• 한국발생생물학회지:발생과생식
• /
• 제22권4호
• /
• pp.379-391
• /
• 2018

Through the development of organic synthetic skill, chemicals that mimic signaling mediators such as steroid hormones have been exposed to the environment. Recently, it has become apparent that this circumstance should be further studied in the field of physiology. Estrogenic action of chronic low-dose nonylphenol (NP) and di-(2-ethylhexyl) phthalate (DEHP) in mouse uterus was assessed in this study. Ten to twelve-week-old female mice (CD-1) were fed drinking water containing NP (50 or $500{\mu}g/L$) or DEHP (133 or $1,330{\mu}g/L$) for 10 weeks. Uterine diameter, the thickness of myometrium and endometrium, and the height of luminal epithelial cells were measured and the number of glands were counted. The expression levels of the known $17{\beta}$-estradiol ($E_2$)-regulated genes were evaluated with real-time RT-PCR methodology. The ration of uterine weight to body weight increased in $133{\mu}g/L$ DEHP. Endometrial and myometrial thickness increased in 133 and $1,330{\mu}g/L$ DEHP treated groups, and in 50, $500{\mu}g/L$ NP and $133{\mu}g/L$ DEHP, respectively. The height of luminal epithelial cell decreased in NP groups. The numbers of luminal epithelial gland were decreased in NP groups but increased in $50{\mu}g/L$ DEHP group. The histological characters of glands were not different between groups. The mRNA expression profiles of the known $17{\beta}$-estradiol ($E_2$) downstream genes, Esr1, Esr2, Pgr, Lox, and Muc1, were also different between NP and DEHP groups. The expression levels dramatically increased in some genes by the NP or DEHP. Based on these results, it is suggested that the chronic low-dose NP or DEHP works as estrogen-like messengers in uterus with their own specific gene expression-regulation patterns.

• 한국수정란이식학회지
• /
• 제12권3호
• /
• pp.229-246
• /
• 1997

Implantation is a most important biological process during pregnancy whereby conceptus establishes its survival as well as maintenance of pregnancy. During the periimplantation period, both uterine endometriurn and conceptus synthesize and secrete a host of growth factors and cytokines which mediate the actions of estrogen and /or progesterone and also exert their steroid-independent actions. Growth factors expressed by the materno-conceptal unit en masse have important roles in cell migration, stimulation or inhibition of cell proliferation, cellular differentiation, maintenance of pregnancy and materno-conceptal communications in an autorcrine /paracrine manner. The present review focuses on the role of the intrauterine IGF system during periimplantation conceptus development. The IGF system comprises of IGF- I and IGF- II ligands, types I and II IGF receptors and six or more IGF-binding proteins(IGFBPs). IGFs and IGFBPs are expressed and secreted by uterine endometrium with tissue, pregnancy stage and species specificities under the influence of estrogen, progesterone and other growth factor(s). Conceptus also synthesizes components of the IGF system beginning from a period between 2-cell and blastocyst stages. Maternal IGFs are utilized by both maternal and conceptal tissues; conceptus-derived growth factors are believed to be taken up primarily by conceptus. IGFs enhance the development of both maternal and conceptal compartments in a wide range of biological processes. They stimulate proliferation and differentiation of endometrial cells and placental precursor cells including decidual transformation from stromal cells, placental formation and the synthesis of some steroid and protein hormones by differentiated endometrial cells or placenta. It is also well-documented in a number of experimental settings that both IGFs stimulate preimplantation embryo development. In slight contrast to these, prenatal mice carrying a null mutation of IGF and /or IGF receptor gene do not exhibit any apparent growth retardation until after implantation. Reason (s) for this discrepancy between the knock-out result and the in vitro ones, however, is not known. IGFBPs, in general, are believed to inhibit IGF action within the materno-conceptal unit, thereby allowing endometrial stromal cell differentiation as well as dampening ex cessive placental invasion into maternal tissue. There is evidence, however, indicating that IGFBP can enhance IGF action depending on environrnental conditions perhaps by directioning IGF ligand to the target cell. There is also a third possibility that certain IGFBPs and their proteolytic fragments may have their own biological activities independent of the IGF. In addition to IGFBPs, IGFBP proteases including those found within the uterine tissue or lumen are thought to enhance IGF bioavailability by degrading their substrates without affecting their bound ligand. In this regard, preliminary results in early pregnant pigs suggest that a partially characterized IGFBP protease activity in uterine luminal fluid enhances intrauterine IGF bioavailability during conceptus morphological development. In summary, a number of in vitro results indicate that IGFs stimulates the development of the rnaterno-conceptal unit during the periimplantation period. IGFBPs appear to inhibit IGF action by sequestering their ligands, whereas IGFBP proteases are thought to enhance intrauterine bioavailability of IGFs. Much is remaining to be clarified, however, regarding the roles of the individual IGF system components. These include in vivo evidence for the role of IGFs in early conceptus development, identification of IGF-regulated genes and their functions, specific roles for individual IGFBPs, identification and characterization of IGFBP proteases. The intrauterine IGF club house thus will be paying a lot of attention to forthcoming results in above and other areas, with its door wide-open!

• 한국수정란이식학회지
• /
• 제23권4호
• /
• pp.229-237
• /
• 2008

Recently, parabens have been believed to act as xenoestrogens, an identified class of endocrine disruptors (EDs). These environmental compounds are the most well-known as preservatives in many commercial products, including food, cosmetics and pharmaceutical industries. It has been demonstrated that the human health risks of parabens result from a long-term exposure to skin in which this chemical group is rapidly absorbed through the skin. On the other hand, parabens are also completely absorbed from gastrointestinal tract. It has reported that these substances possess several biological effects in which inhibitory property involved in membrane transports and mitochondrial functions is considered to be important for their action. Testing of parabens has revealed that estrogen-like activities of these chemicals are much less potent than natural estrogen, $17{\beta}$ estradiol (E2). Additionally, the estrogenicity of individual paraben- compounds is distinct depending upon their biochemical structure. Recent findings of paraben-estrogenic activities have shown that these compounds may affect breast cancer incidence in women, suggesting adverse ecological outcomes of this environmental group on human and animal health. Although the biological and toxicological effects of parabens have been demonstrated in many previous studies, possible mechanism(s) of their action are required to be explored in order to bring the better understanding in the detrimental impacts of parabens in human and wildlife. There have several different types of parabens which are the most widely used as preservatives. These include methyl-paraben, ethylparaben, propylparaben, butylparaben and p-hydroxybenzoic acid, a major metabolite of parabens. In this review, we summarize current database based on in vitro and in vivo assays for estrogenic activities and health risk assessment of paraben- EDs which have been published previously.

• Toxicological Research
• /
• 제20권3호
• /
• pp.251-261
• /
• 2004

A large number of chemical pollutants including phthalates, alkylphenolic compounds and organochlorine pesticides have the ability to disrupt endocrine function in animals, and alter cog-nitive function. Because hormone mediated events play an important role in central nervous system development and function, the changes in cognitive function seem to be mediated by the endocrine-like action of these chemicals. The present study therefore was designed to investigate effect of bisphenol A (BPA), an endocrine disrupting chemical on neuro-behavial patterns, and expression of estrogen receptors and tyrosine hydroxylase, a limiting enzyme of dopamine synthesis pathway. BPA was treated orally for 3 weeks into 3 week old mice, and then the neuro-behavial patterns (stereo-type behaviors such as jumping rearing and forepaw tremor, climbing behavior, tail flick, rotarod and locomotor activity), and the expression of estrogen receptors and tyrosine hydroxylase were deter-mined every 3 week for 9 weeks. During the treatment of BPA, the food uptake and body weight increase were not significantly changed. BPA resulted in the increased stereotype behaviors (jump-ing, rearing and forepaw tremor) 6 or 9 weeks after treatment. The time response to tail flick and locomotor activity were decreased by the treatment of BPA, whereas the time for rotarod was increased by the treatment of BPA. The expression of estrogen receptor alpha and beta was increased in the brain and pituitary gland. Maximum expression was found in the brain after 9 week of 100 mg/kg BPA treatment and in the pituitary gland after 6 week of 100 mg/kg BPA treatment. Tyrosine hydroxylase was increased in dose and time dependent manners in the brain but no change was found in the pituitary gland. The present data show that exposure of BPA in the young mice could alter expression of estrogen receptors and dopamine synthesis pathway, thereby modulate neuro-behavial patterns (increase of stereotype behaviors but decrease locomotor activity).

• 생명과학회지
• /
• 제28권2호
• /
• pp.265-273
• /
• 2018

에스트로겐(E2)은 유방암의 발달과 진행에 관여하며, 에스트로겐 수용체(ER)에 의해 매개된다. ER은 유방암세포에서 epidermal growth factor receptor와 insulin-like growth factor-1 receptor의 신호전달경로들 사이에서 다양한 cross-talk을 통하여 세포의 증식, 이주, 침습 및 약물에 대한 저항성을 일으키는데 중요한 역할을 수행한다. 유방암은 내분비신호전달의 항상성 붕괴에 의해 주로 발생되며, 특히 E2/IGF-1/EGF와 ER/G-protein estrogen receptor (GPER)/IGF-1R/EGFR, 그리고 이들의 세포내 신호전달 매개인자들의 통제되지 않는 발현과 활성증가에 의해 유발된다. 이러한 변화는 E2와 성장인자 신호전달 사이의 복잡한 cross-talk에 영향을 주어 결국 암의 진행과 내분비조절인자들에 대한 저항성을 갖게 된다. 따라서, E2와 성장인자들 사이의 cross-talk에 관한 분자적 기전을 단계별로 규명하는 것은 유방암의 다양한 유형에 따른 맞춤형 치료에 기여할 것으로 사료된다. 특히, 다양한 유전형 및 표현형을 가진 유방암의 치료를 위한 전략으로서, ER+ 호르몬의존성 유방암세포에 대한 aromatase 억제제 및 E2작용 차단제의 사용과 E2와 성장인자들 사이의 cross-talk에 의한 암세포의 증식억제를 위한 IGF-1R/EGFR 활성차단제의 사용 등을 들 수 있다. 뿐만 아니라, ER과 EGFR/IGF-1R 사이의 cross-talk에 의해 조절되는 ECM 분자들의 발현변화는 유방암세포의 전이에 대한 표적치료제를 위해 활용될 수 있다. 따라서, 암의 진행과 관련된 ER, GPER, IGF-1R 및 EGFR 매개에 의한 신호전달경로들 사이의 cross-talk에 관한 보다 더 자세한 분자적 수준의 규명이 필요할 것으로 사료된다.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
• /
• pp.134.2-135
• /
• 2003

A large number of chemical pollutants including phthalates, alkylphenolic compounds, organochlorine pesticides and bisphenol A have the ability to disrupt endocrine function in animals. and alter cognitive function. Because hormone mediated events playa important role in central nervous system development and functions. The speculations that the changes in cognitive function are mediated by the endocrine-like action of these chemicals. (omitted)

• BMB Reports
• /
• 제53권5호
• /
• pp.284-289
• /
• 2020

Tamoxifen, a nonsteroidal estrogen receptor (ER) antagonist, is used routinely as a chemotherapeutic agent for ER-positive breast cancer. However, it is also causes side effects, including retinotoxicity. The retinal pigment epithelium (RPE) has been recognized as the primary target of tamoxifen-induced retinotoxicity. The RPE plays an essential physiological role in the normal functioning of the retina. Nonetheless, potential therapeutic agents to prevent tamoxifen-induced retinotoxicity in breast cancer patients have not been investigated. Here, we evaluated the action mechanisms of sulfasalazine against tamoxifen-induced RPE cell death. Tamoxifen induced reactive oxygen species (ROS)-mediated autophagic cell death and caspase-1-mediated pyroptosis in RPE cells. However, sulfasalazine reduced tamoxifen-induced total ROS and ROS-mediated autophagic RPE cell death. Also, mRNA levels of tamoxifen-induced pyroptosis-related genes, IL-1β, NLRP3, and procaspase-1, also decreased in the presence of sulfasalazine in RPE cells. Additionally, the mRNA levels of tamoxifen-induced AMD-related genes, such as complement factor I (CFI), complement factor H (CFH), apolipoprotein E (APOE), apolipoprotein J (APOJ), toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4), were downregulated in RPE cells. Together, these data provide novel insight into the therapeutic effects of sulfasalazine against tamoxifen-induced RPE cell death.

• Journal of Periodontal and Implant Science
• /
• 제30권2호
• /
• pp.375-390
• /
• 2000

The purpose of this study is to evaluate the expression ofIGF-I, considered as the mediator of action of estrogen, and IGF-IA and IGF-IB, alternative slicing form of IGF-I, using $17{\beta}-estradiol$ in MC3T3-E1 cells. We observed the effect on type I collagen and osteopontin gene expression and DNA synthetic activity of MC3T3-E1 cells, added by estrogen, IGF-I and combination and the interactionon proliferation and differentiation of MC3T3-E1 cells. The results were as follows :RT-PCR experiment for observing timedependantIGF-I gene expression patternshowed IGF-IA and IB gene expression in both of control and test group. In these IGF-IA gene expression was appeared predominantly. In control, IGF-I geneexpression level was maintained until 24hr and then decreased gradually. In testgroup, IGF-I gene expression level increased as time goes by. Experiment measuring DNA synthetic activity, as it is added by $17{\beta}-estradiol$, IGF-I and combination, showed that first day , there was the tendency of more increase of synthetic activity in all test group than control but no statical significance(P>0.05), and third day, there was more increase of DNA synthetic activity in $17{\beta}-estradiol$ group and combination group and it was statically significant. (P<0.005) Experiment for observing type I collagen gene expression pattern showed more increase of expression in $17{\beta}-estradiol$ group than control and no significant difference in IGF-I group and combination group. Experiment for observing osteopontin gene expression pattern showed no significant difference in control and test group. In conclusion, $17{\beta}-estradiol$ in MC3T3- E1 cells increased IGF-I gene and DNA synthetic activity simultaneously, therefore it appeared that IGF-I is related to the action of estrogen. Combination treatment of IGF-I and $17{\beta}-estradiol$ has effect on cell proliferation but this effect is lower than IGF-I or $17{\beta}-estradiol$ alone. However, combination treatment has not great effect on type I collagen or osteopontin gene expression thus little effect of cell differentiation.

• 생명과학회지
• /
• 제19권5호
• /
• pp.593-597
• /
• 2009

자궁은 임신에 필수불가결한 기관으로, 에스트로겐(E2)과 프로게스테론(P4)은 태아와 자궁 사이의 상호 신호전달을 적절하게 조절하여, 임신을 확립하게 하는 필수적 요소이다. 임신 초기 E2는 배아의 안정적인 착상을 위하여 자궁의 성장을 촉진하는 역할을 담당한다. 이 시기 자궁에서 분비되는 인슐린유사 성장인자-I(IGF-I)와 E2/P4 간의 상호 신호전달이 임신 확립에 있어서 매우 중요한 역할을 한다. E2는 에스트로겐 수용체(ER)에 의해 그 작용이 결정되어지는데, 임신 돼지 자궁에서는 ER-${\alpha}$만이 발현됨을 증명하였다. 자궁에서 ER-${\alpha}$의 발현은 임신 중기나 말기보다 임신 초기 단계에서 높게 발현됨이 관찰되었다. 이는 배아에서 분비되는 E2가 ER-${\alpha}$의 발현을 증가시키는 역할을 함을 보여주는 결과이다. IGF-I이 E2 표적 유전자임을 증명하기 위하여 난소를 제거한 쥐에 E2/P4를 처리한 후 IGF-I의 발현을 측정한 결과, E2를 처리한 샘플에서는 IGF-I의 발현이 크게 증가하였으나, P4를 처리한 샘플에서는 큰 영향을 받지 않는 것으로 나타났다. 이 결과는 E2가 자궁에서 IGF-I의 발현을 증가시키는 역할을 수행함을 직접적으로 증명하였다. 임신한 돼지의 자궁에서 임신 시기별로 IGF-I 유전자의 발현을 조사한 결과 임신 초기에 가장 높은 발현을 보였고, 이 양상은 ER-${\alpha}$의 발현 형태와 아주 유사한 패턴을 나타내었다. 이는 임신 자궁에서 ER-${\alpha}$와 IGF-I의 발현이 상호 연관되어 있으며 ER-${\alpha}$와 IGF-I은 E2에 의해서 조절되어지는 유전자이며, 임신초기 배아에서 분비되는 E2가 자궁에서 ER-${\alpha}$의 발현을 증진시키고, 나아가서 이 ER-${\alpha}$가 자궁에서 IGF-I 유전자의 발현을 증가시키는 역할을 함을 보여주는 결과이다.

• Journal of Ginseng Research
• /
• 제24권1호
• /
• pp.8-17
• /
• 2000

스테로이드 호르몬의 일종인 에스트로젠은 생식기능에 영향을 미치는 것 외에 학습 및 기억과 관련된 기능에도 영향을 미치는 것으로 알려져 있다. 최근, 에스트로젠은 기억과 관련된 뇌세포 신 경망의 발달과 뇌 기능 장애를 방지할 수 있다는 부분에서 상당한 관심의 대상이되고 있다. 그러나 에스트로젠 대체 치료가 폐경기의 많은 여성들에게 도움을 주기도 하지만 여러 부작용을 유발하는 것으로도 알려져 있다 인삼 역시도 스테로이드 특성을 보이며 에스트로젠과 유사한 화학구조를 가지는 여러 성분을 가지고 있다. 본 실험의 목적은 첫째로 공간 기억력을 측정하기에 여러 장점을 가지고 있으면서 다른 어떠한 행동학적 실험보다 학습과 기억의 동물 모텔로 잘 알려진 방법인 Morris water maze를 이용하여 에스트로젠의 효과를 확인하고, 두 번째는 인삼이 학습과 기억에서 에스트로젠과 같은 효과를 나타낼 수 있는지를 확인하는 것이다. 본 실험은 인위적으로 난소를 제거한 쥐에 17$\beta$-estradiol(100~250 $\mu\textrm{g}$/ml), panaxadiol(PD), panaxatriol(PT) sapo-nins(15~100 $\mu\textrm{g}$/ml)을 sesame oil에 녹인 capsule을 implant했다. 첫 번째 실험에서 난소를 제거한 쥐에 에스트로젠을 투입했을때 학습과 기억의 효과를 확인했다. 두 번째 실험에서는 난소를 제거한 쥐에 3가지 다른 농도에서의 PD, PT를 투입했을 때 학습과 기억에 대한 에스트로젠의 효과와 비교해 보았다. 2주 동안의implant 후 water maze 실험결과 세 그룹 모두 난소를 제거한 그룹보다 기억력이 향상되었다 이러한 결과를 토대로 에스트로젠이 학습과 기억에 영향을 준다는 것을 확인할 수 있었고 PD, PT 또한 학습과 기억에 관련된 행동에서 에스트로젠과 같은 효과를 나타낼 수 있다는 것을 확인할 수 있었다. 이러한 동물모델에서의 연구를 통하여 인삼이 에스트로젠 장기결핍치료에서 나타나는 여러 호르몬 부작용을 극복할 수 있는 에스트로젠 대체물질로 개발되어 기억력 저하를 수반하는 Alzheimer's disease 및 여러 퇴행성 중추신경 질환의 치료제로 대체의학의 natural compound이용에 그 기초 기전을 제공할 수 있으리라 여긴다.