环境雌激素研究进展

环境雌激素对人类及动物内分泌系统的影响越来越受到全世界的关注。能通过与雌激素受体结合或影响细胞信号途径等其他方式模仿或部分模仿雌激素,发挥类似雌激素效应,干扰人和动物内分泌的外因性化学物质称为环境雌激素。介绍环境雌激素的来源及特点、环境雌激素对人体健康和环境的影响。重点讨论了环境雌激素对雄性生殖影响的可能机制。     

Estrogen Receptors Mediated Negative Effects of Estrogens and Xenoestrogens in Teleost Fishes—Review

Estrogen receptors (ERs) play a key role in many biochemical and physiological processes, that are involved in maintaining organism homeostasis. At the most basic level, they can be divided into nuclear estrogen receptors and membrane estrogen receptors that imply their effect in two ways: slower genomic, and faster non-genomic. In these ways, estrogens and xenoestrogens can negatively affect animal health and welfare. Most of the available literature focuses on human and mammalian physiology, and clearly, we can observe a need for further research focusing on complex mutual interactions between different estrogens and xenoestrogens in aquatic animals, primarily fishes. Understanding the mechanisms of action of estrogenic compounds on the ERs in fishes and their negative consequences, may improve efforts in environmental protection of these animals and their environment and benefit society in return. In this review, we have summarized the ER-mediated effects of xenoestrogens and estrogens on teleost fishes metabolism, their carcinogenic potential, immune, circulatory, and reproductive systems.     

Biodegradation of natural and synthetic estrogens in moving bed bioreactor

Estrogen hormones as a group of endocrine disruptive compounds(EDC) can interfere with endocrine system in humans and animals. The goal of this study was to investigate the elimination rate of Estrone(El), 17β-estradiol(E2) and 17α-ethinyl estradiol(EE2) in Moving Bed Bioreactor(MBBR). These analytes extracted by Dispersive Liquid-Liquid Microextraction(DLLME) technique, followed by derivatization, and detected by GC/MS. Estrogen removal efficiency in MBBR improved at high solid retention times(SRTs), which notion is owing to development of nitrification. Estrogen specific removal rate was between 0.22-1.45 μg·(g VSS)~(-1)·d~(-1) for natural and synthetic hormones. The adsorption rate was 0.9%-3.2%, 0-1.3%, and 0.7%-5.7% for El, E2, and EE2, respectively. In addition, the biodegradation rates were more than 95% for these compounds. These results illustrated that in MBBR,the biodegradation and the adsorption to biomass are considered as two significant routes for elimination of estrogenic compounds. As a whole, the deterioration rate of estrogens enhanced by MBBR compared to other biological wastewater treatment processes such as conventional activated sludge.     

Mechanisms of estrogens' dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia

Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings.     

Physiological and behavioral effects of coniferyl benzoate on avian reproduction

Various plant secondary metabolites related to cinnamic acid are of interest because of their repellency to birds and their occurrence in ecologically important food items. Coniferyl benzoate (CB), a phenylpropanoid ester that occurs in quaking aspen (Populus tremuloides) is of particular ecological interest because of its effect on ruffed grouse (Bonasa umbellus) feeding behavior and its possible influence on the population dynamics of this bird. During detoxification processes, CB and other analogous compounds are metabolized into by-products, such as ferulic acid (FA), that can cause anti-reproductive effects. We tested whether consumption of CB produces antire-productive effects similar to FA using male and female Japanese quail (Coturnix coturnix) as avian models for ruffed grouse. The parameters we investigated included: the production, morphology, and development of eggs; reproductive characteristics influenced by estrogen; serum prolactin levels; and male reproductive behavior. Dietary CB did not produce antireproductive effects similar to FA at intake levels that Japanese quail and ruffed grouse would freely consume. Consumption of CB by Japanese quail significantly reduced egg production and body mass but did not affect male reproductive performance. Coniferyl benzoate's effect on egg production may be explained by lower energy acquisition and retention rather than endocrine changes per se. Contrary to previous reports, it is unlikely that FA, or similar compounds act directly as estrogen mimics or antagonists. Although, CB did reduce egg production in quail, it is unlikely that it would affect egg production in wild ruffed grouse. Detoxification costs and the effects of CB on nutrient utilization may explain why ruffed grouse avoid high dietary levels of CB.     

Adsorption of Endocrine Disruptors and Related Compounds Using Natural Polymer Composite Fibers Formed by Polyion Complexes

Endocrine disruptors are known as chemical compounds that affect living systems. The three investigated polyion complex (PIC) fibers are formed by the interaction of two kinds of oppositely charged polyelectrolytes in aqueous solution and examined for their adsorptive ability as endocrine disruptor adsorbents. Among nine compounds, seven endocrine disruptors and related compounds are adsorbed onto the PIC fibers. Particularly, benzo[a]pyrene is adsorbed in high amounts. The relationships between the structures of endocrine disruptors and the adsorption‐release behavior are investigated. Biphenyl exhibits mostly a repetitive adsorption‐release behavior.     

Pollutants with androgen-disrupting potency

In the 1980s observations of impaired fertility of animals living in aquatic ecosystems of highly industrialized regions were reported for the first time. In vivo and in vitro studies revealed that a chemical that impairs normal embryonic development and disrupts normal reproductive functions in adulthood is an “endocrine disruptor” (ED). First systematic data revealed that some EDs act through mimicking or antagonizing the physiological functions of estrogens. Later endocrine disrupting pathways were described which affect the signal cascade of the androgen receptor. We have learnt in the mean time that it is not always possible to attach each ED to a specific mode of action (estrogenic, anti-estrogenic, androgenic, antiandrogenic, or others). Today the ED discussion has reached man, whose genital tract possibly is affected by EDs (e.g. declining sperm counts, hypospadias, cryptorchism, testicular, and prostate cancer). The list of androgen-disrupting chemicals identified to date comprises chlorinated hydrocarbon insecticides like DDT, DDE, dieldrin, methoxychlor and lindan, fungicides currently used like vinclozolin and benomyl, and widely used herbicides like linuron, diuron and atrazin. Many EDs are industrial chemicals or pesticides of aromatic structure, but it is still not possible to predict their binding to the androgen receptor based on their chemical structure. The substances have low solubility in water and avidly bind to soils and sediments. If no degradation is possible, accumulation and long persistence in the environment is observed. Due to their lipophilic character persistent chemicals are accumulated in the adipose tissue of vertebrates. The risk evaluation of putative EDs has to regard the endocrine-disrupting activity as well as the fate in the environment (e.g. accumulation, chemical and microbial stability).     

GPER1 and microRNA: Two Players in Breast Cancer Progression

Breast cancer is the main cause of morbidity and mortality in women worldwide. However, the molecular pathogenesis of breast cancer remains poorly defined due to its heterogeneity. Several studies have reported that G Protein-Coupled Estrogen Receptor 1 (GPER1) plays a crucial role in breast cancer progression, by binding to estrogens or synthetic agonists, like G-1, thus modulating genes involved in diverse biological events, such as cell proliferation, migration, apoptosis, and metastasis. In addition, it has been established that the dysregulation of short sequences of non-coding RNA, named microRNAs (miRNAs), is involved in various pathophysiological conditions, including breast cancer. Recent evidence has indicated that estrogens may regulate miRNA expression and therefore modulate the levels of their target genes, not only through the classical estrogen receptors (ERs), but also activating GPER1 signalling, hence suggesting an alternative molecular pathway involved in breast tumor progression. Here, the current knowledge about GPER1 and miRNA action in breast cancer is recapitulated, reporting recent evidence on the liaison of these two players in triggering breast tumorogenic effects. Elucidating the role of GPER1 and miRNAs in breast cancer might provide new tools for innovative approaches in anti-cancer therapy.     

水中痕量污染物雌激素的内分泌干扰活性评价

雌激素近年来已成为水中的常见痕量污染物之一,该文对水中常见的雌激素种类、主要来源、物化性质、内分泌活性评价等进行了较为详尽的论述,对雌激素污染可能带来的问题进行了介绍。研究表明,重视水中雌激素污染问题,并寻求合理的解决办法,是当前给排水处理工作者的主要任务之一。     

The Influence of Interaction between Cadmium with 17β-Estradiol, 2-Methoxyestradiol and 16α-Hydroxyestrone on Viability and p-Glycoprotein in Ovarian Cancer Cell Line

Occupational and environmental exposure to xenoestrogens, a subgroup of endocrine disruptors (EDCs), can affect the endocrine system and increase the risk of cancer, primarily the hormone-dependent kind. This type of cancer includes ovarian cancer, which is the leading cause of death from gynecological tumors. The aim of this study was to assess the role of 17β-estradiol and its metabolites: 2-MeOE2, 16α-OHE1 in exposure to the metalloestrogen cadmium. The effect of interactions of cadmium with estrogens on the viability of cells in malignant ovarian cancer cells SKOV-3 was investigated, both in simultaneous action and in the pre-incubation model. There are no known interactions between estrogens and cadmium in ovarian cancer cells. Due to the frequent occurrence of multidrug resistance (MDR) in ovarian cancer, the effects of estrogens and cadmium on MDR in SKOV-3, measured as P-glycoprotein (P-gp), were assessed. An interaction study showed that E2 had an antagonistic effect on cadmium-induced cell damage, while 2-MeOE2 showed less of a protective effect in combination with CdCl₂ than E2. There were two types of interaction: toxic synergism and beneficial antagonism. E2 and cadmium increased P-gp expression in SKOV-3 cells, while 2-MeOE2 decreased P-gp expression to a potentially beneficial effect on MDR prevention. The obtained results constitute an interesting starting point for further research in the field of interactions between estrogens and xenoestrogens in ovarian cancer.     

Catalytic efficiency of natural and synthetic compounds used as laccase-mediators in oxidising veratryl alcohol and a kraft lignin, estimated by electrochemical analysis

The electrochemical properties of eighteen natural and synthetic compounds commonly used to expand the oxidative capacity of laccases were evaluated in an aqueous buffered medium using cyclic voltammetry. This clarifies which compounds fulfil the requisites to be considered as redox mediators or enhancers. Cyclic voltammetry was also applied as a rapid way to assess the catalytic efficiency (CE) of those compounds which oxidise a non-phenolic lignin model (veratryl alcohol, VA) and a kraft lignin (KL). With the exception of gallic acid and catechol, all assayed compounds were capable of oxidising VA with varying CE. However, only some of them were able to oxidise KL. Although the oxidised forms of HBT and acetovanillone were not electrochemically stable, their reduced forms were quickly regenerated in the presence of VA. They thus act as chemical catalysts. Importantly, HBT and HPI did not attack the KL via the same mechanism as in VA oxidation. Electrochemical evidence suggests that violuric acid oxidises both substrates by an electron transfer mechanism, unlike the other N-OH compounds HBT and HPI. Acetovanillone was found to be efficient in oxidising VA and KL, even better than the synthetic mediators TEMPO, violuric acid or ABTS. Most of the compounds produced a generalised increase in the oxidative charge of KL, probably attributed to chain reactions arising between the phenolic and non-phenolic components of this complex molecule.     

Electrochemical behavior of blood coagulation proteins—factors V and VIII

The electrochemical reactions of two blood coagulation proteins, factors V and VIII (AC globulin and antihemophila factor) at platinum -NaCl interface were investigated using cyclic voltammetric techniques. Voltammograms were recorded for three concentrations of each of the proteins (0·1, 1·0 and 10 times the physiologic concentration) at different scan rates. The results of this preliminary study suggest that these compounds take part in more than one electron transfer reaction at the interface. Some of these may be coupled with chemical reactions. With both the proteins, particularly at lower concentrations, their adsorption has a significant influence on the peak current functions. Prediction as to the detailed type or nature of these reactions is not feasible at the present time due to the complexity of the molecules and to the lack of structural information of the proteins.     

New Biodegradable Nonionic-Anionic Surfactants Based on Different Fatty Alcohols as Corrosion Inhibitors for Aluminum in Acidic Medium

Two series of eco-friendly nonionic anionic surfactants based on itaconic acid and 1, 6 hexane diol were synthesized. The chemical structures of the prepared surfactant were confirmed by FTIR and ¹H NMR spectroscopy. The prepared surfactants were evaluated to prevent the corrosion of aluminum in 1.0 M HCl solution by electrochemical and chemical methods. The data obtained showed that the prepared compounds have good inhibition efficiency (IE%) even at 10⁻⁵ M concentrations and act as mixed-type inhibitors, they do not affect the mechanism of the electrode processes, as well as the IE% increase by increasing the concentrations of the inhibitors, immersion time, and hydrophilic chain length. The high inhibition efficiency is due to the adsorption of the inhibitors molecules on the metal surface and the formation of a protective film. The surface activities of these compounds were also investigated and were correlated to their inhibition efficiencies and chemical structure. Through studying biodegradability of the synthesized surfactants we find that they are readily biodegradable in the environment and thus they are considered as eco-friendly corrosion inhibitors. Finally, the effect of the addition of these compounds on the aluminum surface was identified by atomic force microscopy (AFM) technique.     

Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens

Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women’s Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.     

生物合成槲皮素糖苷类衍生物的研究进展

糖苷类天然产物是植物中次级代谢产物的主要存在形式,具有重要的生物活性。通过糖基化修饰可以改变其水溶性、稳定性,产生特殊的生物活性和功能,因此易于商品化应用,具有重要的药用价值和工业价值,尤其在抗癌药物和日化用品中有着广泛应用。近年来糖苷类产物的生物合成也取得了重大的进展。以重要的糖苷化合物槲皮素为例介绍了糖苷化合物的生物合成,从糖基转移酶和前体供应等角度阐述了生物高产糖苷类化合物的工程策略,为利用合成生物学技术获得植物糖苷的高产菌株提供了技术参考。     

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.     

Antifungal Peptides and Proteins to Control Toxigenic Fungi and Mycotoxin Biosynthesis

The global challenge to prevent fungal spoilage and mycotoxin contamination on food and feed requires the development of new antifungal strategies. Antimicrobial peptides and proteins (AMPs) with antifungal activity are gaining much interest as natural antifungal compounds due to their properties such as structure diversity and function, antifungal spectrum, mechanism of action, high stability and the availability of biotechnological production methods. Given their multistep mode of action, the development of fungal resistance to AMPs is presumed to be slow or delayed compared to conventional fungicides. Interestingly, AMPs also accomplish important biological functions other than antifungal activity, including anti-mycotoxin biosynthesis activity, which opens novel aspects for their future use in agriculture and food industry to fight mycotoxin contamination. AMPs can reach intracellular targets and exert their activity by mechanisms other than membrane permeabilization. The mechanisms through which AMPs affect mycotoxin production are varied and complex, ranging from oxidative stress to specific inhibition of enzymatic components of mycotoxin biosynthetic pathways. This review presents natural and synthetic antifungal AMPs from different origins which are effective against mycotoxin-producing fungi, and aims at summarizing current knowledge concerning their additional effects on mycotoxin biosynthesis. Antifungal AMPs properties and mechanisms of action are also discussed.     

Chemical Ecology of Marine Angiosperms: Opportunities at the Interface of Marine and Terrestrial Systems

This review examines the state of the field for chemically mediated interactions involving marine angiosperms (seagrasses, mangroves, and salt marsh angiosperms). Small-scale interactions among these plants and their herbivores, pathogens, fouling organisms, and competitors are explored, as are community-level effects of plant secondary metabolites. At larger spatial scales, secondary metabolites from marine angiosperms function as reliable cues for larval settlement, molting, or habitat selection by fish and invertebrates, and can influence community structure and ecosystem function. Several recent studies illustrate the importance of chemical defenses from these plants that deter feeding by herbivores and infection by pathogens, but the extent to which allelopathic compounds kill or inhibit the growth of competitors is less clear. While some phenolic compounds such as ferulic acid and caffeic acid act as critical defenses against herbivores and pathogens, we find that a high total concentration of phenolic compounds within bulk plant tissues is not a strong predictor of defense. Residual chemical defenses prevent shredding or degradation of plant detritus by detritivores and microbes, delaying the time before plant matter can enter the microbial loop. Mangroves, marsh plants, and seagrasses remain plentiful sources of new natural products, but ecological functions are known for only a small proportion of these compounds. As new analytical techniques are incorporated into ecological studies, opportunities are emerging for chemical ecologists to test how subtle environmental cues affect the production and release of marine angiosperm chemical defenses or signaling molecules. Throughout this review, we point to areas for future study, highlighting opportunities for new directions in chemical ecology that will advance our understanding of ecological interactions in these valuable ecosystems.     

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.