• Toxicological Research
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• 제35권2호
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• pp.191-200
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• 2019

Alismatis rhizoma (AR), the dried rhizome of Alisma orientale (Sam.) Juzep, is a well-known, traditional medicine that is used for the various biological activities including as a diuretic, to lower cholesterol and as an anti-inflammatory agent. The present study was carried out to investigate the potential toxicity of the Alismatis rhizoma aqueous extract (ARAE) following 90-day repeated oral administration to Sprague-Dawley rats. ARAE was administered orally to male and female rats for 90 days at 0 (control), 500, 1,000 and 2,000 mg/kg/day (n = 10 for male and female rats for each dose). Additional recovery groups from the control group and high dose group were observed for a 28-day recovery period. Chromatograms of ARAE detected main compounds with four peaks. Treatment-related effects including an increase in the red blood cells, hemoglobin, hematocrit, albumin, total protein, and urine volume were observed in males of the 2,000 mg/kg/day group (p < 0.05). However, the diuretic effect of ARAE was considered, a major cause of hematological and serum biochemical changes. The oral no-observed-adverse-effect level (NOAEL) of the ARAE was > 2,000 mg/kg/day in both genders, and no target organs were identified.

• Toxicological Research
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• 제35권3호
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• pp.225-232
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• 2019

Thymus vulgaris L. is widely used as an ingredient in cooking and in herbal medicine. However, there is little information about its toxicity. The present study was performed to evaluate the acute and repeated 28-day oral dose toxicity of thyme essential oil in rats. For the acute toxicity test, two groups of three rats were used. The rats received a single dose of essential oil: 300 or 2,000 mg/kg of body weight (bw). The rats were observed individually during the first four hours, and then daily until day 14. For the toxicity test with repeated doses, four groups of 10 rats were used. Doses of 100, 250, and 500 mg/kg/day were tested for 28 days. At the end of the experiment, blood was collected and the animals were sacrificed. Histopathological examination showed that in the lungs of rats given the 2,000 mg/kg bw dose, polymorph nuclear infiltrates, hemosiderin macrophages, and interstitial space thickening were present. In the repeated dose study, all rats survived the 28-day treatment period and apparently showed no signs of toxicity. The hematological and biochemical parameters were not altered. The histopathological study of the organs showed severe changes in the lung, with the dose of 500 mg/kg/day; in the other organs, no alterations were observed or the changes were slight. The body weight was only altered in male rats given the 500 mg/kg dose. The relative weight of the organs did not show any significant changes. Our studies revealed that the essential oil of Thymus vulgaris has moderate oral toxicity according to the results of the acute test, whereas the results of the 28-day oral toxicity test suggest that the no-observed-adverse effect level (NOAEL) is greater than 250 mg/kg/day.

• Toxicological Research
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• 제35권3호
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• pp.241-248
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• 2019

Pesticide exposure may induce biochemical alterations including oxidative stress and lipid peroxidation. However, in the context of developmental origin of health and disease, putative trans-generational effect of exposure to pesticides are insufficiently studied. We therefore aimed to evaluate the biochemical effect of gestational exposure to four pesticides on female Wistar rats and their offspring at adult age. We studied 30 female nulliparous Wistar rats divided into 5 equal groups. Group 1 served as the control group and received distilled water while group 2, 3, 4 and 5 received orally pesticide 1 (imidacloprid), pesticide 2 (chlorpyrifos), pesticide 3 (imidacloprid + lambda cyhalothrin) and pesticide 4 (oxamyl) respectively once daily throughout gestation at a dose equivalent to 1/10 lethal dose 50. The mothers were followed up until one month post gestation. The offspring were followed up from birth until adult age (12 weeks). In all animals at each time point we evaluated malondialdehyde (MDA), oxidative stress and liver function enzymes. There was similar variation of total body weight in all the groups during and after gestation. However, Female Wistar rats of the exposed groups had significant alterations in liver SOD (-30.8% to +64.1%), catalase (-38.8% to -85.7%) and GSH (-29.2% to -86.5%) and; kidney catalase (> 100%), GSH (> 100%). Moreover, MDA, alanine transaminase (ALT) and aspartate transaminase (AST) levels were significantly higher in pesticide exposed rats compared to the control group. Similar alterations in antioxidant enzymes, MDA and liver function enzymes were observed in offspring of treated rats evidenced at weaning and persisting until adult age. Exposure to pesticides causes oxidative stress and lipid peroxidation in exposed female Wistar rats and their offspring. The persistence in offspring at adult age suggests transgenerational adverse effects.

• Toxicological Research
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• 제35권4호
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• pp.361-369
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• 2019

1,2-Dichloropropane (1,2-DCP) has been used as an industrial solvent and a chemical intermediate, as well as in soil fumigants. Human exposure may occur during its production and industrial use. The target organs of 1,2-DCP are the eyes, respiratory system, liver, kidneys, central nervous system, and skin. Repeated or prolonged contact may cause skin sensitization. In this study, 1,2-DCP was dissolved in corn oil at 0, 2.73, 5.75, and 8.75 mL/kg. The skin of mice treated with 1,2-DCP was investigated using western blotting, hematoxylin and eosin staining, and immunohistochemistry. 1,2-DCP was applied to the dorsal skin and both ears of C57BL/6J mice. The thickness of ears and the epidermis increased significantly following treatment, and the appearance of blood vessels was observed in the dorsal skin. Additionally, the expression of vascular endothelial growth factor, which is tightly associated with neovascularization, increased significantly. The levels of protein kinase-B (PKB), phosphorylated PKB, mammalian target of rapamycin (mTOR), and phosphorylated mTOR, all of which are key components of the phosphoinositide 3-kinase/PKB/mTOR signaling pathway, were also enhanced. Taken together, 1,2-DCP induced angiogenesis in dermatitis through the PI3K/PKB/mTOR pathway in the skin.

• Toxicological Research
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• 제35권2호
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• pp.167-179
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• 2019

Ovarian cancer is the fifth main cause of pre-senescent death in women. Although chemotherapy is generally an efficient treatment, its side effects and the occurrence of chemotherapeutic resistance have prompted the need for alternative treatments. In this study, ${\alpha}$-mangostin and apigenin were evaluated as possible anticancer alternatives to the chemotherapeutic drug doxorubicin, used herein as a positive control. The ovarian adenocarcinoma cell line SKOV-3 (ATCC No. HTB77) was used as model ovarian cancer cells, whereas the skin fibroblast line CCD-986Sk (ATCC No. CRL-1947) and lung fibroblast line WI-38 (ATCC No. CCL-75) were used as model untransformed cells. Apigenin and doxorubicin inhibited the growth of SKOV-3 cells in a dose- and time-dependent manner. After 72 hr exposure, doxorubicin was mostly toxic to SKOV-3 cells, whereas apigenin was toxic to SKOV-3 cells but not CCD-986Sk and WI-38 cells. ${\alpha}$-Mangostin was more toxic to SKOV-3 cells than to CCD-986Sk cells. A lower cell density, cell shrinkage, and more unattached (floating round) cells were observed in all treated SKOV-3 cells, but the greatest effects were observed with ${\alpha}$-mangostin. With regard to programmed cell death, apigenin caused early apoptosis within 24 hr, whereas ${\alpha}$-mangostin and doxorubicin caused late apoptosis and necrosis after 72 hr of exposure. Caspase-3 activity was significantly increased in ${\alpha}$-mangostin-treated SKOV-3 cells after 12 hr of exposure, whereas only caspase-9 activity was significantly increased in apigenin-treated SKOV-3 cells at 24 hr. Both ${\alpha}$-mangostin and apigenin arrested the cell cycle at the $G_2/M$ phase, but after 24 and 48 hr, respectively. Significant upregulation of BCL2 (apoptosis-associated gene) and COX2 (inflammation-associated gene) transcripts was observed in apigenin- and ${\alpha}$-mangostin-treated SKOV-3 cells, respectively. ${\alpha}$-Mangostin and apigenin are therefore alternative options for SKOV-3 cell inhibition, with apigenin causing rapid early apoptosis related to the intrinsic apoptotic pathway, and ${\alpha}$-mangostin likely being involved with inflammation.

• 생태와환경
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• 제34권4호통권96호
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• pp.327-336
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• 2001

1993년 7월부터 1994년 8월까지 대청호 내 문의취수탑에서 조류의 엽록소 양 및 투명도에 대한 영양염류 및 현탁물의 영향을 평가하기 위해 물리적, 화학적, 생물학적 요소들이 측정되었다. 1993년 여름기간 동안 집중 강우는 수체의 회석효과(전기전도도=$88\;{\mu}S/cm$),최소의 총질소와 총인 질량 비 (<40),그리고 최대의 총인 농도($59\;{\mu}g/L$)를 야기시켰고, 계절들 가운데 최고점의 엽록소 ($79\;{\mu}g/L$)와 최소의 투명도(<1.5m)를 초래하였다. 이와 동시에 유기현탁물(VSS)과 무기현탁물(NVSS)질량비는 최대 (13.0)였으며, 이것은 감소된 투명도가 식물성 플랑크톤 성장과 연관된 생물학적인 혼탁도로부터 주로 기인되었다는 것을 제시하였다. 반면, 1994년 여름기간동안의 극심한 가뭄은 1993년 여름보다 높은 전기전도도(>$120\;{\mu}S/cm$)와 물의 투명도(>2m),그리고 낮은 총인과 엽록소(<$10\;{\mu}g/L$)를 초래하였다. 영양염류에 대한 엽록소의 회귀분석에 따르면, 엽록소의 변이는 총질소 ($R^2=0.29$)보다는 총인 ($R^2=0.46$)에 의해 설명되었다. 총질소와 총인의 질량비는 조사기간동안 $39{\sim}222$범위에 속하였으며, 총질소의 농도 보다는 총인의 농도에 의해 결정되었다. 조사기간동안 두 영양염류의 농도와 총질소 대 총인의 질량 비는 엽록소의 계절 주기성이 주로 강우의 분포에 반영된 인(Phosphorus)의 농도에 의해 결정된다는 것을 의미하였다. 집중강우 기간동안의 인유입의 저지는 취수탑에서 식수를 위한 보다 나은 수질을 제공할 것으로 사료된다.

• 한국환경생물학회:학술대회논문집
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• 한국환경생물학회 2005년도 추계학술대회 초록집
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• pp.38-45
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• 2005

The egg bags of Korean salamander(Hynobius leechii) were collected from farmlands in Gyeongsangnam-do area. The assumed breeding time, numerical variation of embryos in each egg bag, mortality and the rates of abnormalities were investigated. The toxicity of benomyl, the metabolite carbendazim and BIC which were frequently spread in agricultural area and caused spontaneous embryonic malformation was investigated. The assumed breeding time between the end of February and the end of March has the difference about a month because of a habitat and it takes about 2 or 3 weeks from laying eggs to hatching. The length of each egg bag and the number of embryos were very varied in each area. It is due to geographical variation. Among egg bags in total study area, only 406 of egg bags(17.70% of total egg bags) developed all of embryos to normal larvae, and 78.49% of total embryos were normally developed. The patterns of spontaneous embryonic malformation were 26 species from A to Z and the abnormal patterns in individual were 8 species and above. the geographical differences about the abnormal pattern were identified and 11 habitats categorized 4 groups. The most frequent abnormality in Gyeongsangnam-do area is the dysplasia of external gill. The caudal dysplasia, abdominal blister and dysplasia of fin were also frequently observed. Individuals showing severe external defect were histologically studied and they showed retinal hypo-pigmentation, thyroid carcinoma, somatic muscular dysplasia, degeneration of cephalic neuron and various organ dysplasia. Benomyl and carbendazim were treated by 10pM$^{\sim}$10uM and BIC was treated by 1$^{\sim}$40ppm to know the effect of toxicity about toxic substance of salamander. After benomyl was treated, a survival rate was sharply dropped from 2 to 8 days. $LC_{100}$ identified in $1{\mu}M$, $LC_{50}$ identified between 100nM and $1{\mu}M$. $EC_{50}$ was assumed between 10nM and 100nM. The prevalent external malformation was abdomen swelled abnormally and histo-pathological effects were abdomen, neural tube and lens hernia. This suggests that benomyl is the toxicitic substance which inhibits the development of digestive system and nervous system. The result of treated carbendazim was similar to that of the treated benomyl. The survival rate is sharply dropped between 2 and 6 days. $LC_{100}$ was identified $1{\mu}M$ and $LC_{50}$ was identified between 10nM and 100nM. This shows that cabendazim has stronger lethal toxicity than benomyl. Ventral blister, eye dysplasia and cephalic dysplasia in the individual of external malformation mean that cabendazim affected nervous system much more than benomyl. Because the toxicity of BIC affected less in the beginning but affected more in the near hatching period, the period causing toxicity is somewhat different. $LC_{100}$ identified near 40ppm and $LC_{50}$ identified near 25ppm. The external defect shows mainly ventral blister and histo-pathological results show intestinal deformities. This result suggests the BIC inhibited strongly the development of digestive system. These abnormal developments may be caused by antimitotic action, inhibition of tubulin complex, destruction of microtubule, inhibitions of neurulation and closing of neural fold, and by the inhibition of movement of neural crest cells of benomyl. These abnormal developments may be caused by the rupture of epithelium, the loss of microtubule, the reduction of spindle size, the inhibition of spindle assembly formation, the destruction of spindle poles of carbendazim. These abnormal developments may be caused cytotoxicity by inhibition of the synthesis of a number of macromolecules and similar reaction the inhibition of benomyl.

• Toxicological Research
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• 제4권1호
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• pp.55-84
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• 1988

azinphos-methyl을 S.D.랫트에 투여하여 기형이 유발되는지의 여부와 태아의 기관형성 및 자궁내에서 태아의 발달에 미치는 영향을 알아보기 위하여 무처치의 negative control군, 수도물을 경구투여한 sham control군, 이미 기형효과가 있는 것으로 알려진 aspirin투여의 positive control군, 그리고 azinphosmethyl 0.094 mg/kg, 0.4 mg/kg 및 1.5mg/kg 투여군으로 나누어 각군 30마리씩으로, 임신 6~15일 사이에 경구투여한 결과는 다음과 같다. 즉, 모체의 체중증가율은 임신 7~14일, 즉 약물투여기에 aspirin 투여군과 azinphos-methyl 1.5mg/kg 투여군에서 현저한 감소를 보였다(p<0.01). 모체의 장기무게는 azinphos-methyl 1.5mg/kg 투여군에서 간장의 절대무게비가 유의성(p<0.05) 있는 감소를 보였으며, 신장의 절대 및 상대무게비는 aspirin군에서 (p<0.05, p<0.01), 또 난소의 절대 및 상대무게비는 aspirin 투여군(p<0.01)과 azinphos-methyl 전처치군(p<0.05)에서 유의성 있게 증가하였다. 모체 간장의 단백질량은 aspirin과 azinphos-methyl 1.5mg/kg 투여군에서 현저히 감소되었다(p<0.01). 모체의 배아와 태자에 대한 관찰 결과 azinphos-methyl 1.5mg/kg 투여군에서 암수의 비율에 있어 현저하게 증가(p<0.01) 했으며, 체중은 aspirin과 azinphos-methyl 1.5mg/kg 투여군에서 고도의 유의성(p<0.01) 있게 감소하였고, azinphos-methyl 0.4 mg/kg 투여군에서도 현저하게 감소하였다(p<0.05). 그리고 미숙태자와 흡수태자는 aspirin군에서, 죽은 태자수는 azinphos-methyl 1.5mg/kg 투여군에서 유의성 있게 증가하였다(p<0.05, p<0.01). 태자의 장기에서 나타난 기형은 aspirin과 azinphos-methyl 1.5mg/kg 투여군 공히 횡경막에서 횡격막 천공, 두부에서 무안구증, olfactory bulb의 확장, 수두뇌, 그리고 3뇌실과 측뇌실의 결손, 심장에서 좌심실벽 위축, 심첨확장 등이 유의성(P<0.01, P<0.05) 있게 관찰되었으며, 특히 횡경막, 심장 및 안구등에 높은 기형발생율을 보였다. 또 태자의 골화지연은 두개골에서 후두골, 접형골, 구개, 흉골에서 4번째 흉골편, 검상돌기, 척추에서 경추, 흉추, 미추, 전${\cdot}$후지골, 중족골에서 관찰되었다. 한편, 자연 분만시킨 태자의 사망율은 azinphos-methyl 1.5mg/kg 투여군에서 negative control군에 비해 고도의 유의성(p<0.01) 있게 높음을 알 수 있었으며, 체중도 역시 현저하게(p<0.01) 감소하였고, 발육지표중 pivoting, 체모형성, 청각능력, 시각능력, 사지근육 발달정도 및 고환하강시기 등에서 고도의 유의성(p<0.01)이 관찰되었다.

• Toxicological Research
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• 제23권4호
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• pp.341-345
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• 2007

본 연구는 어성초 함유 한방원료의 지질대사 기능을 가진 한방차를 개발하는데 도움을 줄 목적으로 LPS로 간독성이 유도된 흰쥐에서 어성초에 오미자, 구기자, 사상자, 음양곽을 혼합해서 추출하고 이 혼합 추출물이 지질대사에 미치는 영향을 관찰하였다. 본 실험에서는 어성초 90g, 복분자 1g, 사상자 3g, 구기자 2g, 음양곽 4g을 혼합하고 추출하여 감압 농축하여 실험 샘플로 사용하였으며 생후 7주 암컷 흰쥐를 총 21마리를 7마리씩 3군으로 나누었고 군별로 cage에 분리시키고 고형사료와 물을 자유롭게 섭취하도록 하였다. 정상군은 20일 동안 1.5 ml/kg of 0.9% saline을 투여하고 대조군은 20일 동안 1.5 ml/kg of 0.9% saline을 매일 투여한 후 21일째 되는 날 LPS를 5 mg/kg의 농도로 만들어 1.5 ml/kg의 용량으로 복강 내로 투여하였다. 시료군(HM)에는 100 mg/kg농도의 각각의 분획을 1.5 ml/kg씩 복강 내에 20일간 매일 투여하고 21일째 되는 날에 LPS를 1.5 ml/kg의 용량을 복강 내로 투여하였다. LPS를 투여하고 절식시킨 뒤 4시간 후에 ether로 마취하고 해부하여 혈액을 채취하고 간을 적출하여 실험하여 다음과 같은 결과를 얻었다. Total-lipid 수준에서는 LPS를 투여한 대조군이 정상군에 비교하여 1.7배 증가하였으며 대조군과 비교해 HM군은 66.30% 감소하였다. Total-cholesterol 수준에서는 LPS를 투여한 대조군이 정상군에 비교하여 약 2 1배 감소하여 LPS로 간에 염증이 유발하여 total cholesterol의 수치가 감소하는 것을 확인하였으며 HM군이 대조군에 비교하여 41.13%의 수치로 회복하였다. HDL-cholesterol 수준에서는 LPS를 투여한 대조군이 정상군에 비교하여 약 2.3배 감소하였으며 HM군이 대조군에 비교하여 72.61%의 수치로 회복하였다. LDH 수준에서는 LPS를 투여한 대조군이 정상군에 비교하여 약 5.8배 증가하였으며 HM군이 대조군에 비교하여 68.91%의 수치로 감소하였다. TG의 수준에서도 LPS를 투여한 대조군이 정상군에 비교하여 약 3.8배 증가하였으며 HM군이 대조군에 비교하여 101.14%의 수치로 감소하였다. MDA는 LPS를 투여한 대조군이 정상군에 비해서 약 3.5배 정도로 높게 나타났고 HM군은 대조군에 비해 58.65%의 감소효과를 보였다. LPS가 간에 염종을 유발하여 혈청 속의 total-cholesterol과 HDL-cholesterol level이 감소하고 total-lipid와 LDH, TG의 수준이 증가한 것으로 사료되며 대조군에 비교하여 HM군이 혈청 속의 total-cholesterol과 HDL-cholesterol level을 증가시키고 total-lipid와 LDH, TG의 수준을 감소시킨 것으로 보아 HM이 동맥경화 등 지질대사 이상에 의한 성인병에 효과가 있을 것으로 사료된다. MDA에서는 대조군에서 LPS가 간 염증을 유발하여 과산화지질함량이 증가한 것으로 사료되며 대조군에 비해 HM군이 과산화 지질함량이 감소된 것으로 보아 HM이 활성산소의 생성을 억제하여 높아진 간 조직 과산화지질함량을 감소시킴으로써 간기능 개선효과가 있을 것으로 사료된다.

• Toxicological Research
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• 제24권3호
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• pp.175-182
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• 2008

DNA-dependent protein kinase(DNA-PK) is involved in joining DNA double-strand breaks induced by ionizing radiation or V(D)J recombination and is activated by DNA ends and composed of a DNA binding subunit, Ku, and a catalytic subunit, DNA-PKcs. It has been suggested that DNA-PK might be $2^{nd}$ upstream kinase for protein kinase B(PKB). In this report, we showed that Ser473 phosphorylation in the hydrophobic-motif of PKB is blocked in DNA-PK knockout mouse embryonic fibroblast cells(MEFs) following insulin stimulation, while there is no effect on Ser473 phosphorylation in DNA-PK wild type MEF cells. The observation is further confirmed in human glioblastoma cells expressing a mutant form of DNA-PK(M059J) and a wild-type of DNA-PK(M059K), indicating that DNA-PK is indeed important for PKB activation. Furthermore, the treatment of cells with doxorubicin, DNA-damage inducing agent, leads to PKB phosphorylation on Ser473 in control MEF cells while there is no response in DNA-PK knockout MEF cells. Together, these results proposed that DNA-PK has a potential role in insulin signaling as well as DNA-repair signaling pathway.