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Results for “Endocrine disruptors”

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PubMed2024

Common genetic variants associated with urinary phthalate levels in children: A genome-wide study.

INTRODUCTION: Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes. OBJECTIVE: In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS). METHODS: The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value < 1E-05) was done with the FUMA web-tool. RESULTS: We identified four genome-wide significant (p-value < 5E-08) loci at chromosome (chr) 3 (FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1 for MECPP_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 additional loci were found at suggestive significance (p-value < 1E-05). Two CNVs located at chr11 (MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion. CONCLUSION: Through genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification, transmembrane transfer, and renal excretion.

Humans↗

PubMed2026

Harnessing probiotics to combat nonylphenol toxicity: a multiomics approach of gut microbiome remodelling in Silurus meridionalis.

BACKGROUND: As a ubiquitous environmental endocrine disruptor, nonylphenol (NP) threatens aquatic organisms, driving the need for sustainable mitigation strategies. While probiotics represent promising eco-friendly supplements, their molecular mechanisms against NP toxicity remain unclear. In this study, S. meridionalis received 7-week of probiotic (Bacillus subtilis and Lactobacillus acidophilus) pretreatment followed by 15 days of NP exposure. Integrated metagenomics, transcriptomics, and metabolomics analyses, with Reverse transcription quantitative real-time PCR (RT‒qPCR) and Enzyme-linked immunosorbent assay (ELISA) validation, were performed to elucidate microbial, genetic and metabolic responses. Growth performance, including the specific growth rate (SGR) and weight gain rate (WGR), was concurrently assessed. RESULTS: NP exposure significantly suppressed WGR and SGR, and induced gut microbiota dysbiosis alongside and lipid metabolism disorders in S. meridionalis. Probiotic pretreatment effectively reversed these toxic effects and restored the inhibited WGR and SGR. Multiomics integration revealed that the protective effects of probiotics were mediated by a coherent "microbe-host" co-metabolism network across 3 progressive layers: (1) Microbial Remodelling: in which beneficial taxa (e.g., Bacteroides eggerthii and Cetobacterium sp.) were enriched, and the functional capacity for short-chain fatty acid (SCFA) synthesis and ethanolamine metabolism was enhanced; (2) Host Gene Regulation: in which key lipid metabolism genes (ek1, cept1, ept1, mogat2, and abcg2a) were upregulated, and lipase activity was restored; and (3) Metabolic Pathway Activation and Physiological Repair: in which the activity of the NP-suppressed Kennedy pathway was reactivated, thereby promoting phosphatidylethanolamine (PE) and phosphatidylcholine (PC) synthesis and ultimately restoring gut barrier function. These results were further were corroborated by RT‒qPCR and ELISA. CONCLUSION: This study systematically elucidated that probiotics alleviated NP toxicity by remodelling a "microbiota-host Kennedy pathway gene-metabolite (PE and PC)-growth performance" regulatory network. The key mechanism is the beneficial microbiota activating the host Kennedy pathway and restoring gut phospholipid homeostasis and barrier function. These findings provide a theoretical basis for developing targeted, lipid metabolism focused probiotic feed additives for use in sustainable aquaculture.

Probiotics↗

PubMed2024

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Humans↗

PubMed2025

A three-dimensional mouse liver organoid platform for assessing EDCs metabolites simulating liver metabolism.

Hepatic metabolism is an important process for evaluate the potential activity and toxicity of endocrine disrupting chemicals (EDCs) metabolites. Organization for Economic Co-operation and Development (OECD) has advocated the development of in vitro assays that mimic in vivo hepatic metabolism to eventually replace classical animal tests. In response to this need, we established a 3D mouse liver organoid (mLO) platform that mimics the animal model and is distinct from existing models. We evaluated the effects the activity of EDC metabolites generated through mLOs based on human cell-based reporter gene assays in addition to existing models. This study emphasizes the importance of hepatic ex-vivo and suggests the need a new metabolic model through a 3D mLOs platform. These results indicate that mLOs provides a novel biological method to screen for potential endocrine-disrupting activities of EDC metabolites.

Animals↗

PubMed2026

Screening of Estrogenic and Antiestrogenic Effects of Estradiol, Bisphenol A, and Fulvestrant Using 2D and 3D Breast Cancer Cell Systems With a Luciferase Reporter Gene Assay.

Endocrine-disrupting chemicals (EDCs) like bisphenol A (BPA) pose health risks by interfering with hormones. This study develops and utilizes in vitro 2D and 3D cell models to evaluate the estrogenic and antiestrogenic properties of compounds. Human breast cancer cell lines T47D and MCF7, stably transfected with a luciferase reporter gene (ERE-LUC), were first compared in 2D. Due to the significantly higher sensitivity and responsiveness observed in the T47D line during preliminary 2D screenings, this cell line was exclusively selected for the development of the 3D spheroid model. Cells were treated with 17β-estradiol (E2), BPA, and Fulvestrant (FUL) to assess cell viability and luciferase activity. In 2D models, T47D ERE-LUC cells showed higher responsiveness than MCF7 ERE-LUC, which failed to show significant luciferase induction with E2. In the 3D T47D model, cells exhibited significant and robust changes in luciferase activity in response to E2 and BPA, highlighting the enhanced fidelity of 3D cultures in replicating tissue conditions compared to their 2D counterparts. The study highlights the effectiveness of 3D models over 2D in evaluating estrogenic activity. Specifically, the 3D T47D ERE-LUC system serves as a superior, sensitive, and reliable platform for screening EDCs, offering benefits in cost, data speed, and reduced in vivo reliance.

Humans↗

PubMed2026

Endocrine-disrupting chemical-induced gene networks confer coronary heart disease risk revealed by causal inference and single-cell analyses.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) are linked to coronary heart disease (CHD), but underlying mechanisms remain unclear. We aimed to identify EDC-related genes and evaluate their causal roles in CHD. METHODS: We curated EDC-related genes from a compound-gene interaction database and integrated them with CHD genome-wide association study (GWAS) summary statistics and tissue-specific expression quantitative trait loci (eQTL) data. Two-sample Mendelian randomization (MR) and Bayesian colocalization were applied to infer causality. Functional enrichment, single-cell RNA sequencing of human coronary arteries, and EDC-gene networks were further analyzed. RESULTS: After FDR correction, 39 genes were significantly associated with CHD risk via MR. Four genes-ZNF827, FCHO1, IPO9 (protective), and RPL13 (risk-increasing)-showed strong colocalization (PPH4 > 0.9). Pathway and single-cell analyses of coronary artery tissue indicated that vascular and immune pathways mediate these effects. An interaction network highlighted associations between specific EDCs and candidate genes implicated in CHD susceptibility. CONCLUSION: This integrative genomic study provides evidence that EDCs influence CHD susceptibility through distinct gene networks, revealing potential mechanisms and molecular targets for prevention and therapy.

Humans↗

PubMed2026

Bisphenols and their role in female infertility and hormone-related cancer.

Various types of external chemicals can disrupt the endocrine system, interfering with normal hormone function and causing a broad spectrum of negative health effects. Endocrine-disrupting chemicals (EDCs) are a diverse group of natural and synthetic chemicals that are known to contaminate the environment. It is postulated that these agents can contribute to the development of many diseases, including infertility and cancer, because of their ability to interfere with estrogen receptors (ERs). Bisphenols (BPs) are a group of compounds that belong to EDCs, the most common of which is bisphenol A (BPA). Due to restrictions on the use of BPA in industry, analogues such as bisphenol S (BPS) and bisphenol F (BPF) have been introduced. However, some reports indicate that BPA analogues also have negative effects on the endocrine system in both humans and animals because of their structural similarity. This review summarises current knowledge related to BPA, its analogues and their role in female infertility and hormone-related cancers. Furthermore, this review also points to the problem of exposure to more than one estrogenic agent and highlights the importance of considering exposure to multiple chemicals when assessing health effects and setting daily limits.

Humans↗

PubMed2025

Uncovering parental exposure risks of TCPP: Impaired development and metabolic homeostasis in zebrafish offspring.

As brominated flame retardants are phased out, tris (1‑chloro-2-propyl) phosphate (TCPP), a phosphorus-based flame retardant, has emerged as a prominent detectable flame retardant in the environment. However, TCPP has been found to exhibit endocrine-disrupting effects on organisms, raising significant safety concerns. In our study, we utilized the zebrafish model to explore the toxic effects of parental TCPP exposure on offspring and uncover its regulatory mechanisms through metabolomics analysis. Moreover, the impact on the nervous system and lipid metabolism was examined through behavioral analysis and specific staining. Our findings demonstrated that both embryonic and parental TCPP exposure induced developmental disorders in larvae, along with decreased locomotor activity and disordered lipid metabolism homeostasis. Parental exposure to TCPP, exhibiting stronger developmental toxicity than direct embryonic exposure, notably led to reductions in crucial energy substrates such as amino acids and carbohydrates. Meanwhile, embryonic TCPP exposure primarily affected the endogenous lipid-related metabolites including phospholipids, lipid-soluble vitamins, steroids and fatty acids, promoting lipid accumulation in larval liver and subcutaneous tissue. What's more, continuously parental and embryonic exposure showed the most pronounced effects on zebrafish development and metabolic regulation. Our study highlights the risk posed by parental exposure to TCPP on offspring zebrafish, underscoring the need for comprehensive consideration of the impact from parental exposure in pollutants regulation.

Animals↗

PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗

PubMed2023

Water a major source of endocrine-disrupting chemicals: An overview on the occurrence, implications on human health and bioremediation strategies.

Endocrine disrupting chemicals (EDCs) are toxic compounds that occur naturally or are the output of anthropogenic activities that negatively impact both humans and wildlife. A number of diseases are associated with these disruptors, including reproductive disorders, cardiovascular disorders, kidney disease, neurological disorders, autoimmune disorders, and cancer. Due to their integral role in pharmaceuticals and cosmetics, packaging companies, agro-industries, pesticides, and plasticizers, the scientific awareness on natural and artificial EDCs are increasing. As these xenobiotic compounds tend to bioaccumulate in body tissues and may also persist longer in the environment, the concentrations of these organic compounds may increase far from their original point of concentrations. Water remains as the major sources of how humans and animals are exposed to EDCs. However, these toxic compounds cannot be completely biodegraded nor bioremediated from the aqueous medium with conventional treatment strategies thereby requiring much more efficient strategies to combat EDC contamination. Recently, genetically engineered microorganism, genome editing, and the knowledge of protein and metabolic engineering has revolutionized the field of bioremediation thereby helping to breakdown EDCs effectively. This review shed lights on understanding the importance of aquatic mediums as a source of EDCs exposure. Furthermore, the review sheds light on the consequences of these EDCs on human health as well as highlights the importance of different remediation and bioremediation approaches. Particular attention is paid to the recent trends and perspectives in order to attain sustainable approaches to the bioremediation of EDCs. Additionally, rigorous restrictions to preclude the discharge of estrogenic chemicals into the environment should be followed in efforts to combat EDC pollution.

Animals↗