Search Results (101)

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

Bisphenols (BPs), particularly bisphenol A (BPA) and its structural analogues, are synthetic compounds widely used in plastics and industrial materials. These substances are also recognised as endocrine-disrupting chemicals (EDCs) due to their ability to interfere with hormonal systems, which has significant implications for aquatic organisms. This review summarises the occurrence, environmental distribution, and toxicity of BPs in fish, with a focus on estrogenic, androgenic, thyroid, and glucocorticoid disruptions. Studies consistently show that exposure to BPs leads to altered gene expression, developmental abnormalities, impaired reproduction, and disrupted hormonal signalling in various fish species. Although BPA alternatives like bisphenol S, bisphenol F, or bisphenol AF were introduced as safer options, emerging evidence suggests they may pose equal or greater risks. Regulatory measures are evolving, particularly within the European Union, but legislation remains limited for many bisphenol analogues. This review emphasises the need for comprehensive environmental monitoring, stricter regulatory frameworks, and the development of genuinely safer alternatives to minimise the ecological and health impacts of BPs in aquatic systems. Full article

Bisphenol A (BPA) is an endocrine-disrupting chemical with estrogen-like activity, known to impair immune function. BPA may act as a pro-inflammatory agent, reducing immune response efficacy, increasing bacterial load in E. coli infections, and altering immune responses in parasitic infections (Leishmania major, Nippostrongylus brasiliensis, Toxocara canis) through cytokine and regulatory T-cell modulation. Following its ban in food contact materials in Europe, several analogs have been introduced. This study assessed the immunotoxicity of BPA and six analogs, namely BPAP, BPE, BPP, BPS-MAE, BPZ, and TCBPA, by evaluating in vitro the antibody production. Peripheral blood mononuclear cells from healthy male and female donors were exposed to increasing concentrations of each compound for 24 h. After stimulation with rhIL-2 and ODN2006, IgM and IgG secretion were measured on day six. All compounds suppressed antibody production in a concentration-dependent manner, with some sex-related differences. IC₅₀ values showed BPP as the most potent suppressor, and BPE as the weakest. Similarly, IC₂₀ values confirmed these differences in potency, except for BPA being the weakest for IgM in males. Overall, te results do not support the idea that BPA analogs are safer than BPA. Full article

Background/Objectives: Bisphenol A (BPA) is an organic compound used in producing polycarbonates and epoxy resins found in products such as food containers, disposable bottles, CDs, and DVDs. Its structure resembles that of endogenous estrogen, which classifies BPA as an endocrine-disrupting chemical (EDC). BPA has been associated with various health abnormalities, including cancer and reproductive system cancer. In this study, we examine the association between BPA exposure, BPA levels in blood serum, and the occurrence of breast cancer and reproductive system cancer. Methods: A total of 84 females were included in this cross-sectional study. All participants completed a questionnaire assessing BPA exposure and underwent a blood test to measure BPA levels in serum. Results: Analysis of the lifestyle questionnaire revealed behavioral differences potentially associated with BPA exposure. A statistically significant difference was observed for responses to Question 13, related to food preparation methods, while responses to Questions 5, 6, and 17 showed trends approaching statistical significance in cancer groups. Serum BPA concentrations were significantly higher in patients with reproductive system cancer compared to the control group (p = 0.045), while a non-significant trend was observed between breast cancer patients and patients with reproductive system cancer (p = 0.0884). Conclusions: In summary, our study demonstrated significantly elevated serum BPA levels in patients with reproductive system cancer compared to controls. These results suggest the hypothesis that higher exposure to BPA may influence or be associated with the development of estrogen-dependent cancers such as breast and endometrial cancer. However, due to the cross-sectional design of the study, causality cannot be established, and further longitudinal studies are warranted. Full article

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that interfere with the endocrine system by mimicking or blocking the action of endogenous hormones such as estrogens, androgens, and thyroid hormones. This systematic review aims to evaluate the current epidemiological evidence linking EDC exposure with adverse reproductive outcomes in males and females of reproductive age. A total of 14 observational studies published between 2014 and 2024 were included following structured searches in PubMed, Scopus, and Google Scholar. The most commonly studied EDCs included bisphenol A (BPA), its analogs (such as bisphenol S, BPS), phthalates, parabens, per- and polyfluoroalkyl substances (PFAS), and persistent organic pollutants (POPs). The review found consistent associations between EDC exposure and multiple reproductive endpoints, such as impaired semen quality, decreased ovarian reserve, infertility, polycystic ovary syndrome (PCOS), altered hormone levels—specifically estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)—and adverse outcomes in assisted reproductive technologies (ART), including in vitro fertilization (IVF). Despite methodological heterogeneity, the findings support the biological plausibility of EDCs in disrupting reproductive function. The review highlights the urgent need for regulatory measures, increased public awareness, and longitudinal studies to assess the cumulative effects of chronic EDC exposure on human fertility. Full article

Objective: To evaluate the cytotoxicity and endocrine-disrupting potential of materials used in removable orthodontic retainers. Methods: A literature search (2015–2025) covered in vitro cytotoxicity, estrogenicity, in vivo tissue responses, and clinical biomarkers in PMMA plates, thermoplastic foils, 3D-printed resins, PEEK, and fiber-reinforced composites. Results: Thirty-eight in vitro and ten clinical studies met inclusion criteria, identified via a structured literature search of electronic databases (2015–2025). Photopolymer resins demonstrated the highest cytotoxicity, whereas thermoplastics and PMMA exhibited predominantly mild effects, which diminished further following 24 h water storage. Bisphenol-type compound release was reported, but systemic exposure remained below regulatory limits. No statistically significant mucosal alterations or endocrine-related effects were reported in clinical studies. Conclusions: Retainer materials are generally biocompatible, though data on long-term endocrine effects are limited. Standardized biocompatibility assessment protocols are necessary to enable comparative evaluation across diverse orthodontic materials. Single-use thermoplastics contribute to microplastic release and pose end-of-life management challenges, raising concerns regarding environmental sustainability. Full article

Bisphenol A diglycidyl ether (BADGE) is the main component of epoxy resin and is used for the inner coating of canned foods and plastic food containers. BADGE can easily migrate from containers and result in food contamination; the compound is known as an endocrine-disrupting chemical. We previously reported that maternal exposure to bisphenol A bis (2,3-dihydroxypropyl) ether (BADGE·2H₂O), which is the most detected BADGE derivative not only in canned foods but also in human specimens, during gestation and lactation, could accelerate neuronal differentiation in the cortex of fetuses and induce anxiety-like behavior in juvenile mice. In this study, we investigated the effects of low-dose BADGE·2H₂O (1–100 pM) treatment on neurites and the mechanism of neurite outgrowth in cortical neurons. BADGE·2H₂O exposure significantly increased the number of dendrites and neurite length in cortical neurons; these accelerating effects were inhibited by estrogen receptor (ER) antagonist ICI 182,780 and G-protein-coupled estrogen receptor (GPER) antagonist G15. BADGE·2H₂O down-regulated Hes1 expression, which is a transcriptional repressor, and increased levels of neuritogenic factor neurogenin-3 (Ngn3) in the cortical neurons; the changes were significantly blocked by G15. These data suggest that direct BADGE·2H₂O exposure can accelerate neuritogenesis and outgrowth in cortical neurons through down-regulation of Hes1 and by increasing Ngn3 levels through ERs, particularly GPER. Full article

OP, a systemic bone disorder marked by reduced bone mass and heightened fracture risk, poses a significant global health burden, particularly among aging populations. Current treatments, including bisphosphonates and calcium supplementation, are limited by adverse effects and incomplete efficacy. Emerging research highlights ferroptosis—an iron-dependent cell death driven by lipid peroxidation—as a critical contributor to OP pathogenesis, characterized by dysregulated iron metabolism, oxidative stress, and lipid peroxide accumulation, which disrupt bone remodeling by impairing osteoblast function and enhancing osteoclast activity. This review elucidates the mechanistic interplay between ferroptosis and OP subtypes (diabetic osteoporosis (DOP), glucocorticoid-induced (GIOP), and postmenopausal osteoporosis (PMOP)) and evaluates the efficacy of Chinese herbal interventions in mitigating ferroptosis-driven bone loss. Key findings reveal that excess iron exacerbates lipid peroxidation via the Fenton reaction, while glutathione peroxidase 4 (GPX4) inactivation and system Xc- inhibition amplify oxidative damage. In DIOP, hyperglycemia-induced ROS and advanced glycation end products suppress osteogenesis, countered by melatonin and naringenin via nuclear factor -related factor 2 (Nrf2)/GPX4 activation. GIOP involves dexamethasone-mediated GPX4 downregulation, mitigated by exosomes and melatonin through phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. PMOP driven by estrogen deficiency-induced iron overload is alleviated by aconitine and icariin (ICA) via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. Chinese herbs, including active compounds (quercetin, gastrodin, ICA, etc.) and formulations (Bugu Shengsui Capsule, Erxian Decoction (EXD), etc.), regulate iron metabolism, enhance antioxidant defenses (Nrf2/heme oxygenase 1(HO-1)), and inhibit lipid peroxidation, effectively restoring bone homeostasis. These findings underscore ferroptosis as a pivotal mechanism in OP progression and highlight the therapeutic promise of Chinese herbs in bridging traditional medicine with modern mechanistic insights. Future research should prioritize elucidating precise molecular targets, optimizing formulations, and validating clinical efficacy to address current therapeutic gaps. Full article

Endocrine-disrupting compounds (EDCs) are emerging pollutants that can potentially accumulate in aquatic ecosystems at significant levels, with the potential to impact the health of both animals and humans. Many scientists have correlated human exposure to high concentrations of EDCs with critical physiological impacts, including infertility, thyroid imbalance, early sexual development, endometriosis, diabetes, and obesity. Several substances, such as heavy metals, belong to this family, ranging from natural to synthetic compounds, including pesticides, pharmaceuticals, and plastic-derived compounds. Domestic sewage represents a significant source of EDCs in the surrounding aquatic ecosystems. To this day, most rural and urban domestic wastewater in the municipality of Maricá is directly discharged into local aquatic environments without any treatment. The present study aimed to assess the potential contamination of the riverine and lagoonal environment in the municipality of Maricá. Water and sediment samples were collected seasonally at 18 sites along the Maricá watershed and the main lagoon, into which most of the watershed’s contributors flow. Water physico-chemical parameters (pH, reduction–oxidation potential—Eh, dissolved oxygen levels, salinity, turbidity, temperature, and fecal coliforms) were analyzed to characterize the urban influence on the aquatic environment. Sediment samples were also analyzed for grain size, total organic carbon percentage, potential bioavailable fraction of trace metals (Cd, Pb, Cu, Cr, Hg, Ni, Zn), and metalloid As. Finally, the sediment toxicity was assessed using yeast estrogen screen (YES) assays. The results obtained already demonstrate the presence of estrogenic effects and raise concerns about water quality. The current study indicates that, despite the absence of agricultural and industrial activities in the city of Maricá, EDCs are already present and have the potential to impact the local ecosystem, posing potential risks to human health. Full article

Parabens are widely used in various industries, which are including chemical, pharmaceutical, food, cosmetic, and plastic processing industries. Among these, methyl paraben (MP) serves as an antimicrobial preservative in processed foods, pharmaceuticals, and cosmetics, and it is particularly detected in baby care products. Studies indicate that MP functions as an endocrine-disrupting compound with estrogenic properties, negatively affecting mitochondrial bioenergetics and antioxidant activity in testicular germ cells. However, limited information exists regarding studies on the effects of MP in oocytes. The aim of this study was to investigate the specific mechanism and the toxic effects of MP during oocyte maturation cultured in vitro using a porcine oocyte model. The results indicated that MP (50 μM) inhibited oocyte expansion, significantly reducing the expression of expansion-related genes MAPK1 and ERK1, and decreased the first polar body extrusion significantly as well. ATP levels decreased, reactive oxygen species (ROS) levels remained unchanged, and glutathione (GSH) levels decreased significantly, resulting in an elevated ROS/GSH ratio. The expression of antioxidant genes SOD1 and GPX was significantly decreased. Additionally, a significant decrease in levels of mitochondrial production and biosynthesis protein PGC1α+β, whereas levels of antioxidant-related protein Nrf2 and related gene expression were significantly increased. Autophagy protein LC3B and gene expression significantly decreased, and apoptosis assay indicated a significant increase in levels of caspase3 protein and apoptosis-related genes. These results demonstrated the negative effect of MP on oocyte maturation. In conclusion, our findings indicate that MP disrupts redox balance and induces mitochondrial dysfunction during meiosis in porcine oocytes, resulting in the inhibition of meiotic progression. The present study reveals the mechanism underlying the effects of methyl para-hydroxybenzoate on oocyte maturation. Full article

Background: Although estrogenic compounds promise therapeutic potential in treating various conditions, concerns regarding their endocrine-disrupting effects have been raised. Current methodologies for screening estrogenicity in rodent models are limited to the female-specific uterotrophic bioassay. Studies have reported enlargement of the seminal vesicles in orchiectomized males treated with estrogens. However, identifying estrogenicity strictly through changes in wet weights is uninformative regarding the molecular mechanisms of these agents. Therefore, protein-based biomarkers can complement and improve the sensitivity of weight-based assessments. To this end, we present a discovery-driven proteomic analysis of 17β-estradiol’s effects on the seminal vesicles. Methods: We treated orchidectomized mice with the hormone for five days and used the vehicle-treated group as a control. Seminal vesicles were analyzed by shotgun approach using data-dependent nanoflow liquid chromatography–tandem mass spectrometry and label-free quantification. Proteins found to be differentially expressed between the two groups were processed through a bioinformatics pipeline focusing on pathway analyses and assembly of protein interaction networks. Results: Out of 668 identified proteins that passed rigorous validation criteria, 133 were regulated significantly by 17β-estradiol. Ingenuity Pathway Analysis^® linked them to several hormone-affected pathways, including those associated with immune function such as neutrophil degranulation. The altered protein interaction networks were also related to functions including endocrine disruption, abnormal metabolism, and therapeutic effects. Conclusions: We identified several potential biomarkers for estrogenicity in mouse seminal vesicles, many of them not previously linked with exogenous 17β-estradiol exposure. Full article

Fish are exposed to increased water temperatures and aquatic pollutants, including endocrine-disrupting compounds (EDCs). Although each stressor can disturb fish liver metabolism independently, combined effects may exist. To unveil the molecular mechanisms behind the effects of EDCs and temperature, fish liver cell lines are potential models needing better characterisation. Accordingly, we exposed the rainbow trout RTL-W1 cells (72 h), at 18 °C and 21 °C, to ethynylestradiol (EE2), levonorgestrel (LNG), and a mixture of both hormones (MIX) at 10 µM. The gene expression of a selection of targets related to detoxification (CYP1A, CYP3A27, GST, UGT, CAT, and MRP2), estrogen exposure (ERα, VtgA), lipid metabolism (FAS, FABP1, FATP1), and temperature stress (HSP70b) was analysed by RT-qPCR. GST expression was higher after LNG exposure at 21 °C than at 18 °C. LNG further enhanced the expression of CAT, while both LNG and MIX increased the expressions of CYP3A27 and MRP2. In contrast, FAS expression only increased in MIX, compared to the control. ERα, VtgA, UGT, CYP1A, HSP70b, FABP1, and FATP1 expressions were not influenced by the temperature or the tested EDCs. The RTL-W1 model was unresponsive to EE2 alone, sensitive to LNG (in detoxification pathway genes), and mainly insensitive to the temperature range but had the potential to unveil specific interactions. Full article

Estrogenic chemicals are widely distributed and structurally diverse. They primarily disrupt estrogen-related metabolism in animals or humans by mimicking the agonistic receptor effects of natural estrogens, thereby influencing the transcription of estrogen receptors to regulate their quantity and sensitivity. This disruption of estrogen-related metabolism can lead to estrogen-related effects, posing risks to biological health, emphasizing the urgent need for simple and effective methods to screen compounds with estrogenic effects. Herein, a new electrochemical biological effect biosensor based on human estrogen receptor α (hERα) is developed, which uses hERα as the biorecognition element and employs the electroactive horseradish peroxidase (HRP) labeled 17β-estradiol (E2) multifunctional conjugate HRP-E2 as the signal-boosting element and ligand competition agent. Based on the specific ligand–receptor interaction principle between the target and nuclear receptor, by allowing the test compound to compete with HRP-E2 conjugate for binding to hERα and testing the electrocatalytic signal of the conjugate that fails to bind to the hERα estrogen receptor, rapid screening and quantitative detection of chemical substances with estrogenic effect have been achieved. The biosensor shows a wide linear range of 40 pM to 40 nM with a detection limit of 17 pM (S/N = 3) for E2, and the detection limit is 2 orders of magnitude better than that of the previously reported sensors. The biosensor based on ligand–receptor binding can not only quantitatively analyze the typical estrogen E2, but also evaluate the relative estrogen effect strength of other estrogen compounds, which has good stability and selectivity. This electrochemical sensing platform displays its promising potential for rapid screening and quantitative detection of chemicals with estrogenic effects. Full article

Approximately 80% of breast cancer (BC) cases are estrogen receptor positive (ER+) and sensitive to hormone treatment; Tamoxifen is a prodrug, and its main plasmatic active metabolites are 4-hydroxytamoxifen (4-OH Tam) and endoxifen. Despite the effectiveness of tamoxifen therapy, resistance can be developed. An increment in eukaryotic initiation factor-4A complex (eIF4A) activity can result in tamoxifen-resistant tumor cells. For this work, we developed a cell variant resistant to 4-OH Tam and endoxifen, denominated MCF-7^{Var E}; then, the aim of this research was to reverse the acquired resistance of this variant to tamoxifen metabolites by incorporating the natural compound auraptene. Combination treatments of tamoxifen derivatives and auraptene successfully sensitized the chemoresistant MCF-7^{Var E}. Our data suggest a dual regulation of eIF4A and ER by auraptene. Joint treatments of 4-OH Tam and endoxifen with auraptene identified a novel focus for chemoresistance disruption. Synergy was observed using the auraptene molecule and tamoxifen-derived metabolites, which induced a sensitization in MCF-7^{Var E} cells and ERα parental cells that was not observed in triple-negative breast cancer cells (TNBC). Our results suggest a synergistic effect between auraptene and tamoxifen metabolites in a resistant ER+ breast cancer model, which could represent the first step to achieving a pharmacologic strategy. Full article

Green agronomy promotes the implementation of natural and naturally derived substances in crop protection. In the present study, we evaluated the endocrine-disrupting potential of the allelopathic herbicide tembotrione in Wistar rats by studying the hormone status of offspring from the treated dams. Three doses of tembotrione (0.0004, 0.0007, and 4.0 mg/kg b.w./day) have been administered to dams during gestation and/or lactation. In the serum of newborn, weaning, and pubertal female and male offspring, 17β-estradiol and testosterone were determined using enzyme-linked immunosorbent assay. A decrease in 17β-estradiol and testosterone was observed in female and male weaning and pubertal offspring exposed to all doses of tembotrione during gestation and lactation. In weaning offspring exposed only during lactation, 17β-estradiol dropped significantly after exposure to the two lower doses and testosterone after exposure to the lowest dose of tembotrione. The greatest effect was observed at the lowest dose of tembotrione. In newborns, we observed increased 17β-estradiol after exposure to two lower doses of tembotrione and significantly increased testosterone after exposure to the lowest dose. The highest dose of tembotrione decreased 17β-estradiol significantly in newborn females. The obtained results suggest that tembotrione might be considered a pro-estrogenic or estrogen agonistic compound under the exposure conditions applied in this investigation. Full article