• Title/Summary/Keyword: teratogenicity study

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Assessment of Embryotoxicity of 2-Bromopropane in ICR Mice

  • Kim, Jong-Choon;Shin, Dong-Ho;Kim, Sung-Ho;Oh, Ki-Seok;Kim, Hyeon-Yeong;Her, Jeong-Doo;Jiang, Cheng-Zhe;Chung, Moon-Koo
    • Toxicological Research
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    • v.19 no.3
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    • pp.227-234
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    • 2003
  • 2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones (CFCs) which have a great potential to destroy the ozone layer and to warm the earth's environment. The present study was undertaken to evaluate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure during the gestational days (GD) 6 through 17 in ICR mice. The test chemical was administered subcutaneously to pregnant mice at dose levels of 0, 313, 625 or 1,250 mg/kg/day. All dams were subjected to caesarean section on GD 18 and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1,250 mg/kg group, maternal toxicity included an increase in the incidence of abnormal clinical signs and a decrease in the maternal body weight, body weight gain, and corrected body weight. Developmental toxicity included a decrease in the fetal body weight, a reduction in the placental weight, an increase in the fetal skeletal variation and ossification delay. There were no adverse effects on either pregnant dams or embryo-fetal development in the 313 and 625 mg/kg groups. These results suggest that a 12-day subcutaneous dose of 2-BP is embryotoxic at a maternally toxic dose (i.e., 1,250 mg/kg/day) in ICR mice. In the present experimental condition, the no-observed-adverse-effect level of 2-BP is considered to be 625 mg/kg/day for dams and embryo-fetuses, respectively.

Teratogenicity of phenytoin in ICR mouse and antiteratogenic effect of dimethyl sulfoxide (ICR마우스에서 phenytoin의 최기형성 및 dimethyl sulfoxide의 항최기형 효과)

  • Lee, Jae-kwon;Lee, Chang-eop;Lee, Mun-han;Ryu, Pan-dong;Cho, Myung-haing;Sung, Ha-jung;Park, Jin-bong
    • Korean Journal of Veterinary Research
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    • v.34 no.4
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    • pp.821-831
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    • 1994
  • Phenytoin(PHT), a commonly prescribed anticonvulsant, has been known as a teratogen in experimental animals and human. However, PHT has strain-specific teratogenic effects for mice and human. Dimethyl sulfoxids(DMSO) has been known to antagonize the teratogenic effects of secalonic acid D, a toxic mold metabolite that has similar teratogenic effects to PHT. Therefore, this study was performed to examine the embryopathic effects of PHT in terms of treatment period and the antiteratogenic effect of DMSO in ICR mice. PHT(75mg/kg, BW) was administered intrapetitoneally on day 10, 10-11 and 10-12 of gestation with or without DMSO(2ml/kg, BW), and the fetal malformation was observed on day 18. Major malformation of fetuses treated with PHT on day 10, 10-11 and 10-12 of gestation was cleft palate, and the percentages of fetus with cleft palate were 14.5%, 31.7% and 51.7%, respectively. Also, there was a significant decrease of cleft palate from 51.7% in PHT alone group to 30.8% in PHT plus DMSO group. Our findings suggest that cleft palate is one of major malformation by PHT treatment in ICR mouse and DMSO has strong antiteratogenic effect.

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A Teratogenicity Study on Dimethyl Dimethoxy Biphenylate Derivative (DDB-S) in Rats (염산 DDB-S가 랫드의 생식독성에 미치는 영향에 관한 연구)

  • Kim, Hyun-Woo;Park, Jin-Hong;Moon, Seo-Hyun;Eu, Gook-Jong;Kim, Hwa;Kim, Joon-Seong;Park, Jong-Ha;Cho, Hyun-Sun;Kang, Ka-Mi;Hwang, Seong-Hee;Kim, Pan-Gyi;Moon, Jeon-Ok;Lee, Chi-Ho;Cho, Maing-Haing
    • Toxicological Research
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    • v.19 no.1
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    • pp.21-27
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    • 2003
  • A teratogenic study of dimethyl dimethoxy biphenylate derivative (DDB-S) was carried out on Sprague-Dawley rats. DDB-S dissolved in saline was administered to male and female rats by intravenously injection at daily doses of 50 mg/kg, 75 mg/kg, and 100 mg/kg. A half of dams were sacrificed at 20th day of gestation to scrutinize the pregnant performances and fetal development. And the remaining dams were allowed to deliver. The growth, reflex, behaviour and reproductive function of F1 offsprings were examined. There was no treatment-related difference in body weight, food consumption and necropsy findings of dams. No gross, skeletal and visceral abnormalities was observed in F1 fetuses from dams treated with DDB-S. F1 offsprings did not show any treatment-related difference in growth, reflex, behaviour and reproductive performance. At caesarean section of F1 dams, no growth retardation and gross abnormality was observed in F2 fetuses. In conclusion, DDB-S did not show any potential teratogenic effect in rats.

Development Toxicity Evaluation (랫드에서 표준 및 사료제한 시험에 의한 fluoroquinolone 항균제 DW-116의 발생독성평가)

  • 김종춘;윤효인;이희복;한상섭;정문구
    • Journal of Life Science
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    • v.11 no.5
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    • pp.447-456
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    • 2001
  • We have recently demonstrated that the fluoroquinolone antibacterial DW-116 caused a significant developmental toxicity in rats. The present study was conducted to determine whether the development toxicity induced by DW-116 treatment was the result of malnutrition fro reduced food intake or the direct effects of test chemical on conceptuses. The test chemical was administered by gavage to pregnant rats from gestational days 6 through 16 at dose levels of 0 and 500 mg/kg/day. A pair-feeding study was also performed in which the pregnant rats received the same amount of diet consumed by the DW-116-treated pregnant rats. All dams were subjected to caesarean section on day 20 of gestation and their fetuses were examined for examined for external, visceral, and skeletal abnormalities. In this treatment group, the maternal toxicities included increased abnormal clinical signs, decreased maternal body weight, suppressed body weight gain during treatment and posttreatment periods, and reduced food intake. The significant developmental toxicities included increased fetal deaths, decreased live fetuses, reduced fetal body weight and placental weight, increased incidence of fetal abnormalities, and increased fetal ossification delay. In this pair-fed group, however, slight maternal toxicities including decreased body weight and suppressed body weight gain during treatment period were observed in comparison with the control group, and minimal development toxicities including reduced fetal and placental weights and increased fetal ossification delay were found. The number of fetal deaths and live fetuses, and the incidences of malformed fetuses and litters with affected fetuses were comparable to the control values. Based on the results, it could be concluded that the development toxicity observed in the treatment group is attributable to the direct effects of Dw-116 treatment, but not to the maternal malnutrition from reduced food consumption during pregnancy.

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Effects of Pesticides(Benomyl, Carbofuran, Thiobencarb) on the Asian Toad(Bufo Gargarizans) Embryo Development (농약류(Benomyl, Carbofuran, Thiobencarb)가 두꺼비(Bufo Gargarizans) 배아발달에 미치는 영향)

  • Ko, Sun-Kun
    • Korean Journal of Environment and Ecology
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    • v.34 no.3
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    • pp.207-215
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    • 2020
  • In this experiment, investigated toxicity evaluation of chemicals using Asian toad embryos, along FETAX(Frog Embryo Teratogenesis Assay-Xenopus) protocol. Asian toad, Bufo gargarizans embryo incubated and investigation of Benomyl(Germicide), Carbofuran(Insecticide) and Thiobencarb(Herbicide) effect by probit analysis. As a result, depends on the concentrations of Benomyl, Carbofuran and Thiobencarb, along mortality and malformation rates were increases and larval body length were decreased. The teratogenic concentration(EC50) of Benomyl, Carbofuran and Thiobencarb were 1.03, 8.74, 4.98mg/ℓ, respectively. And when exposed to Benomyl, larvae responded most sensitively to malformations. Embryo lethal concentration (LC50) Benomyl, Carbofuran and Thiobencarb were 7.26, 560.72, 16.87mg/ℓ, respectively. And Benomyl were at the lowest concentration of lethal the embryos. The teratogenic index(TI) were 7.05 in Benomyl, 64.16 in Carbofuran and 3.39 in Thiobencarb, thus TI values were above 1.5, which is the criterion of teratogenicity. Three of the pesticides used in this study were considered to be a teratogenic substances and Carbofuran was the most potent teratogen. And more specific researches are needed to investigate the effects of pesticides on the embryo development of toads and amphibians and their mechanism.

Effects of Nitric Oxide Donor Supplementation on Copper Deficient Embryos and Nitric Oxide-Mediated Downstream Signaling (Nitric Oxide Donor 첨가가 구리 결핍 배아의 발달과 Nitric Oxide 하위 신호전달체계에 미치는 영향)

  • Yang, Soo-Jin
    • Journal of Nutrition and Health
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    • v.41 no.8
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    • pp.691-700
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    • 2008
  • One suggested mechanism underlying copper (Cu) deficiency teratogenicity is a low availability of nitric oxide (NO), signaling molecule which is essential in developmental processes. Increased superoxide anions secondary to decreased activities of Cu-zinc superoxide dismutase (Cu-Zn SOD) in Cu deficiency can interact with NO to form peroxynitrite, which can nitrate proteins at tyrosine residues. In addition, peroxynitrite formation can limit NO bioavailability. We previously reported low NO availability and increased protein nitration in Cu deficient (Cu-) embryos. In the current study, we tested whether Cu deficiency alters downstream signaling of NO by assessing cyclic GMP (cGMP) and phosphorylated vasodilator-stimulating phosphoprotein (VASP) levels, and whether NO supplementation can affect these targets as well as protein nitration. Gestation day 8.5 embryos from Cu adequate (Cu+) or Cu- dams were collected and cultured in either Cu+ or Cu- media for 48 hr. A subset of embryos was cultured in Cu- media supplemented with a NO donor (DETA/NONOate; 20 ${\mu}M$) and/or Cu-Zn SOD. Cu-/Cu- embryos showed a higher incidence of embryonic and yolk sac abnormalities, low NO availability, blunted dose-response in NO concentrations to increasing doses of acetylcholine, low mRNA expression of endothelial nitric oxide synthase (eNOS), increased levels of 3-nitrotyrosine (3-NT) compared to Cu+/Cu+ controls. cGMP concentrations tended to be low in Cu-/Cu- embryos, and they were significantly lower in Cu-/Cu- yolk sacs than in controls. Levels of phosphorylated VASP at serine 239 (P-VASP) were similar in all groups. NO donor supplementation to the Cu- media ameliorated embryonic and yolk sac abnormalities, and resulted in increased levels of cGMP without altering levels of P-VASP and 3-NT. Taken together, these data support the concept that Cu deficiency limits NO availability and alters NO/cGMP-dependent signaling in Cu- embryos and yolk sacs, which contributes to Cu deficiency-induced abnormal development.

Predicting the Fetotoxicity of Drugs Using Machine Learning (기계학습 기반 약물의 태아 독성 예측 연구)

  • Myeonghyeon Jeong;Sunyong Yoo
    • Journal of Life Science
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    • v.33 no.6
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    • pp.490-497
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    • 2023
  • Pregnant women may need to take medications to treat preexisting diseases or diseases that develop during pregnancy. However, some drugs may be fetotoxic and lead to, for example, teratogenicity and growth retardation. Predicting the fetotoxicity of drugs is thus important for the health of the mother and fetus. The fetotoxicity of many drugs has not been established because various challenges hinder the ability of researchers to determine their fetotoxicity. The need exists for in silico-based fetotoxicity assessment models, as they can modernize the testing paradigm, improve predictability, and reduce the use of animals and the costs of fetotoxicity testing. In this study, we collected data on the fetotoxicity of drugs and constructed fetotoxicity prediction models based on various machine learning algorithms. We optimized the models for more precise predictions by tuning the hyperparameters. We then performed quantitative performance evaluations. The results indicated that the constructed machine learning-based models had high performance (AUROC >0.85, AUPR >0.9) in fetotoxicity prediction. We also analyzed the feature importance of our model's predictions, which could be leveraged to identify the specific features of drugs that are strongly associated with fetotoxicity. The proposed model can be used to prescreen drugs and drug candidates at a lower cost and in less time. It provides a predictive score for fetotoxicity risk, which may be beneficial in the design of studies on fetotoxicity in human pregnancy.

Embryotoxicity and Teratogenicity of Excess Zinc on Xenopus laevis (과량의 아연에 의한 아프리카 발톱개구리 (Xenopus laevis)의 배발생 이상과 독성)

  • Yoon, Chun-Sik;Jin, Jung-Hyo;Cheong, Seon-Woo
    • Korean Journal of Ecology and Environment
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    • v.36 no.1 s.102
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    • pp.83-94
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    • 2003
  • Concentrated releases of zinc into water usually results from discharges associated with industrial purpose. The released zinc into soil is corroded and released into water. In aquatic environment, exess zinc is toxic to the organisms and causes the growth inhibition and malformation of them as a heavy metal. In this study, excess zinc toxicity was tested by FETAX (frog embryo teratogenetic assay with Xenopus)as in vivo system. Xenopus embryos at st.9 were exposed to $100{\sim}900\;{\mu}M$ of zinc for 7 days and 81% of individuals were survived in 100 ${\mu}M$, and 25% were survived in 1000M of zinc solution. In external malformations, swelled belly and intestinal dysplasia were common, and all of tested individuals showed these malformations in 200 ${\mu}M$ or higher concentration of zinc. In 400 ${\mu}M$ or higher concentration, all of tested tadpoles showed faded heart. Also, hypo-pigmentation, lens hernia and loose digestive track were very frequently found in 100 ${\mu}M$ of zinc. The histological study with paraffin section of zinc treated tadpoles showed following abnormalities; regeneration of photoreceptor on retina, reduced vitreous chamber in eye, reduction of red blood cells in heart, abnormal liver, swelling of pronephric cell, muscle dysplasia and palatal papilloma. These abnormalities may be caused by the degeneration of mitochondria, inhibition of cell adhesion, and the formation of leghemoglobin by zinc due to the substitution of $Ca^{2+}$ by $Zn^{2+}$. The body length was reduced due to the excess zinc. From a statistical result, body lengths of 300 ${\mu}M$ or higher concentrative g개ups was significantly reduced comparing that of control group. Recently, many spontaneous malformations and reduction of amphibians are reported, From the results of present study, excess zinc mi호t be a factor of amphibian reduction, and the control of zinc discharges is very important.

Efficacy and Safety of Topical Application of Epidermal Growth Factor (EGF) for Korean Acne Patient (한국인 여드름 환자에서 표피성장인자가 함유된 외용제의 피부 적용에 대한 유효성 및 안전성 평가)

  • Suh, Joon Hyuk;Hyun, Moo Yeol;Jang, Seong Eum;Choi, Sun Young;Kim, Myeung Nam;Kim, Beom Joon
    • Journal of the Society of Cosmetic Scientists of Korea
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    • v.42 no.2
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    • pp.111-118
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    • 2016
  • Acne vulgaris is a chronic inflammatory condition characterized by comedo, papule, cyst, nodule and postinflammatory hyperpigmentation. Meanwhile, it is also induced by adverse event of drugs. Among them, acneiform folliculitis is a side effect of epidermal growth factor receptor (EGFR) inhibitor, which is an anticancer agent, and its incidence may occur in upward of 75 ~ 100% of cases. The main method of acne vulgaris treatment is oral antibiotics, retinoids, topical medication and so on. However, it is limitation that teratogenicity caused by retinoids and antibiotic resistance increased by using antibiotics. In this study, we aimed to evaluate the clinical efficacy and safety of topical recombinant human (rh) EGF in treating facial acne vulgaris. Twenty three Koreans (age: 10 ~ 29 years) with mild to moderate acne vulgar participated in the study and applied topical rhEGF cream (trouble control EGF) with 3 products (trouble control clarifying cleansing foam, trouble control all-clear filling toner, redroll calming moisture) on their face twice daily for four weeks. Several assessment methods were applied: Acne lesion counts score by investigator's global assessment, efficacy and satisfaction score by subjects. Skin sebum output level, hydration level and redness level were also measured at each visit. At the final visit, skin sebum level, transepidermal water loss, skin redness statistically decreased and acne lesions (comedone, papule) were statistically reduced. No severe side effects were observed during the study. In conclusion, topical rhEGF seems to be an effective and safe adjuvant treatment option for mild acne vulgaris.