• Toxicological Research
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• v.2 no.1
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• pp.37-50
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• 1986

This paper describes the effects of nitrofen (Hi-TOK), a herbicide on the fetuses of rats. The results were observed as follows: The internal soft tissue anomalies were classified as diaphragmatic hernia, cardiac malformation (T.G.V., V.S.D., S.V.), dilatation of ventricle in brain, dilatation of renal pelvis, underdevelopment of fetal lung, shortening of cortex length and increasing of immatured glomeruli counts in the fetal kidney. The heart and diaphragm appear to be the target organs.

• Journal of The Korean Society of Maternal and Child Health
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• v.21 no.3
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• pp.159-165
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• 2017

The thalidomide tragedy in the 1960s has resulted in a perpetuation of a certain perception amongst physicians and pregnant women that the use of medication during pregnancy is a potential teratogen. Consequently, physicians hesitate in prescribing medication to pregnant women. In addition, pregnant women often refuse medication despite therapeutic necessity because of this existing perception. Recently there have been frequent adverse pregnancy outcomes related to the recurrence of chronic diseases, such as hypertension and diabetes, following pregnancy in older women. And there are lots of unnecessary termination of pregnancy due to the of information of medication exposed to medication following over 50% of unintended pregnancy. In light of this, better dissemination of information regarding the safe usage of medication for pregnant women is required. This would not only be cost-effective in terms of medical expenditure, but also prove beneficial for the treatment of diseases. In addition, Korea needs to adapt to the increasing changes of the international information system regarding supporting the safe usage of medication during pregnancy. An example of this is shown by the recent changes to the labeling of medication by the United States Food and Drug Administration. The new labeling includes information on the risk of usage, rather than just an arbitrary alphabetic classification of B, C, D, or X. Furthermore, this information is limited in Korea because of the lack of research, which in turn is due to several limitations on ethics and methodology, as well as present regulations on the research of pregnant women. From this, we can learn that government support is critical for the establishment of research so that we can alter the perception that all medication is harmful to pregnant women.

• Obstetrics & gynecology science
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• v.61 no.6
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• pp.649-654
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• 2018

Objective Isotretinoin is a notorious teratogen otherwise used for the treatment of acne vulgaris. Some countries, including those in North America and the European Union, implemented the pregnancy prevention program (PPP); however, no PPP has yet been established in South Korea. So the aim of this study was to evaluate the rate of pregnant women exposed to isotretinoin among the callers of the Korean Mother Safe Counseling Center. Methods This is a prospective cohort study. We evaluated the demographic characteristics, obstetric history, and isotretinoin exposure of pregnant women based on the mother safe registry from April 2010 to July 2016. Results Among 22,374 callers, 650 (2.9%) pregnant women were exposed to isotretinoin. The mean age was $29.0{\pm}4.4$ years in the isotretinoin-exposed group and $32.0{\pm}4.2$ years in the unexposed group (P<0.001). Moreover, the incidence of pregnancies within 30 days after isotretinoin discontinuation or during isotretinoin intake was 78.9% (513/650). The median duration of isotretinoin exposure was 18 (1-4,231) days. Furthermore, from 2011 to 2015, the incidence of isotretinoin exposure was $2.9{\pm}1.2$ pregnancies per 10,000 births in South Korea. Conclusion Approximately 80% of pregnant women are exposed to isotretinoin within the recommended 30 days of contraception or during pregnancy. Therefore, the PPP has to be established in South Korea.

• Environmental Analysis Health and Toxicology
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• v.18 no.3
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• pp.175-182
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• 2003

Bisphenol A shares similarities in structure, metabolism and action with DES, a known human teratogen and carcinogen. Bisphenol A, a monomer of polycarbonate and epoxy resins, has been detected in canned food and human saliva. The purpose of the this study was to evaluate the cytotoxicity, cell proliferation of bisphenol A In the presence of a rat liver S9 mix, contaning cytochrome P450 enzymes, and Cu (II). In the present study, Bisphenol A in combination with Cu (II) exhibited a enhancement in cytotoxicity which were inhibited by free radical scavengers. The content of malondialdehyde, an end product of lipid peroxidation, was also found to increase with concentration of bisphenol A. Also, we examined the change of CuZn-SOD, Mn-SOD, catalase and GPx activities in the MCF-7 cells exposed to bisphenol A. The activities of CuZn-SOD, CPx, catalase were found to decrease with bisphenol A concentration. Meanwhile, the activity of Mn-SOD was unchanged. This indicated that elevated oxidative stress caused by imbalance between the production and removal of free radicals occurred in cells.

• 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.

• Environmental Analysis Health and Toxicology
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• v.24 no.1
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• pp.33-41
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• 2009

Among the toxicants in the environment dioxin-like compounds, including TCDD(2,3,7,8-Tetrachlorodibenzo-p-Dioxin), are well known as carcinogen and teratogen. TCDD the most toxic of these compounds, may result in a wide variety of adverse health effects in humans and environment, including carconogenesis, hepatotoxicity, teratogenesis, and immunotoxicity. Also TCDD increases superoxide, peroxide radicals and induces oxidative stress that leads to breakage of DNA single-strand and mitochondrial dysfunction. Recently, there have been reports that persistent organic pollutants(POPs) may be causing metabolic disease through mitochondrial toxicity. In order to examine if dioxin brings about toxicity on mitochondria directly, we measured the change of the mitochondrial membrane potential after exposure to TCDD using JC-1 dye. After short time exposure of dioxin, mitochondrial depolarization was observed but it recovered to the control level immediately. This TCDD effect on mitochondrial membrane potential was not correlated either to the production of reactive oxygen species(ROS) or extracellular $Ca^{2+}$ by TCDD. Less than 2 hours exposure of TCDD did not show any change in ROS production but 0.25 nM TCDD for 48 hours or 0.5 nM TCDD for 12 hours exposure did increase in ROS production. Under these conditions of ROS production by TCDD, no changes in the mitochondrial membrane potential by TCDD was observed.

• YAKHAK HOEJI
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• v.52 no.2
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• pp.111-116
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• 2008

Diethylstilbestrol (DESB) is a synthetic estrogen not only that routinely prescribed, but also that known to be a teratogen. In this study, we found a novel pharmacological feature that DESB is able to positively modulate CD29 $({\beta}1-integrin)$ function. Thus, DESB up-regulated homotypic cell-cell adhesion of monocytic U937 cells mediated by CD29. However, DESB did not increase the surface level of CD29 and its binding activity to ligand (fibronectin), according to flow cytometric analysis and cell-fibronectin adhesion assay. Instead, the DESB-mediated up-regulation of cell-cell adhesion was blocked by several signaling enzyme inhibitors. Treatment of U0126 [an extracellular signal-regulated kinase (ERK) inhibitor], SB20358 (a p38 inhibitor) or Rp-8-pCPT-cGMP (a protein kinase G inhibitor) clearly inhibited DESB-mediated up-regulation of cell-cell adhesion induced by CD29. However, estrogen receptor antagonist ICI 182,780 failed to abrogate DESB effect. Therefore, our data suggest that DESB may up-regulate CD29-mediated cell-cell adhesion via modulating intracellular signaling enzymes such as ERK, PKG, and p38, independent of estrogen receptor function.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2002.05a
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• pp.48-64
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• 2002

The primary recognized health risk from common deficiencies in glucose-6-phosphate dehydrogenase (G6PD), a cytoprotective enzyme for oxidative stress, is red blood cell hemolysis. Here we show that litters from untreated pregnant mutant mice with a hereditary G6PD deficiency had increased prenatal (fetal resorptions) and postnatal death. When treated with the anticonvulsant drug phenytoin, a human teratogen that is commonly used in pregnant women and causes embryonic oxidative stress, G6PD-deficient dams had higher embryonic DNA oxidation and more fetal death and birth defects. The reported G6PD gene mutation was confirmed and used to genotype fetal resorptions, which were primarily G6PD deficient. This is the first evidence that G6PD is a developmentally critical cytoprotective enzyme for both endogenous and xenobiotic-initiated embryopathic oxidative stress and DNA damage. G6PD deficiencies accordingly may have a broader biological relevance as important determinants of infertility, in utero and postnatal death, and teratogenesis.-Nicol, C. J., Zielenski, J., Tsui, L.-C., Wells, P. G. An embryoprotective role for glucose-6-phosphate dehydrogenase in developmental oxidative stress and chemical teratogenesis.

• Toxicological Research
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• v.13 no.1_2
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• pp.95-101
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• 1997

Ethyl carbamate (EC) is a potent teratogen in rodents and is present at low concentration in fermented foods and alcohol beverages. It has been well hypothesized that some metabolic products are responsible for the teratogenic effects of the compound. In the present study, the effects of phenobarbital (PB) on EC-induced embryotoxicity were investigated in SD rats. Six groups were constructed: EC 300 (EC 300 mg/kg/day), EC 600 (EC 600 mg/kg/day), EC 600+PB (EC 600 mg/kg/day and PB 80 mg/kg/day), PB (PB 80 mg/kg/day), DR (dietary restriction, 8 g/day/rat) and a control group. Rats of the EC 600+PB group were pretreated with phenobarbital intraperitoneally for three days to induce cytochrome P450 enzymes, followed by oral administration of EC for two consecutive days. The incidence of fetal deaths in the EC 600+PB group was higher than that of the EC 600 group(42.7 vs. 14.3%). The incidence of fetal realformations in the EC 600+PB group was higher than that of the EC 600 group (external; 7.0 vs. 4.1%, visceral; 31.4 vs. 11.3%, skeletal; 11.1 vs. 6.5%). There was no embryotoxicity in the control, EC 300, PB and DR groups. These results show that the pretreatment with phenobarbital augments EC-induced embryotoxicity in rats, indicating an evidence that metabolic activation by cytochrome P450 may be the major pathway of EC to its embryotoxic forms.

• Toxicological Research
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• v.34 no.2
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• pp.111-125
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• 2018

Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the "Guideline Q3C (R6) on impurities: guideline for residual solvents" issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which "no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found". We performed a risk assessment of DIPE based on available toxicological data, after carefully assessing their reliability using the Klimisch score approach. We found sufficiently reliable studies investigating subchronic, developmental, neurological toxicity and carcinogenicity in rats and genotoxicity in vitro. Recent studies also investigated a wide array of toxic effects of gasoline/DIPE mixtures as compared to gasoline alone, thus allowing identifying the effects of DIPE itself. These data allowed a comprehensive toxicological evaluation of DIPE. The main target organs of DIPE toxicity were liver and kidney. DIPE was not teratogen and had no genotoxic effects, either in vitro or in vivo. However, it appeared to increase the number of malignant tumors in rats. Therefore, DIPE could be considered as a non-genotoxic animal carcinogen and a PDE of 0.98 mg/day was calculated based on the lowest No Observed Effect Level (NOEL) value of $356mg/m^3$ (corresponding to 49 mg/kg/day) for maternal toxicity in developmental rat toxicity study. In a worst-case scenario, using an exceedingly high daily dose of 10 g/day, allowed DIPE concentration in pharmaceutical substances would be 98 ppm, which is in the range of concentration limits for ICH Q3C guideline class 2 solvents. This result might be considered for regulatory decisions.