Synthetic, structural, and computational approaches were used to solve the puzzle as to how a phenolic nonsteroidal estrogen 1 with only a single H‐bond to its receptor was more potent than an isomer ...2 which formed an intricate network of H‐bonds. Synthesis of a series of substituted phenols revealed that pKa was not a determinant of estrogenic activity. First‐principles calculation also failed to explain the difference in activity of 1 and 2. Molecular dynamics revealed that 1 formed a more stable receptor complex compared to 2, which may explain its increased activity despite forming fewer apparent H‐bonds with the protein. Dedicated to an inspirational teacher and mentor Scott E. Denmark on the occasion of his 70th birthday and award of the Paracelsus prize
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•RNA-seq revealed genome-wide alteration of gene expression by karanjin in MCF-7 cells.•Karanjin-modulated gene-repertoire is enriched in G2/M checkpoint, and estrogen-response-early ...genes.•Karanjin exhibits partial estrogen-like effects.
Karanjin, an abundantly occurring furanoflavonoid in edible and non-edible legumes, exerts diverse biological effects in vivo, and in vitro. Its potential as an anticancer agent is gaining traction following recent demonstrations of its anti-proliferative, cell cycle inhibitory, and pro-apoptotic effects. However, the genomic correlates of these activities are not known. In the present study we delineated the transcriptomic footprint of 10 μM karanjin in MCF-7 breast cancer cells, using next generation sequencing technology (RNA-seq). We show that karanjin-modulated gene-expression repertoire is enriched in several hallmark gene sets, which include early estrogen-response, and G2/M checkpoint genes. Genes modulated by karanjin overlapped with those modulated by 1 nM 17β-estradiol (E2), or 1 μM tamoxifen. The results suggest partial estrogen-like activity of karanjin, thereby presenting a caveat to its anticancer potential. Further investigations into its mechanisms of action are warranted to ascertain the true potential of karanjin in anticancer, or endocrine therapy.
Synthetic pyrethroids are used worldwide as insecticides. Their metabolites are regularly detected in the urine of adults and children from the general population. There is increasing concern that ...they may induce sex-hormone disrupting effects. The present work reviews available published information on the (anti)estrogenic and (anti)androgenic activity of pyrethroids in in vitro screening tests.
In recent years, a large number of pyrethroids have been evaluated using various common testing methods. In tests using recombinant yeast or mammalian cells, the pyrethroids were found to be essentially negative or weakly estrogenic. More inconsistent results were found regarding their estrogenic action in proliferation tests. Conflicting findings were also reported across studies and/or assays which evaluated their anti-estrogenic or anti-androgenic potential. Some studies have suggested that certain pyrethroids may have potential antagonist activity. However, no strong interaction with the estrogenic or androgenic pathway was reported. The present review confirms the interest in performing a screening battery and in adopting an integrative approach for identifying the potential of different compounds from a chemical family to interfere with the endocrine system.
•Pyrethroids are one of the most commonly used classes of insecticides.•This is a review of the (anti)estrogenic and (anti)androgenic activity of pyrethroids in in vitro screening tests.•They were essentially negative or weakly estrogenic in tests using recombinant yeast or mammalian cells.•Conflicting findings were reported across studies and/or assays evaluating their antiestrogenic or anti-androgenic potential.
4-Methylbenzylidene camphor (4-MBC), an emerging contaminant, is a widely-used ultraviolet (UV) filter incorporated into cosmetics because it protects the skin from UV rays and counters ...photo-oxidation. Despite the well-established estrogenic activity of 4-MBC, the link between this activity and its effects on neurobehavior and the liver remains unknown. Thus, we exposed zebrafish larvae to environmentally relevant concentrations of 4-MBC with 1.39, 4.17, 12.5 and 15.4 μg/mL from 3 to 5 days postfertilization. We found that 4-MBC produced an estrogenic effect by intensifying fluorescence in the transgenic zebrafish, which was counteracted by co-exposure with estrogen receptor antagonist. 4-MBC-upregulated estrogen receptor alpha (erα) mRNA, and an interaction between 4-MBC and ERα suggested ERα′s involvement in the 4-MBC-induced estrogenic activity. RNA sequencing unearthed 4-MBC-triggered responses in estrogen stimulus and lipid metabolism. Additionally, 4-MBC-induced hypoactivity and behavioral phenotypes were dependent on the estrogen receptor (ER) pathway. This may have been associated with the disruption of acetylcholinesterase and acetylcholine activities. As a result, 4-MBC increased vitellogenin expression and caused lipid accumulation in the liver of zebrafish larvae. Collectively, this is the first study to report 4-MBC-caused estrogenic effects through the brain-liver-gonad axis. It provides novel insight into how 4-MBC perturbs the brain and liver development.
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•4-MBC dose-dependently produces an estrogenic effect via ERα signaling pathway.•4-MBC induces developmental deformities and stimulates lipid accumulation in liver.•4-MBC alters neurotransmitter metabolism and causes hypoactivity via ER pathway.•4-MBC causes estrogenic effects through the brain-liver-gonad axis.
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•Distinct phenolic profiles were identified in leaves from six Syzygium species.•More than 400 phenolics were putatively annotated.•Flavonoids, phenolic acids, tyrosols, stilbenes and ...lignans were the most represented.•In vitro biological assays revealed a possible estrogenic activity.•Lignans, stilbenes and isoflavones correlated with estrogenic activity.
Untargeted metabolomics was used in this study to discriminate the phenolic fingerprints of six Syzygium species. This approach resulted in the annotation of 441 compounds that belong to different phenolic classes, such as flavonoids, lignans, stilbenes, tyrosols, alkylphenols, and phenolic acids. Multivariate data analysis unraveled the main differences between the studied species. S. paniculatum and S. aqueum were the richest sources in terms of phenolic compounds, cumulatively amounting to 355.3 and 266.4 mg/g dry matter, respectively. Nevertheless, S. jambos showed reduced amounts of phenolics, when compared with other species. The biological activity of Syzygium leaf extracts was assessed on MCF-7 breast adenocarcinoma and MDA-MB-231 breast cancer cell lines. Potent estrogenic activity was detected using the SRB assay on MCF-7. This activity may be ascribable to the presence of phenolic compounds miming phytoestrogens such as lignans, stilbenes, and isoflavonoids in the investigated Syzygium extracts. By examining the biological effect of Syzygium extracts against MDA-MB-231 cell lines, the Syzygium gratum leaf extract exhibited the strongest inhibition, with IC50 = 19.4 µg/mL, followed by S. paniculatum (IC50 = 50.9 µg/mL). However, the Syzygium gratum leaf extract showed a potent cytotoxic effect on normal human skin fibroblasts, HSF (IC50 = 1.24 µg/mL), assuming a nonselective cytotoxic effect. On the other hand, other studied Syzygium leaves proved as safe nutraceuticals (IC50 ≥ 100 µg/mL) on HSF cell lines. Our study suggested a possible implication of Syzygium malaccense and Syzygium aqueum leaves as potential estrogenic candidates in relation to their health-promoting phenolic constituents.
Postmenopausal women experience several symptoms, including inflammation and a sharp rise in oxidative stress caused by estrogen deprivation. Although estrogen replacement therapy (ERT) is generally ...regarded as an effective treatment for menopause, it has been used less frequently due to some adverse effects and high costs. Therefore, there is an immediate need to develop an effective herbal-based treatment that is affordable for low-income populations. Acordingly, this study explored the estrogen-like properties of methanol extracts from
(CW) and
(PM), two important medicinal plants in Republic of Korea, Japan, and China. Due to the similar names and morphologies of these two radixes, they are frequently confused in the marketplace. Our previous colleagues discriminated between these two plants. In this study, we investigated the estrogenic activity of PM and CW using several in vitro assays with their possible mechanism of action. First, their phytochemical contents, such as gallic acid, 2,3,5,4'-tetrahydroxystilbene-2-O-glucoside (TSG) and emodin, were quantified using high-performance liquid chromatography (HPLC). Secondly, estrogen-like activity was assessed utilizing the well-known E-screen test and gene expression analysis in estrogen receptor (ER)-positive MCF7 cells. ROS inhibition and anti-inflammatory effects were analyzed using HaCaT and Raw 264.7 cells, respectively. Our findings demonstrate that PM extracts significantly increased the expression of the estrogen-dependent genes (ERα, ERβ, pS2) and boosted MCF7 cell proliferation in comparison to CW extracts. Additionally, PM extract demonstrated a significant reduction in reactive oxygen species (ROS) production as well as an enhanced antioxidant profile compared to the CW extract. Further, the PM extract treatment significantly reduced the generation of nitric oxide (NO) in RAW 264.7 cells, a murine macrophage cell line, demonstrating the anti-inflammatory properties of the extract. Finally, this research offers an experimental foundation for the use of PM as a phytoestrogen to minimize menopausal symptoms.
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•Biochar, corn stalks and mushrooms showed the highest efficiency in reducing E2.•The RB is more effective than WB in promoting microbial activity.•Biochar minimized the nitrogen loss ...through ammonia volatilization.•Biochar decreased availability of As and Cd while had little influence on Cu and Zn.
Inadequate handling of poultry manure can cause significant releases of NH3, heavy metals, and estrogen, thereby impairing environmental quality. This study was a composting experiment involving the combination of poultry manure with plant residues (corn stalks, mushroom residues, and vegetable straw), as well as with either wheat stalk biochar (WB) or rice husk biochar (RB). The integrated effects of plant residues and biochar on NH3 loss, heavy metal (Cu, Zn, As, and Cd) stabilization, and 17β-estradiol (E2) dissipation were investigated during composting. The poultry manure co-composted with corn straw and mushroom residue showed the highest potential for E2 degradation. Biochar enhanced E2 dissipation and decreased estrogenic activity in all treatments, with RB showing a stronger effect than WB. Both biochars decreased microbial diversity and increased bacterial groups related to E2 and organic matter degradation·NH3 emission was reduced by 50–82% with 15% WB and 86–97% with 15% RB. The extractable fraction of As was reduced by 0–53% with WB and 50–84% with RB, while that of Cd was reduced by 5–28% for WB and 25–41% for RB in poultry manure compost. However, biochar showed little effect on Cu and Zn. Biochar appears to have a promotional effect and enhances the microbial degradation of E2. Specifically, the integration of corn stalks, mushroom residues, and RB in poultry manure compost had a positive effect by preventing nitrogen loss while reducing the bioavailability of heavy metals and hormones.
Estrogen mimics are a diverse group of synthetic and naturally occurring compounds that can interact with estrogen receptors (ERs) in animals, including humans. These interactions rely on key ...structural features of 17b-estradiol (E2) and if these molecular features are in a similar spatial arrangement on other compounds, they are likely to elicit an agonist (i.e., they are E2 mimics) or antagonist response. The structural diversity of some compounds vis-à-vis analogies with E2 makes it difficult to reliably predict E2 mimicry on simple structural grounds alone. We propose a new approach methodology: in silico molecular modelling augmented by an in vitro transactivation reporter gene assay to predict E2 mimicry and thus further reduce regulatory reliance on animal studies. Transactivation reporter gene assay dose response curves and in silico molecular modelling were used to obtain EC50-values and docking parameters (DockScores), respectively of thirty E2 mimics to assess the reliability of in silico receptor interaction parameters to predict E2 mimicry. A linear relationship (R2 = 0.75) was found between DockScores and EC50s, suggesting molecular modelling is a good tool for predicting E2 mimicry in a regulatory setting.
•In silico-derived ERα binding parameters reflect cell responses.•In silico ERα binding studies can be used to predict estrogen mimics.•This supports use of in silico estrogen mimic screening in a regulatory context.
Lignin-derivable bisguaiacols/bissyringols are viable alternatives to commercial bisphenols; however, many bisguaiacols/bissyringols (e.g., bisguaiacol F BGF) have unsubstituted bridging carbons ...between the aromatic rings, making them more structurally similar to bisphenol F (BPF) than bisphenol A (BPA) – both of which are suspected endocrine disruptors. Herein, we investigated the estrogenic activity (EA) and developmental toxicity of dimethyl-substituted bridging carbon-based lignin-derivable bisphenols (bisguaiacol A BGA and bissyringol A BSA). Notably, BSA showed undetectable EA at seven test concentrations (from 10−12 M to 10−6 M) in the MCF-7 cell proliferation assay, whereas BPA had detectable EA at five concentrations (from 10−10 M to 10−6 M). In silico results indicated that BSA had the lowest binding affinity with estrogen receptors. Moreover, in vivo chicken embryonic assay results revealed that lignin-derivable monomers had minimal developmental toxicity vs. BPA at environmentally relevant test concentrations (8.7–116 μg/kg). Additionally, all lignin-derivable compounds showed significantly lower expression fold changes (from ∼1.81 to ∼4.41) in chicken fetal liver tests for an estrogen-response gene (apolipoprotein II) in comparison to BPA (fold change of ∼11.51), which was indicative of significantly reduced estrogenic response. Altogether, the methoxy substituents on lignin-derivable bisphenols appeared to be a positive factor in reducing the EA of BPA alternatives.
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•Bissyringol A had undetectable estrogenic activity in MCF-7 cell assays.•Lignin-derivable monomers had reduced estrogenic responses vs. bisphenol A and F.•Developmental toxicity of lignin-derivable monomers was tested for the first time.•Lignin-derivable monomers had minimal developmental toxicity in chicken embryos.
