Estrogen Receptor Binding Activity Research Articles

Degradation of contaminants of PPCPs by photocatalysis for water purification: Kinetics, mechanisms, and cytotoxicity analysis

Pharmaceuticals and personal care products (PPCPs) have drawn increasing regulatory attention and research interest in recent years. Since it does not require any additional dissolved oxidants, heterogeneous photocatalytic technology has attracted much interest in the efficient degradation of PPCPs in recent years. The present study examined the degradation kinetics of PPCPs using Fe-ZnS@TiO2/nickel foam photocatalytic system (ZTN PS) in Milli-Q water and a solid surface water background, including estrone, diclofenac, cyclophosphamide, triclosan, and sulfamethoxazole. To evaluate ZTN PS, MF-treated water samples from the Songhua River (SR) were obtained and used as reaction matrices with spiked additions of PPCPs. The influence of single ion addition on degradation kinetics was investigated to determine the degradation rule under various water parameter conditions. Using high-resolution mass spectrometry to identify transformation products (TPs), potential degradation pathways of a few PPCPs were hypothesised. During photocatalysis, the oxidation properties of different oxidants (photogenic holes, OH, O2−) on different structural sites of PPCPs were analysed. To examine possible environmental impacts of PPCP degradation by ZTN PS, cytotoxicity and estrogen (ER) receptor-binding activity were evaluated. It was found that ZTN PS substantially reduced cytotoxicity and estrogenic activity while degrading PPCPs in Milli-Q water. Also, the presence of complex substances in water did not significantly affect the toxicity of mixed PPCP degradation TPs. However, comparing natural water to Milli-Q water, the toxicity and ER-binding activity of TPs under natural water background increased marginally (9%–13％). Thus, this study aimed to understand the effects of post-ZTN PS PPCPs and TPs on human and environmental health at the cellular level.

Predictive modeling of estrogen receptor agonism, antagonism, and binding activities using machine- and deep-learning approaches

As defined by the World Health Organization, an endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, its progeny, or (sub)populations. Traditional experimental testing regimens to identify toxicants that induce endocrine disruption can be expensive and time-consuming. Computational modeling has emerged as a promising and cost-effective alternative method for screening and prioritizing potentially endocrine-active compounds. The efficient identification of suitable chemical descriptors and machine-learning algorithms, including deep learning, is a considerable challenge for computational toxicology studies. Here, we sought to apply classic machine-learning algorithms and deep-learning approaches to a panel of over 7500 compounds tested against 18 Toxicity Forecaster assays related to nuclear estrogen receptor (ERα and ERβ) activity. Three binary fingerprints (Extended Connectivity FingerPrints, Functional Connectivity FingerPrints, and Molecular ACCess System) were used as chemical descriptors in this study. Each descriptor was combined with four machine-learning and two deep- learning (normal and multitask neural networks) approaches to construct models for all 18 ER assays. The resulting model performance was evaluated using the area under the receiver- operating curve (AUC) values obtained from a fivefold cross-validation procedure. The results showed that individual models have AUC values that range from 0.56 to 0.86. External validation was conducted using two additional sets of compounds (n = 592 and n = 966) with established interactions with nuclear ER demonstrated through experimentation. An agonist, antagonist, or binding score was determined for each compound by averaging its predicted probabilities in relevant assay models as an external validation, yielding AUC values ranging from 0.63 to 0.91. The results suggest that multitask neural networks offer advantages when modeling mechanistically related endpoints. Consensus predictions based on the average values of individual models remain the best modeling strategy for computational toxicity evaluations.

Degradation of contaminants of emerging concern by UV/H2O2 for water reuse: Kinetics, mechanisms, and cytotoxicity analysis

Advanced oxidation using UV and hydrogen peroxide (UV/H2O2) has been widely applied to degrade contaminants of emerging concern (CECs) in wastewater for water reuse. This study investigated the degradation kinetics of mixed CECs by UV/H2O2 under variable H2O2 doses, including bisphenol A, estrone, diclofenac, ibuprofen, and triclosan. Reverse osmosis (RO) treated water samples from Orange County Water District’s Groundwater Replenishment System (GWRS) potable reuse project were collected on different dates and utilized as reaction matrices with spiked additions of chemicals (CECs and H2O2) to assess the application of UV/H2O2. Possible degradation pathways of selected CECs were proposed based on high resolution mass spectrometry identification of transformation products (TPs). Toxicity assessments included cytotoxicity, aryl hydrocarbon receptor-binding activity, and estrogen receptor-binding activity, in order to evaluate potential environmental impacts resulting from CEC degradation by UV/H2O2. Cytotoxicity and estrogenic activity were significantly reduced during the degradation of mixed CECs in Milli-Q water by UV/H2O2 with high UV fluence (3200 mJ cm−2). However, in GWRS RO-treated water samples collected in April 2017, the cytotoxicity and estrogen activity of spiked CEC-mixture after UV/H2O2 treatment were not significantly eliminated; this might be due to the high concentration of target CEC and their TPs, which was possibly affected by the varied quality of the secondary treatment influent at this facility such as sewer-shed and wastewater discharges. This study aimed to provide insight on the impacts of post-UV/H2O2 CECs and TPs on human and ecological health at cellular level.

Estrogenic phytochemical from Labisia pumila (Myrsinaceae) with selectivity towards estrogen receptor alpha and beta subtypes

Labisia pumila var. alata (Myrsinaceae) or “Kacip fatimah” is a famous Malay traditional herb used for the maintenance of women's health. The extracts of L.pumila displayed estrogenic activity in rats. Nonetheless, the estrogenic bioactives were not identified. The aim of the study is to identify estrogenic compounds contributing to the established estrogenic activity. Bioactivity-guided-isolation method guided the isolation of pure bioactives. The hexane extract was subjected to a series of silica gel flash and open column chromatography with increasing amount of ethyl acetate in hexane or methanol in chloroform. Each fraction or pure compounds were evaluated on it's estrogen receptor (ER) binding activity with the fluorescence polarization competitive ERα and ERβ binding assay kit. Cytotoxic assay using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay method was used to establish the cytotoxic activity of the compounds. Four alkyl resorcinols and a dimeric 1,4-benzoquinone, namely belamcandol B (1), 5-pentadec-10′-(Z)-enyl resorcinol (2), 1,3-dihydroxy-5-pentadecylbenzene (3), 5-(heptadec-12′-(Z)-enyl) resorcinol (4) and demethylbelamcandaquinone B (5) were identified with selective binding affinities towards either ERα or ERβ exhibiting selectivity ratio from 0.15–11.9. Alkyl resorcinols (2)–(4) exhibited cytotoxic activity towards HL60 cells with IC50 values from 19.5–22.0 μM. Structural differences between compounds influence the binding affinities to ER subtypes. Further study is needed to establish the agonist or antagonist effect of these compounds on various tissues and to identify if these compounds exert cytotoxic activity through the ERs. When consuming L.pumila as a complementary medicine, careful consideration regarding it's estrogenic compound content should be given due consideration.

Antimutagenic, antitumor and estrogen receptor binding activity of the rare plant Shortia galacifolia: An ethnobotanical and chemosystematic approach.

Shortia and other members of the Diapensiaceae family have ethnomedicinal history in both Eastern and Western hemispheres. Based on ethnopharmacological and chemosystematic evidence, pharmacological and toxicological bioassays were conducted on the rare plant Oconee Bell, Shortia galacifolia. Extracts were examined in assays for antimutagenicity, antitumor and estrogen receptor (ER)-binding activity. Antitumor activity was assessed by the tumor induction assay (TiA), using Agrobacterium tumefaciens based on its ability to transform plant tissue. Antimutagenicity was examined using the Ames bacterial reverse mutation test. Recombinant human ERα and ERβ proteins were utilized to screen extracts for receptor selectivity. All concentrations of extracts inhibited A. tumefaciens-induced tumor formation on potato discs, with the mature rhizome extracts having the most marked inhibition. All three plant extracts significantly inhibited the formation of histidine-independent revertant colonies after exposure to the mutagen 2-aminoanthracene (2-AA) in the Ames Salmonella mutagenicity assay. In the ER binding assays, ERβ, but not ERα, displayed affinity for Shortia extracts. Antitumor, ER binding and antimutagenic activities of S. galacifolia extracts were identified using rapid bench-top assays and warrant further investigations.

A systematic evaluation of analogs and automated read-across prediction of estrogenicity: A case study using hindered phenols

Read-across is an important data gap filling technique used within category and analog approaches for regulatory hazard identification and risk assessment. Although much technical guidance is available that describes how to develop category/analog approaches, practical principles to evaluate and substantiate analog validity (suitability) are still lacking. This case study uses hindered phenols as an example chemical class to determine: (1) the capability of three structure fingerprint/descriptor methods (PubChem, ToxPrints and MoSS MCSS) to identify analogs for read-across to predict Estrogen Receptor (ER) binding activity and, (2) the utility of data confidence measures, physicochemical properties, and chemical R-group properties as filters to improve ER binding predictions. The training dataset comprised 462 hindered phenols and 257 non-hindered phenols. For each chemical of interest (target), source analogs were identified from two datasets (hindered and non-hindered phenols) that had been characterized by a fingerprint/descriptor method and by two cut-offs: (1) minimum similarity distance (range: 0.1–0.9) and, (2) N closest analogs (range: 1–10). Analogs were then filtered using: (1) physicochemical properties of the phenol (termed global filtering) and, (2) physicochemical properties of the R-groups neighboring the active hydroxyl group (termed local filtering). A read-across prediction was made for each target chemical on the basis of a majority vote of the N closest analogs. The results demonstrate that: (1) concordance in ER activity increases with structural similarity, regardless of the structure fingerprint/descriptor method, (2) increased data confidence significantly improves read-across predictions, and (3) filtering analogs using global and local properties can help identify more suitable analogs. This case study illustrates that the quality of the underlying experimental data and use of endpoint relevant chemical descriptors to evaluate source analogs are critical to achieving robust read-across predictions.

Consensus Modeling for Prediction of Estrogenic Activity of Ingredients Commonly Used in Sunscreen Products.

Sunscreen products are predominantly regulated as over-the-counter (OTC) drugs by the US FDA. The “active” ingredients function as ultraviolet filters. Once a sunscreen product is generally recognized as safe and effective (GRASE) via an OTC drug review process, new formulations using these ingredients do not require FDA review and approval, however, the majority of ingredients have never been tested to uncover any potential endocrine activity and their ability to interact with the estrogen receptor (ER) is unknown, despite the fact that this is a very extensively studied target related to endocrine activity. Consequently, we have developed an in silico model to prioritize single ingredient estrogen receptor activity for use when actual animal data are inadequate, equivocal, or absent. It relies on consensus modeling to qualitatively and quantitatively predict ER binding activity. As proof of concept, the model was applied to ingredients commonly used in sunscreen products worldwide and a few reference chemicals. Of the 32 chemicals with unknown ER binding activity that were evaluated, seven were predicted to be active estrogenic compounds. Five of the seven were confirmed by the published data. Further experimental data is needed to confirm the other two predictions.

A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β

The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC50=62.2nM) while also exhibiting good binding activity to both ER-α (EC50=72.1nM) and ER-β (EC50=70.8nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.

Synthesis, antiproliferative and pro-apoptotic activity of 2-phenylindoles

Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50 values of 2.71μM and 1.86μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.

Biological activities of unique isoflavones prepared from Apios americana Medik.

Four unique isoflavone aglycones (barpisoflavone A (1), 2'-hydroxygenistein (2), 5-methylgenistein (3), and gerontoisoflavone A (4)) whose structures were related to genistein were prepared from the tuber of Apios americana Medik. We examined the estrogen receptor and androgen receptor binding activities, estrogen agonistic activities, antioxidant activities, and α-glucosidase inhibitory activities of 1-4. The results obtained showed that 2 possessed potent and 1, 3, and 4 possessed moderate estrogen partial agonistic activities, 1 and 2 possessed moderate antioxidant activities, and 2 and 3 possessed moderate α-glucosidase inhibitory activities.

Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities.

Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.

Can Soy Prevent Male Osteoporosis? A Review of the Current Evidence

The Asian population whose soy intake is higher compared to Western populations shows a significantly lower incidence of osteoporotic fracture. Several meta-analyses have revealed that supplementation of soy isoflavones improve bone health status in women. This review examined the current evidence as to whether soy could exhibit similar bone protective effects on the male population. In vivo studies revealed that supplementation of soy protein or soy isoflavones improved bone health in both normal and osteoporotic male rodents. Cell culture studies showed that soy isoflavones influenced osteogenesis and osteoclastogenesis through mechanisms such as estrogen receptor binding activity, antiinflammatory activity and anti-parathyroid hormone activity. Soy isoflavones also affected calcium channel signaling and might exhibit direct effects on the osteoblastogenesis modulator, core binding factor 1. However, limited clinical trials involving soy intervention in males generally showed insignificant results. This could be attributed to the short duration of intervention, characteristics of the subjects or method of bone health assessment. More well-planned clinical trials are required to establish possible bone protective effects of soy in men.

Synthesis of Naturally Occurring Norlignan (±)-Nyasol

The norlignans including nyasol 1, hinokiresinol 2, agatharesinol 3, sequirin C 4 and sugiresinol 5 have received widespread interest as pharmaceutically valuable compounds, mainly because of their various clinically important biological activities: e.g. antiplasmodial activity, antifungal activity, anticancer activity, antimalarial activity, anti-oomycete activity, and estrogen receptor binding activity. Nyasol is one of the naturally occurring norlignans, which constitute abundant classes of phenylpropanoids. Nyasol has been isolated from various species of plants (Asparagus africanus, Anemarrhena asphodeloides, Asparagus officinalis, and Asparagus cochinchinensis). Nyasol and hinokiresinol are geometrical isomers and the confusion concerning the nomenclature of the two compounds nyasol and hinokiresinol was settled by Oketch-Rabah et al., who agreed that the Z-isomer should be named nyasol and the Eisomer hinokiresinol. In particular, nyasol shows various biological activities. For example, nyasol stimulated the proliferation of estrogendependent T47D breast cancer cells, and their stimulatory effects were blocked by an estrogen antagonist. In addition, nyasol showed binding affinity for the bovine uterine estrogen receptor, but (+)-nyasol was found to bind approximately seven times more strongly than (−)-nyasol. It was reported that (−)-nyasol increases hexobarbital sleeping time in mice. Nyasol was also reported to possess antifungal activity and inhibit testosterone 5α-reductase. Furthermore, nyasol was found to exhibit antioxidant and antiatherogenic activities. These results have encouraged us to complete adaptable and scalable total synthesis of these classes of natural products for further pharmacological study. So far, hinokiresinol derivatives have been easily prepared from chalcones by using reduction and dehydration. However, few successful synthetic procedures for nyasol have been reported other than the recent report by the Hoveyda group, which limits a scalable synthesis of nyasol. Quan et al. also reported an approach to synthesis of di-O-methyl ethers of (+)-nyasol and related norlignans, however, they might fail deprotection of the methyl ethers to obtain the final nyasol since there

Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish

Organophosphate flame retardants (OPFRs) are frequently detected in environment and biota. However, knowledge on their potential toxicological effects is limited. Endocrine disrupting potentials of six OPFRs, i.e., tris-(2-chloroethyl) phosphate (TCEP), tris-(2-chloroisopropyl) phosphate (TCPP), tris-(1,3-dichloro-2-propyl) phosphate (TDCPP), tris-(2-butoxyethyl) phosphate (TBEP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP), were investigated using human cell lines as well as zebrafish (Danio rerio). Sex hormone synthesis and steroidogenic gene transcriptions were measured using H295R cells. With MVLN cells, estrogen receptor binding activities of OPFRs were evaluated. In zebrafish, sex hormones and related gene transcriptions were determined for each sex after 14d exposure to OPFRs. All six OPFRs increased both 17β-estradiol (E2) and testosterone (T) concentrations in H295R cells. In addition, transcription of four major steroidogenic genes was up-regulated and that of two sulfotransferase genes was down-regulated. In MVLN cells, no OPFRs acted as estrogen receptor agonists, while TDCPP, TPP, and TCP acted as antagonists inhibiting binding of E2 to estrogen receptor. After 14d of zebrafish exposure, TCP, TDCPP, or TPP significantly increased plasma T and E2 concentrations, but did not change 11-ketotestosterone (11-KT) among female fish. Among males, both T and 11-KT decreased and E2 increased. In general, transcription of CYP17 and CYP19a genes was significantly up-regulated in both sexes, while vitellogenin (VTG) 1 gene was down- and up-regulated in female and male fish, respectively. The results of this study showed that OPFRs could alter sex hormone balance through several mechanisms including alterations of steroidogenesis or estrogen metabolism.

Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole

A novel class of silver N-heterocyclic carbene complexes ( 5a–f) were synthesized in high yield by reacting silver(I) oxide with 4,5-diarylimidazolium halides ( 4a–f). The complexes were characterized using NMR and IR spectroscopy. The structure was confirmed on the example of bromo[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]silver(I) ( 5c) by crystal structure analysis. The X-ray structure indicated a three-dimensional coordination polymer with a repeating unit consisting of a C carben-Ag 2-Br 2-C carben cluster. Pharmacological investigations revealed that all silver complexes possessed growth inhibitory effects against breast cancer (MCF-7 and MDA-MB-231) as well as colon carcinoma (HT-29) cells. The most active compound 5c was slightly less active against MCF-7 cells, more active against MDA-MB-231 cells and comparable active as cisplatin against HT-29 cells. Further pharmacological investigations were performed with selected compounds on estrogen receptor (ER) binding, DNA intercalation, cyclooxygenase (COX) inhibition and antibacterial activity. The complexes were only marginally active at the DNA, ER and the COX enzymes, so these targets can be excluded to be involved in the mode of action. However, the growth of bacteria was significantly inhibited by 5c and 5f and opens a new application of this complex type.

Transducin-like enhancer protein 1 mediates estrogen receptor binding and transcriptional activity in breast cancer cells

Estrogen receptor (ER) binds to distal enhancers within the genome and requires additional factors, such as the Forkhead protein FoxA1, for mediating chromatin interactions. We now show that the human Groucho protein, Transducin-like enhancer protein 1 (TLE1), positively assists some ER-chromatin interactions, a role that is distinct from its general role as a transcriptional repressor. We show that specific silencing of TLE1 inhibits the ability of ER to bind to a subset of ER binding sites within the genome, a phenomenon that results in perturbations in phospho-RNA Pol II recruitment. Furthermore, TLE1 is essential for effective ER-mediated cell division. We have discovered a distinct role for TLE1, as a necessary transcriptional component of the ER complex, where it facilitates ER-chromatin interactions.

QSAR classification of estrogen receptor binders and pre-screening of potential pleiotropic EDCs

Endocrine disrupting chemicals (EDCs) are suspected of posing serious threats to human and wildlife health through a variety of mechanisms, these being mainly receptor-mediated modes of action. It is reported that some EDCs exhibit dual activities as estrogen receptor (ER) and androgen receptor (AR) binders. Indeed, such compounds can affect the normal endocrine system through a dual complex mechanism, so steps should be taken not only to identify them a priori from their chemical structure, but also to prioritize them for experimental tests in order to reduce and even forbid their usage. To date, very few EDCs with dual activities have been identified. The present research uses QSARs, to investigate what, so far, is the largest and most heterogeneous ER binder data set (combined METI and EDKB databases). New predictive classification models were derived using different modelling methods and a consensus approach, and these were used to virtually screen a large AR binder data set after strict validation. As a result, 46 AR antagonists were predicted from their chemical structure to also have potential ER binding activities, i.e. pleiotropic EDCs. In addition, 48 not yet recognized ER binders were in silico identified, which increases the number of potential EDCs that are substances of very high concern (SVHC) in REACH. Thus, the proposed screening models, based only on structure information, have the main aim to prioritize experimental tests for the highlighted compounds with potential estrogenic activities and also to design safer alternatives.

Semantic Similarity for Automatic Classification of Chemical Compounds

With the increasing amount of data made available in the chemical field, there is a strong need for systems capable of comparing and classifying chemical compounds in an efficient and effective way. The best approaches existing today are based on the structure-activity relationship premise, which states that biological activity of a molecule is strongly related to its structural or physicochemical properties. This work presents a novel approach to the automatic classification of chemical compounds by integrating semantic similarity with existing structural comparison methods. Our approach was assessed based on the Matthews Correlation Coefficient for the prediction, and achieved values of 0.810 when used as a prediction of blood-brain barrier permeability, 0.694 for P-glycoprotein substrate, and 0.673 for estrogen receptor binding activity. These results expose a significant improvement over the currently existing methods, whose best performances were 0.628, 0.591, and 0.647 respectively. It was demonstrated that the integration of semantic similarity is a feasible and effective way to improve existing chemical compound classification systems. Among other possible uses, this tool helps the study of the evolution of metabolic pathways, the study of the correlation of metabolic networks with properties of those networks, or the improvement of ontologies that represent chemical information.

A Versatile Microbial System for Biosynthesis of Novel Polyphenols with Altered Estrogen Receptor Binding Activity

Isoflavonoids possess enormous potential for human health with potential impact on heart disease and cancer, and some display striking affinities for steroid receptors. Synthesized primarily by legumes, isoflavonoids are present in low and variable abundance within complex mixtures, complicating efforts to assess their clinical potential. To satisfy the need for controlled, efficient, and flexible biosynthesis of isoflavonoids, a three-enzyme system has been constructed in yeast that can convert natural and synthetic flavanones into their corresponding isoflavones in practical quantities. Based on the determination of the substrate requirements of isoflavone synthase, a series of natural and nonnatural isoflavones were prepared and their binding affinities for the human estrogen receptors (ER alpha and ER beta) were determined. Structure activity relationships are suggested based on changes to binding affinities related to small variations on the isoflavone structure.

Effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on reproductive system of mouse pups

The aim of this study was to analyze the effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on the reproductive system of mouse pups. The two synthetic isomers used in this study showed higher (3E22NP) or lower (44NP) estrogen receptor (ER) binding activity on in vitro yeast assay than a commercial NP (NPmix). Female mice were implanted with a tube filled with one of three NPs and estradiol-17 β (E2) before mating. The tube was kept in the mice throughout pregnancy and lactation period, until their pups had weaned at 28 days of age (PND 28). The data indicated that in males, NPs decreased body weight in some dose groups on PND28 and increased weights of testes and epididymides. However, the rate of seminiferous tubules having elongate spermatids (steps 10-16) decreased significantly in NPs and E2 treated groups, except for the 44NP groups. In female mice, NPs and E2 increased weights of ovaries, uterus and vagina in the pups in some dose groups on PND 28. However, there were no differences in the day of vaginal opening and numbers of corpus lutea. The present study demonstrates that the effects of these two isomers of NP on the pup reproduction at PND 28 are not quite different, despite them showing different levels of ER binding activity using in vitro yeast assay.