• Proceedings of the PSK Conference
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• 2003.04a
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• pp.165.2-166
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• 2003

Diesel exhaust is suspected to cause acute and chronic adverse effects on health. In recent. the effect of estrogenic endocrine disruptor in diesel particulate matter was little studied. Therefore, we examined the estrogenic activity of respirable diesel exhaust particulate matter derived from diesel engine motor. PM2.5 diesel exhaust of vehicle was collected using a high volume samples equipped with a cascade impactor. (omitted)

• Molecular & Cellular Toxicology
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• v.2 no.1
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• pp.15-20
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• 2006

Genistein is a potent, plant-derived isoflavone that displays estrogenic activity at low concentrations but inhibits proliferation at high amounts. However, the molecular mechanism of genistein is not completely understood. In the present study, the biphasic effects (estrogenic and antiestrogenic activity) of genistein on the growth of MCF-7 cells were identified. Genistein within a low range of concentration, $1-10\;{\mu}M$, stimulated proliferation, while $50-100\;{\mu}M$ caused apoptotic cell death. Additionally, genistein at a low concentration induced estrogen receptor (ER)-mediated gene expression and ER phosphorylation. When pre-treated with PD98059, an MEK inhibitor, ER-mediated gene expression and ER phosphorylation by genistein were noticeably increased. However, the increased gene expression and phosphorylation did not enhance cell proliferation. Moreover, it was observed that ER-mediated signaling performs an important role in the MAPK pathway. The proliferation and apoptosis in genistein-treated MCF-7 cells were partially dependent on the Bcl-2 level. The addition of IC1 182, 780, an estrogen receptor antagonist, inhibited Bcl-2 expression induced by genistein. This study suggests that there is a close relationship between Bcl-2 and the ER signaling pathways in MCF-7 cells.

• Journal of Applied Biological Chemistry
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• v.48 no.2
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• pp.49-57
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• 2005

Soy is an important food in Asia and many studies have suggested that the low incidences of chronic diseases in Asian countries are associated with diets that are rich in soy. Soy contains many kinds of phytochemicals, and soy isoflavones and soyasaponins have received considerable attention. Twelve isoflavone components have been isolated from soy: three aglycones (daidzein, genistein, and glycitein), and their respective nine glucosidic conjugates. Soy isoflavones are similar in structure to estrogen and exhibit both estrogenic and antiestrogenic activities. Soy isoflavones exhibit anticancer activity, can reduce the risk of cardiovascular disease, and are beneficial to brain and bone health. Soyasaponins are divided into three groups (A, B, and E saponins), and they exhibit hypocholesterolemic, anticancer, hepatoprotective, antioxidative, and anti-human-immunodeficiency-virus effects. Despite the abundant literature suggesting that soy isoflavones and soyasaponins have potential applications in preventive medicine, further research is needed to standardize dosages and ensure their efficacy.

• Natural Product Sciences
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• v.21 no.1
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• pp.34-41
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• 2015

The objective of this study is to characterize a toxicity of Epimedii Herba (EH) in F344 rats and to find a dose levels for the 13 weeks toxicity study. EH is well known as medicinal herb in many Asian countries for traditional medicines of antibacterial and antiviral effects, estrogenic and antiestrogenic effects, and for treatment of osteoporosis, hypotensives, fatigue, kidney disorders, and related complications. However, the indispensable and basic information of toxicological evaluation of EH extract is insufficient to support its safe use. Therefore, we conducted toxicological evaluation of this drug in compliance with OECD and MFDS guideline in this study. The extract of EH was administered orally to F344 rats at dose levels of 0, 500, 1000, 2000, 3500, and 5000 mg/kg/day for 2 weeks. Each group was composed of 5 male and female rats. In this study, there were no treatment of EH-related adverse changes in clinical observations, mortality, body weights, food consumption, urinalysis, gross finding at necropsy, and organ weight examination. Total red blood cell count, hematocrit, mean corpuscular hemoglobin concentration, total cholesterol, and phospholipid were decreased in males and females at 5000 mg/kg/day compared to the control animals. Mean corpuscular volume and reticulocyte counts were increased in males and females at 5000 mg/kg/day compared to control animals. Therefore, we recommend that dose level of 5000 mg/kg/day is a highest treatment group in 13-week EH extract exposure study for further toxicity assessment.

• Biomolecules & Therapeutics
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• v.8 no.1
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• pp.78-83
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• 2000

The objective of this study was to prevalidate the Organization for Economic Cooperation and Development's (OECD) rodent uterotrophic assay as a test method for screening of potential endocrine disrupting chemicals (EDCs). This study was conducted exactly as described in the OECD protocol documents. A positive control substance, 17$\alpha$-ethinyl estradiol (EE), was administered daily for three days to ovariectomized (OVX) Sprague-Dawley rats at various doses for determine the dose-response curve. Additionally, a pure antiestrogenic chemical, ZM189, 154 was administered to OVX rats at the same time EE to determine the effectiveness of the material against blocking the estrogenic effects of EE. At higher concentration of EE (10 $\mu\textrm{g}$/kg), a statistically significant difference in body weight gain and food consumption was observed compared to vehicle controls. In uterine responses, EE produced a dose-related increase in uterus weights compared to vehicle control. These increases were statistically significant at the >1.0 $\mu\textrm{g}$/kg doses. However, a similar dose-response relationship was not observed in vagina weight. A comparison of the two groups receiving ZM189,154 (0.1 and 1.0 mg/kg) with 0.3 $\mu\textrm{g}$/kg of EE and the group receiving only 0.3 $\mu\textrm{g}$/kg of EE showed dose-related decreases in uterus weights. However, statistical significance was shown in 1.0 mg/kg of ZM189,154. In conclusion, administration of EE produced a dose-related increase in uterine (wet and blotted) weights. Additionally, the 1.0mg/kg dose of ZM189,154 was effective in blocking the estrogenic activity of EE. These data suggest 3-day uterotrophic assay using OVX rats may serve as a good tool for EDCs screening.

• Proceedings of the Korea Society of Environmental Toocicology Conference
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• 2003.10a
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• pp.57-69
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• 2003

It is well known that many pesticides possess hormonal activity, and affect the developments of wildlife and mammals including human. Currently, pyrethroid insecticides are in worldwide use to control in and outdoor pests, providing potential far environmental exposure. Hormonal activities of these pyrethroid insecticides, however, have been little studied, and the developmental effects of them were no reported. Therefore, we firstly examined the potential estrogenic activities of some pyrethroid insecticides (permethrin, cypermethrin, tetramethrin, deltamethrin, sumithrin, fenvalerate and bioallethrin) by immature rat uterotrophic assay, luciferase reporter gene assay and Calbindin-D$\sub$9k/ (CaBP-9k) gene expression assay. Uterine wet weights were increased by permethrin and the permethrin-induced weights were inhibited by ICI 182780 in the uterolrophic assay. On the other hand tetramethrin significantly reduced uterine and vaginal wet weights, and also inhibited the E2-induced weight increases at all doses tested. Cypermethrin and sumithrin had a tendency to increase uterine weights, although not statistically significant. Permethrin and cypermethrin dose-dependently increased the luciferase activity in reporter gene assay. Northern blot analysis showed that permethrin induced CaBP-9k mRNA expression whereas tetramethrin inhibted. Subsequent studies were conducted to investigate the possible developmental effects of four pyrethroid insecricides (permethrin, cypermethrin, sumithrin and teramethrin). Either diethlbestrol (DES) or 17${\beta}$ -estradiol (E2) was used as a reference control in this study. Pyrethroid insecticides were administered to Sprague Dawley rats via subcutaneous injection at 6 to 18 days of gestation or 1 to 5 days after birth. In utero treatment of permethrin (10mg/kg/day) in female rat resulted in significant increases in uterine and ovarian weights while significant decreases in serum E2 concentration, uterine and ovarian ER${\alpha}$ mRNA levels. Sumithrin and permethrin led to acceleration in vaginal opening of female rat, while delay in preputial separation of male after neonatal treatment. Anogenital distances of PND 18 were significantly reduced in sumthrin-treated, and permerhrin-treated male rats after neonatal treatment. All the pyrethroid insecticides tested caused significant increases in uterine weights on PND 18, while significant reductions in the first diestrus phase when neonataly treated. In addition, exposure to pyrethroids in neonatal period led to significant reduction in relative brain weight in female rat on PND 18, but its weight was recovered in diestrus phase. In summary, Our experimental data demonstrate the possibilities of developmental effects of pyrethroid insecticides via estrogenic or antiestrogenic activity.

• Fisheries and Aquatic Sciences
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• v.12 no.4
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• pp.293-298
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• 2009

Several studies have reported that nonylphenol (NP) and 2,2', 4,6,6'-pentachlorobiphenyl (PCB104) exhibit estrogenic activity. To investigate the estrogenic potency of NP and PCB104 during oocyte maturation, fully vitellogenic oocytes (0.76 mm diameter in average) of yellow fin goby, Acanthogobius flavimanus, were exposed in vitro to these chemicals at different concentrations (0.1, 1, 10, 100, and 1,000 ng/mL) with the exogenous precursor $17\alpha$-hydroxyprogesterone ($17{\alpha}OHP$) 50 ng/mL in the presence or absence of human chorionic gonadotropin (HCG). The production of testosterone (T), estradiol-$17\beta$ (E2), and $17\alpha,20\beta$-dihydroxy-4-pregnen-3-one ($17\alpha20{\beta}OHP$) in response to NP or PCB104 were measured by radioimmunoassay. Steroid levels were also expressed as E2/T and E2/$17\alpha20{\beta}OHP$ ratios. In the absence of HCG, no significant differences in either NP or PCB104 treatment groups were observed. In the presence of HCG, NP treatment did not show significant differences in the production of T, E2, and $17\alpha20{\beta}OHP$ at any concentrations tested, but E2/T ratios were decreased at concentrations of 0.1, 1, 10, and 1,000 ng/mL compared with the control group. PCB104 decreased E2 production at concentrations of 0.1, 10, and 1000 ng/mL, but did not show significant differences in the production of T and $17\alpha20{\beta}OHP$ at any concentration tested. While E2/T ratios were decreased at PCB104 concentrations of 0.1, 1, 10, and 1,000 ng/mL, E2/$17\alpha20{\beta}OHP$ ratios were also decreased at 0.1, 10, and 1,000 ng/mL compared with the control. Results indicate that both NP and PCB104 appeared to have antiestrogenic effects during this phase.

• Biomedical Science Letters
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• v.11 no.2
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• pp.175-183
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• 2005

The two major isoflavones in soy, genistein and daidzein, are well known to prevent hormone-dependent cancers by their anti estrogenic activity. The exact molecular mechanisms for the protective action are, however, not provided yet. It has been reported that genistein and daidzein have a potential anticancer activity through their antiproliferative effect in many hormone-dependent cancer cell lines. Transforming growth $factor-\beta1(TGF-\beta1)$ has also been found to have cell growth inhibitory effect, especially in mammary epithelial cells. This knowledge led to a hypothetical mechanism that the soy isoflavones-induced growth inhibitory effect can be derived from the regulation of $TGF-\beta1$ and $TGF-\beta$ receptors. In order to test this hypothesis, the effects of the soy isoflavones at various concentrations and periods on the expression of $TGF-\beta1$and $TGF-\beta$ receptors were investigated by using Northern blot analysis in human breast carcinoma epithelial cell lines, an estrogen receptor positive cell line (MCF-7) and an estrogen receptor negative cell line (MDA-MB-231). As a result, only genistein has shown a profound dose-dependent effect on $TGF-\beta1$ expression in the $ER^+$ cell line within the range of doses tested, and the expression levels are correspondent to their inhibitory activities of cell growth. Moreover, daidzein showed down-regulated $TGF-\beta1$ expression at a low dose, the cell growth proliferation was promoted at the same condition. Therefore, antiproliferative activity of the soy isoflavones can be mediated by $TGF-\beta1$ expression, and the effects are mainly, if not all, occurred by ER dependent pathway. The expression of $TGF-\beta$ receptors was induced at a lower dose than the one for $TGF-{\beta}1$ induction regardless of the presence of ER, and the expression patterns are similar to those of the cell growth inhibition. These results indicated that the regulation of $TGF-\beta$ receptor expression as well, prior to $TGF-\beta1$ expression, may be involved in the antiproliferative activity of soy isoflavones. Little or no expression of $TGF-\beta$ receptors was found in the MCF-7 and MDA-MB-231 cells, suggesting refractory properties of the cells to growth inhibitory effect of the $TGF-\beta$. The soy isoflavones can seemingly restore the sensitivity of growth inhibitory responses to $TGF-\beta1$ by re-inducing $TGF-\beta$ receptors expression. In conclusions, our findings presented in this study show that the antitumorigenic activity of the soy isoflavones could be mediated by not only $TGF-\beta1$induction but $TGF-\beta$ receptor restoration. Thus, soy isoflavones could be good model molecules to develop new nonsteroidal antiestrogenic chemopreventive agents, associated with, regulation of $TGF-\beta$ and its receptors.