Talc Induces Infiltration of Macrophages and Upregulation of Manganese Superoxide Dismutase in Rats.

Talc is a mineral that is widely used in cosmetic products, antiseptics, paints, and rubber manufacturing. Although the toxicological effects of talc have been studied extensively, until now no detailed inhalation study of talc focusing on oxidative stress has been done. This repeated 4 weeks whole-body inhalation toxicity study of talc involved Sprague-Dawley rats. Male and female groups of rats were exposed to inhaled talc at 0, 5, 50, and 100 mg/m3 for 6 hours daily, 5 days/week for 4 weeks. The objective was to identify the 4-week inhalation toxicity of talc and investigate antioxidant activity after exposure to talc. There were no treatment-related symptoms or mortality in rats treated with talc. Glucose (GLU) was decreased significantly in male rats exposed to 50 and 100 mg/m3 of talc. Histopathological examination revealed infiltration of macrophages on the alveolar walls and spaces near the terminal and respiratory bronchioles. In male and female rats exposed to 100 mg/m3 talc, expression of superoxide dismutase 2, a typical biological indicator of oxidative damage, was significantly increased. Thus, inhalation of talc induces macrophage aggregations and oxidative damage in the lung.

Potentiation of Sodium Metabisulfite Toxicity by Propylene Glycol in Both in Vitro and in Vivo Systems

Many consumer products used in our daily lives result in inhalation exposure to a variety of chemicals, although the toxicities of the active ingredients are not well known; furthermore, simultaneous exposure to chemical mixtures occurs. Sodium metabisulfite (SM) and propylene glycol (PG) are used in a variety of products. Both the cytotoxicity and the sub-acute inhalation toxicity of each chemical and their mixtures were evaluated. Assays for cell viability, membrane damage, and lysosome damage demonstrated that SM over 100 μg/ml induced significant cytotoxicity; moreover, when PG, which was not cytotoxic, was mixed with SM, the cytotoxicity of the mixture was enhanced. Solutions of 1, 5, and 20% SM, each with 1% PG solution, were prepared, and the whole body of rats was exposed to aerosols of the mixture for 6 h/day, 5 days/week for 2 weeks. The rats were sacrificed 1 (exposure group) or 7 days (recovery group) after termination of the exposure. The actual concentration of SM in the low-, medium-, and high-exposure groups was 3.91 ± 1.26, 35.73 ± 6.01, and 80.98 ± 5.47 mg/m3, respectively, and the actual concentration of PG in each group was 6.47 ± 1.25, 8.68 ± 0.6, and 8.84 ± 1.77 mg/m3. The repeated exposure to SM and PG caused specific clinical signs including nasal sound, sneeze, and eye irritation which were not found in SM single exposure. In addition, the body weight of treatment group rats decreased compared to that of the control group rats in a time-dependent manner. The total protein concentration and lactate dehydrogenase activity in the bronchoalveolar lavage fluid (BALF) increased. Histopathological analysis of the lungs, liver, and nasal cavity was performed. Adverse effects were observed in the nasal cavity, with squamous cell metaplasia identified in the front of the nasal cavity in all high-exposure groups, which completely recovered 7 days after exposure was terminated. Whereas inhalation of SM for 2 weeks only reduced body weight in the high-dose group, inhalation of SM and PG mixtures for 2 weeks significantly decreased body weight and induced metaplasia of the respiratory epithelium into squamous cells in the medium- and high-dose groups. In conclusion, PG potentiated the toxicity of SM in human lung epithelial cells and the inhalation toxicity in rats.