Search Results (83)

As typical environmental hormones, endocrine-disrupting chemicals (EDCs) have become a global environmental health issue of high concern due to their property of interfering with the endocrine systems of organisms. As a commonly used substitute for bisphenol A (BPA), bisphenol E (BPE) has been frequently detected in environmental matrices such as soil and water in recent years. Existing research has unveiled the developmental and reproductive toxicity of BPE; however, only one in vitro cellular experiment has preliminarily indicated potential neurotoxic risks, with its underlying mechanisms remaining largely unelucidated in the current literature. Potential toxic mechanisms and action targets of BPE were predicted using the zebrafish model via network toxicology and molecular docking, with RT-qPCRs being simultaneously applied to uncover neurotoxic effects and associated mechanisms of BPE. A significant decrease (p < 0.05) in the frequency of embryonic spontaneous movements was observed in zebrafish at exposure concentrations ≥ 0.01 mg/L. At 72 hpf and 144 hpf, the larval body length began to shorten significantly from 0.1 mg/L to 1 mg/L, respectively (p < 0.01), accompanied by a reduced neuronal fluorescence intensity and a shortened neural axon length (p < 0.01). By 144 hpf, the motor behavior in zebrafish larvae was inhibited. Through network toxicology and molecular docking, HSP90AB1 was identified as the core target, with the cGMP/PKG signaling pathway determined to be the primary route through which BPE induces neurotoxicity in zebrafish larvae. BPE induces neuronal apoptosis and disrupts neurodevelopment by inhibiting the cGMP/PKG signaling pathway, ultimately suppressing the larval motor behavior. To further validate the experimental outcomes, we measured the expression levels of genes associated with neurodevelopment (elavl3, mbp, gap43, syn2a), serotonergic synaptic signaling (5-ht1ar, 5-ht2ar), the cGMP/PKG pathway (nos3), and apoptosis (caspase-3, caspase-9). These results offer crucial theoretical underpinnings for evaluating the ecological risks of BPE and developing environmental management plans, as well as crucial evidence for a thorough comprehension of the toxic effects and mechanisms of BPE on neurodevelopment in zebrafish larvae. 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

This study analyzes publicly available RNA-seq data to comprehensively include the complex heterogeneity of prostate cancer (PCa) etiology. It combines prostate and prostate cancer (PCa) cell lines, representing primary PCa cells, Gleason scores, ages, and PCa of different racial origins. Additionally, some cell lines were exposed to endocrine-disrupting chemicals (EDCs). The research aims to identify hub genes and transcription factors (TFs) of the prostate carcinogenesis pathway as molecular targets for clinical investigations to elucidate EDC-induced aggressiveness and to develop potential biomarkers for their exposure risk assessments. PCa cells rely on androgen receptor (AR)-mediated signaling to survive, develop, and function. Fifteen various RNA-seq datasets were normalized for distribution, and the significance (p-value < 0.05) threshold of differentially expressed genes (DEGs) was set based on |log2FC| ≥ 2 change. Through integrated bioinformatics, we applied cBioPortal, UCSC-Xena, TIMER2.0, and TRRUST platforms, among others, to associate hub genes and their TFs based on their biologically meaningful roles in aggressive prostate carcinogenesis. Among all RNA-Seq datasets, we found 75 overlapping DEGs, with BUB1B (32%) and CCNB1 (29%) genes exhibiting the highest degree of mutation, amplification, and deletion. EDC-associated CCNB1, BUB1B, and CCNA2 in PCa cells exposed to EDCs were consistently shown to be associated with high Gleason scores (≥4 + 3) and in the >60 age group of patients. Selected TFs (E2F4, MYC, and YBX1) were also significantly associated with DEGs (NCAPG, MKI67, CCNA2, CCNB1, CDK1, CCNB2, AURKA, UBE2C, BUB1B) and influenced the overall survival (p-value < 0.05) of PCa cases. This is one of the first comprehensive studies combining 15 publicly available RNA-seq datasets to demonstrate the association of EDC-associated hub genes and their TFs aligning with the aggressive carcinogenic pathways in the higher age group (>60 years) of patients. The findings highlight the potential of these hub genes as candidates for further studies to develop molecular biomarkers for assessing the EDC-related PCa risk, diagnosing PCa aggressiveness, and identifying therapeutic targets. Full article

Bifenthrin (BF) is a widely used pyrethroid pesticide recognized as an endocrine-disrupting chemical (EDC). Previous studies have confirmed that chronic exposure to BF is associated with various health risks. However, its potential association with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) remains unclear. In this study, the potential targets of BF were identified using several databases, including the Comparative Toxicogenomics Database (CTD), TargetNet, GeneCards, SwissTargetPrediction, and STITCH. Differentially expressed genes (DEGs) associated with RIF were obtained from bulk RNA-seq datasets in the GEO database. Candidate targets were identified by intersecting the predicted BF-related targets with the RIF-associated DEGs, followed by functional enrichment analysis using the DAVID and g:Profiler platforms. Subsequently, hub genes were identified based on the STRING database and Cytoscape. A diagnostic model was then constructed based on these hub genes in the RIF cohort and validated in an independent recurrent pregnancy loss (RPL) cohort. Additionally, we performed single-cell type distribution analysis and immune infiltration profiling based on single-cell RNA-seq and bulk RNA-seq data, respectively. Molecular docking analysis using AutoDock Vina was conducted to evaluate the binding affinity between BF and the four hub proteins, as well as several hormone-related receptors. Functional enrichment results indicated that the candidate genes were mainly involved in apoptotic and oxidative stress-related pathways. Ultimately, four hub genes—BCL2, HMOX1, CYCS, and PTGS2—were identified. The diagnostic model based on these genes exhibited good predictive performance in the RIF cohort and was successfully validated in the RPL cohort. Single-cell transcriptomic analysis revealed a significant increase in the proportion of myeloid cells in RPL patients, while immune infiltration analysis showed a consistent downregulation of M2 macrophages in both RIF and RPL. Moreover, molecular docking analysis revealed that BF exhibited high binding affinity to all four hub proteins and demonstrated strong binding potential with multiple hormone receptors, particularly pregnane X receptor (PXR), estrogen receptor α (ESRα), and thyroid hormone receptors (TR). In conclusion, the association of BF with four hub genes and multiple hormone receptors suggests a potential link to immune and endocrine dysregulation observed in RIF and RPL. However, in vivo and in vitro experimental evidence is currently lacking, and further studies are needed to elucidate the mechanisms by which BF may contribute to RIF and RPL. Full article

This overview explores the complex relationship between environmental factors, particularly obesity, and the timing of puberty, with a focus on how hormonal and genetic interactions are influenced by external conditions. Puberty (gonadarche) is characterised by the activation of the hypothalamic–pituitary–gonadal (HPG) axis. The onset and progression of puberty vary significantly among individuals, primarily due to genetic factors, with key genes like kisspeptin 1 (KISS1) and makorin ring finger protein 3 (MKRN3) playing a crucial role. Cohesively, this paper emphasises that environmental factors, particularly obesity and exposure to endocrine-disrupting chemicals (EDCs), have become significant influences on the timing of puberty. Childhood obesity has risen significantly in recent decades and the age of pubertal onset has declined over the same period. Obesity greatly disrupts hormone regulation in pre-pubertal children. Leptin accelerates the onset of puberty in girls but not in boys. The underlying mechanism is proposed to be the increase in Kiss1/GnRH signalling. On the contrary, excess leptin in boys suppresses testosterone production by increasing oestrogen conversion. Low adiponectin in obese girls may contribute to earlier puberty due to a reduced inhibition of Kiss1/GnRH signalling. Low adiponectin in boys is linked to delayed puberty due to its role in maintaining insulin sensitivity and testosterone production. Hyperinsulinemia influences pubertal timing through central and peripheral mechanisms. Insulin acting synergistically with leptin promotes the earlier onset of puberty in girls but not in boys. The effects of exposure to certain EDCs—mostly obesogenic chemicals that mimic the action of natural hormones—on the timing of puberty remain unclear; hence, further research on this topic is needed. Addressing and preventing obesity in children could potentially mitigate these alterations in pubertal timing. Full article

Background/Objectives: In crop genetic engineering, morphogenic genes have attracted increasing attention, given their ability to facilitate the transformation of a broad range of otherwise nontransformable cultivars. However, few callus-specific promoters have been identified to date that can be employed to avoid the adverse effects resulting from the ectopic expression of morphogenic genes on shoot regeneration and growth. Methods: A set of potential callus-specific genes were initially selected based on publicly available data. These genes were then screened using quantitative real-time polymerase chain reaction (qPCR), followed by promoter activity evaluation using a transgenic approach with the GUS gene serving as a reporter. Results: Of the 24 evaluated promoters, 12 were verified as being callus-specific using qPCR. Five genes (Os11g0295900, Os10g0207500, Os01g0300000, Os02g0252200, and Os04g0488100) were chosen, and their promoters were cloned. Based on GUS staining, the pOsTDL1B (Os10g0207500) promoter showed strong callus-specific expression, pOsEDC (Os01g0300000) was a medium-level callus-specific promoter, and pOsDLN53 (Os02g0252200) was strictly callus-specific, although its activity was low. Quantification of GUS activity indicated that all three pOsTDL1B:GUS transgenic lines exhibited strong callus specificity relative to the various tissues tested. Conclusions: A callus-specific promoter was identified that can be used to drive the expression of morphogenic genes in crop transformation. Full article

Background: Preeclampsia (PE) is a critical complication of pregnancy that affects 3% to 5% of all pregnancies and has been linked to aberrant placentation, causing severe maternal and fetal illness and death. Objectives: This systematic review aims to elucidate the association of in-utero endocrine-disrupting chemical (EDC) exposure and microRNAs and their imprinted genes from prenatal and maternal circulation of PE patients. Methods: Databases such as PubMed, PubMed Central, ScienceDirect, the Comparative Toxicogenomics Database (CTD), ProQuest, EBSCOhost, and Google Scholar were utilized to search for articles that investigate the relationships between selected EDCs and epigenetic events such as DNA methylation and microRNAs that are associated with PE. Results: A total of 29 studies were included in the database search. Altered expression of microRNAs (miR-15a-5p, miR-142-3p, and miR-185) in the placenta of PE patients was positively associated with the urinary concentration of phthalates and phenols in the development of the disease in the first trimester. EDCs such as phenols, phthalates, perfluoroalkyl substances (PFOAs), polybrominated diphenyl ethers (PBDEs), and organochlorine phosphates (OCPs) have been reported to be associated with hypertensive disorders in pregnancy. miRNA-31, miRNA-144, miRNA-145, miRNA-210, placental specific clusters (C14MC, and C19MC) may be used as possible targets for PE because of their potential roles in the onset and progression of PE. Conclusions: Prenatal EDC exposure, including exposure to BPA, showed association with signaling pathways including estrogen, sFlt-1/PlGF, ErbB, MAPK/ERK, and cholesterol mechanisms with placental hemodynamics. Even low EDC exposures leave altered epigenetic marks throughout gestation, which might cause PE complications. Full article

Endocrine-disrupting chemicals (EDCs) are notable for their persistence, bioaccumulation, and associations with cancer. Human nuclear receptors (hNRs) are primary targets disrupted by these persistent EDCs, resulting in alterations to xenobiotic metabolism, lipid homeostasis, and endocrine function, which can lead to carcinogenic effects. Despite their hazardous effects, comprehensive studies on EDC interactions and their impacts on hNRs remain limited. Here, we profiled the interactions of persistent EDCs, including PFAS, plastic additives, bisphenols, polybrominated diphenyl ethers, and phthalates, with key hNRs such as PXR, CAR, PPARα, PPARγ, PPARδ, AR, and RORγt. Through controlled molecular docking simulations, we observed strong binding of the EDCs to these receptors. Further analysis showed that EDCs exhibit strong binding activity towards hNRs by preferentially interacting with hydrophobic amino acids, namely leucine, isoleucine, methionine, and phenylalanine. PFAS demonstrated the highest binding affinity, characterized by a combination of complementary hydrophobic interactions from their fluorinated carbon chains and polar interactions from their functional groups (e.g., carboxylate, sulfonate) across all receptors. Distinct polycyclic and hydrophobic trends, contributing to strong NR binding, were evident in non-PFAS and nonplastic EDCs. The hNR activity assay in HepG2 cells revealed agonistic effects of dicyclohexyl phthalate (DCHP) and di-2-ethylhexyl phthalate (DEHP) on most receptors, except for PPARα. The hNR transcription factor pathway assay in HepG2 cells demonstrated increased gene expression of VDRE and PXR, suggesting potential chronic effects on xenobiotic metabolism and calcium homeostasis. Overall, our findings demonstrate the need for further research into the endocrine disruption and carcinogenic effects of these persistent EDCs. Full article

Reptiles, birds, mammals and amphibians, together forming the clade tetrapods, have a large diversity of cornified skin appendages, such as scales, feathers, hair and claws. The skin appendages consist of dead epithelial cells that are tightly packed with specific structural proteins. Here, we review the molecular diversity and expression patterns of major types of skin appendage proteins, namely keratin intermediate filament proteins, keratin-associated proteins (KRTAPs) and proteins encoded by genes of the epidermal differentiation complex (EDC), including corneous beta-proteins, also known as beta-keratins. We summarize the current knowledge about the components of skin appendages with a focus on keratins and EDC proteins that have recently been identified in reptiles and birds. We discuss gaps of knowledge and suggest directions of future research. Full article

Endocrine-disrupting chemicals (EDCs), including phthalates, have been implicated in the development of non-alcoholic fatty liver disease (NAFLD) and hepatic fibrosis. This study investigates the age-dependent effects of butyl benzyl phthalate (BBP) exposure on lipid metabolism in the livers of young and aged mice. Young (2-month-old) and aged (20-month-old) male C57BL/6 mice were exposed to BBP through drinking water at a dose of 169 μg/kg/day for 6 and 4 months, respectively. Young mice exposed to BBP showed fatty liver, with downregulation of key fatty acid oxidation genes (CPT1A, CPT1B, CPT2, and Acox1) and elevated pro-inflammatory cytokines (TNF-α and IL-6). In contrast, aged mice exhibited hepatic fibrosis, with increased collagen deposition and upregulation of genes related to fibrosis (Acta2, MMP2, TGF-ß1, and Col1a2), cirrhosis (CXCR4, SOX9, DCN, and MFAP4), and cancer (Bcl2, CDKN2a, c-Myc, and Fn1). Overall, these findings emphasize the importance of age when evaluating the risks of EDC exposure, such as BBP. Future research should focus on understanding the molecular mechanisms behind these age-related differences and explore Grem1 and SOCS3 as potential therapeutic targets for treating EDC-induced and age-related liver diseases. Full article

Endocrine-disrupting chemicals (EDCs) significantly damage biological systems related to reproductive, neurological, and metabolic functions. Approximately 1000 chemicals are known to possess endocrine-acting properties, including bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP). This study primarily focuses on the potential effects of EDCs on the transcriptional levels of innate immune prophenoloxidase (proPO) system-related genes under oxidative stress in the gonads and stomach of the mud crab Macrophthalmus japonicus, an indicator species for assessing coastal benthic environments, when exposed to 1 µg L⁻¹, 10 µg L⁻¹, and 30 µg L⁻¹ BPA or DEHP. After EDC exposure, the expression of lipopolysaccharide and β-1,3-glucan-binding protein (LGBP), a pattern recognition protein that activates the proPO system, was upregulated in the stomach of M. japonicus, whereas LGBP gene expression was downregulated in the gonads. In the gonads, which is a reproductive organ, EDC exposure mainly induced the transcriptional upregulation of trypsin-like serine protease (Tryp) at relatively low concentrations. In the stomach, which is a digestive organ, LGBP expression was upregulated at relatively low concentrations of EDCs over 7 days, whereas all proPO system-related genes (LGBP, Tryp, serine protease inhibitor (Serpin), and peroxinectin (PE)) responded to all concentrations of EDCs. These results suggest that the antioxidant and immune defense responses of the proPO system to EDC toxicity may vary, causing different degrees of damage depending on the tissue type in the mud crab. Full article

Endocrine-disrupting chemicals (EDCs) impair growth and development. While EDCs can occur naturally in aquatic ecosystems, they are continuously introduced through anthropogenic activities such as industrial effluents, pharmaceutical production, wastewater, and mining. To elucidate the chronic toxicological effects of endocrine-disrupting chemicals (EDCs) on aquatic organisms, we collected experimental data from a standardized chronic exposure test using Daphnia magna (D. magna), individuals of which were exposed to a potential EDC, trinitrotoluene (TNT). The chronic toxicity effects of this compound were explored through differential gene expression, gene ontology, network construction, and putative adverse outcome pathway (AOP) proposition. Our findings suggest that TNT has detrimental effects on the upstream signaling of Tcf/Lef, potentially adversely impacting oocyte maturation and early development. This study employs diverse bioinformatics approaches to elucidate the gene-level toxicological effects of chronic TNT exposure on aquatic ecosystems. The results provide valuable insights into the molecular mechanisms of the adverse impacts of TNT through network construction and putative AOP proposition. 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

The epidermal differentiation complex (EDC) is a cluster of genes that code for protein components of cornified cells on the skin surface of amniotes. Squamates are the most species-rich clade of reptiles with skin adaptations to many different environments. As the genetic regulation of the skin epidermis and its evolution has been characterized for only a few species so far, we aimed to determine the organization of the EDC in a model species of squamates, the common wall lizard (Podarcis muralis). By comparative genomics, we identified EDC genes of the wall lizard and compared them with homologs in other amniotes. We found that the EDC of the wall lizard has undergone a major rearrangement leading to a unique order of three ancestral EDC segments. Several subfamilies of EDC genes, such as those encoding epidermal differentiation proteins containing PCCC motifs (EDPCCC) and loricrins, have expanded by gene duplications. Most of the EDPCCC proteins have cysteine contents higher than 50%, whereas glycine constitutes more than 50% of the amino acid residues of loricrin 1. The extremely biased amino acid compositions indicate unique structural properties of these EDC proteins. This study demonstrates that cornification proteins of the common wall lizard differ from homologous proteins of other reptiles, illustrating the evolutionary dynamics of diversifying evolution in squamates. Full article

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) are a group of organic chemicals containing three-ring structures that can be substituted with one to eight chlorine atoms, leading to 75 dioxin and 135 furan congeners. As endocrine-disrupting chemicals (EDCs), they can alter physiological processes causing a number of disorders. In this study, quantitative structure–toxicity relationship (QSTR) studies were used to determine the correlations between the PCDD/Fs’ molecular structures and various toxicity endpoints. Strong QSTR models, with the coefficients of determination (r²) values greater than 0.95 and ANOVA p-values less than 0.0001 were established between molecular descriptors and the endpoints of bioconcentration, fathead minnow LC50, and Daphnia magna LC50. The ability of PCDD/Fs to bind to several nuclear receptors was investigated via molecular docking studies. The results show comparable, and in some instances better, binding affinities of PCDD/Fs toward the receptors relative to their natural agonistic and antagonistic ligands, signifying possible interference with the receptors’ natural biological activities. These studies were accompanied by the molecular dynamics simulations of the top-binding PCDD/Fs to show changes in the receptor–ligand complexes during binding and provide insights into these compounds’ ability to interfere with transcription and thereby modify gene expression. This introspection of PCDD/Fs at the molecular level provides a deeper understanding of these compounds’ toxicity and opens avenues for future studies. Full article