The increasing use of industrial chemicals has raised concerns regarding exposure to endocrine-disrupting chemicals (EDCs), which interfere with developmental, reproductive and metabolic processes. Of particular concern is their interaction with adipose tissue, a vital component of the endocrine system regulating metabolic and hormonal functions. The SGBS (Simpson Golabi Behmel Syndrome) cell line, a well-established human-relevant model for adipocyte research, closely mimics native adipocytes' properties. It responds to hormonal stimuli, undergoes adipogenesis and has been successfully used to study the impact of EDCs on adipose biology. In this study, we screened human exposure-relevant doses of various EDCs on the SGBS cell line to investigate their effects on viability, lipid accumulation and adipogenesis-related protein expression. Submicromolar doses were generally well tolerated; however, at higher doses, EDCs compromised cell viability, with cadmium chloride (CdCl2) showing the most pronounced effects. Intracellular lipid levels remained unaffected by EDCs, except for tributyltin (TBT), used as a positive control, which induced a significant increase. Analysis of adipogenesis-related protein expression revealed several effects, including downregulation of fatty acid-binding protein 4 (FABP4) by dibutyl phthalate, upregulation by CdCl2 and downregulation of perilipin 1 and FABP4 by perfluorooctanoic acid. Additionally, TBT induced dose-dependent upregulation of C/EBPα, perilipin 1 and FABP4 protein expression. These findings underscore the importance of employing appropriate models to study EDC-adipocyte interactions. Conclusions from this research could guide strategies to reduce the negative impacts of EDC exposure on adipose tissue.

• Klíčová slova
• SGBS cells, Simpson Golabi Behmel Syndrome cell line, adipocyte, adipogenesis, endocrine disruptors,
• MeSH
• adipogeneze * účinky léků   MeSH
• buněčné linie MeSH
• endokrinní disruptory * toxicita   MeSH
• fluorokarbony toxicita   MeSH
• kapryláty toxicita   MeSH
• lidé MeSH
• metabolismus lipidů účinky léků   MeSH
• proteiny vázající mastné kyseliny * metabolismus   genetika   MeSH
• trialkylcínové sloučeniny toxicita   MeSH
• tuková tkáň účinky léků   metabolismus   MeSH
• tukové buňky účinky léků   metabolismus   MeSH
• viabilita buněk * účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endokrinní disruptory * MeSH
• FABP4 protein, human MeSH Prohlížeč
• fluorokarbony MeSH
• kapryláty MeSH
• perfluorooctanoic acid MeSH Prohlížeč
• proteiny vázající mastné kyseliny * MeSH
• trialkylcínové sloučeniny MeSH
• tributyltin MeSH Prohlížeč

The prevalence of metabolic diseases, such as obesity, diabetes, metabolic syndrome and chronic liver diseases among others, has been rising for several years. Epidemiology and mechanistic (in vivo, in vitro and in silico) toxicology have recently provided compelling evidence implicating the chemical environment in the pathogenesis of these diseases. In this review, we will describe the biological processes that contribute to the development of metabolic diseases targeted by metabolic disruptors, and will propose an integrated pathophysiological vision of their effects on several organs. With regard to these pathomechanisms, we will discuss the needs, and the stakes of evolving the testing and assessment of endocrine disruptors to improve the prevention and management of metabolic diseases that have become a global epidemic since the end of last century.

• Klíčová slova
• TBT, appetite, bisphenol, dioxin, inflammation, insulin resistance, microbiota, perfluorinated compounds, phthalate,
• MeSH
• endokrinní disruptory * toxicita   MeSH
• fenoly MeSH
• lidé MeSH
• metabolický syndrom * MeSH
• obezita chemicky indukované   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• endokrinní disruptory * MeSH
• fenoly MeSH

Phthalates are endocrine disruptors frequently occurring in the general and industrial environment and in many industrial products. Moreover, they are also suspected of being carcinogenic, teratogenic, and mutagenic, and they show diverse toxicity profiles depending on their structures. The European Union and the United States Environmental Protection Agency (US EPA) have included many phthalates in the list of priority substances with potential endocrine-disrupting action. They are: dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butylbenzyl phthalate (BBP), diethylhexyl phthalate (DEHP), di-iso-nonyl phthalate (DINP), di-iso-decyl phthalate (DIDP), di-n-decyl phthalate (DnDP), and dioctyl phthalate (DOP). There is an ever-increasing demand for new analytical methods suitable for monitoring different phthalates in various environmental, biological, and other matrices. Separation and spectrometric methods are most frequently used. However, modern electroanalytical methods can also play a useful role in this field because of their high sensitivity, reasonable selectivity, easy automation, and miniaturization, and especially low investment and running costs, which makes them suitable for large-scale monitoring. Therefore, this review outlines possibilities and limitations of various analytical methods for determination of endocrine-disruptor phthalate esters in various matrices, including somewhat neglected electroanalytical methods.

• Klíčová slova
• Carcinogens, endocrine disruptors, phthalates,
• MeSH
• elektrochemické techniky * MeSH
• endokrinní disruptory analýza   MeSH
• estery analýza   MeSH
• kyseliny ftalové analýza   MeSH
• molekulární struktura MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• endokrinní disruptory MeSH
• estery MeSH
• kyseliny ftalové MeSH
• phthalic acid MeSH Prohlížeč

The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.

• Klíčová slova
• Airborne polychlorinated biphenyls, Endocrine disruption, HydroxyLated PCBs, Metabolism of xenobiotics, Tumor promotion,
• MeSH
• buněčné linie MeSH
• endokrinní disruptory metabolismus   toxicita   MeSH
• epitelové buňky účinky léků   MeSH
• hydroxylace MeSH
• konstitutivní androstanový receptor MeSH
• látky znečišťující vzduch toxicita   MeSH
• lidé MeSH
• nádory metabolismus   MeSH
• polychlorované bifenyly metabolismus   toxicita   MeSH
• pregnanový X receptor MeSH
• receptory cytoplazmatické a nukleární metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• steroidní receptory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endokrinní disruptory MeSH
• konstitutivní androstanový receptor MeSH
• látky znečišťující vzduch MeSH
• polychlorované bifenyly MeSH
• pregnanový X receptor MeSH
• receptory cytoplazmatické a nukleární MeSH
• steroidní receptory MeSH

ERGO (EndocRine Guideline Optimization) is the acronym of a European Union-funded research and innovation action, that aims to break down the wall between mammalian and non-mammalian vertebrate regulatory testing of endocrine disruptors (EDs), by identifying, developing and aligning thyroid-related biomarkers and endpoints (B/E) for the linkage of effects between vertebrate classes. To achieve this, an adverse outcome pathway (AOP) network covering various modes of thyroid hormone disruption (THD) in multiple vertebrate classes will be developed. The AOP development will be based on existing and new data from in vitro and in vivo experiments with fish, amphibians and mammals, using a battery of different THDs. This will provide the scientifically plausible and evidence-based foundation for the selection of B/E and assays in lower vertebrates, predictive of human health outcomes. These assays will be prioritized for validation at OECD (Organization for Economic Cooperation and Development) level. ERGO will re-think ED testing strategies from in silico methods to in vivo testing and develop, optimize and validate existing in vivo and early life-stage OECD guidelines, as well as new in vitro protocols for THD. This strategy will reduce requirements for animal testing by preventing duplication of testing in mammals and non-mammalian vertebrates and increase the screening capacity to enable more chemicals to be tested for ED properties.

• Klíčová slova
• AOP, IATA, OECD, adverse outcome pathway, biomarkers, cross-species extrapolation, endocrine disruption, integrated approach to testing and assessment, test guideline, thyroid hormone disruption,
• MeSH
• biologické markery MeSH
• biotest * metody   MeSH
• druhová specificita MeSH
• endokrinní disruptory škodlivé účinky   analýza   MeSH
• endokrinní systém účinky léků   metabolismus   MeSH
• hodnocení rizik MeSH
• hodnocení vlivů na zdraví MeSH
• lidé MeSH
• monitorování životního prostředí * metody   MeSH
• průběh práce MeSH
• skladování dat MeSH
• zdravotnické plány - realizace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• endokrinní disruptory MeSH

Triclosan and Triclocarban, preservatives widely used in cosmetics and other consumer products, underwent evaluation using a battery of new-approach methodologies in vitro (NAMs). Specifically, the Microplate Ames Test (MPF™ Test, Xenometrix, Allschwil, Switzerland) was employed to assess mutagenicity, the Comet assay in vitro on the HaCat cell line and the Mammalian Chromosome Aberration Test were utilized to evaluate genotoxicity, and the XenoScreen® YES/YAS assay was applied to investigate endocrine disruption. The chemicals did not exhibit any positive responses for mutagenicity. However, the mammalian chromosome aberration test identified both chemicals as being positive for genotoxicity at 10 µg/mL. In the Comet assay, the percentage of DNA in the tail significantly increased in a concentration-dependent manner (at 5 and 10 µg/mL for Triclosan, at 2.5, 5, and 10 µg/mL for Triclocarban). The positive response depended on the increasing concentration and the duration of exposure. Triclosan, but not Triclocarban in any of the endocrine assays performed, indicated a potential for endocrine activity in the anti-estrogenic and anti-androgenic assays. The positive in vitro results detected were obtained for concentrations relevant to final products. The alarming findings obtained with the use of new-approach methodologies (NAMs) justify the current precautionary regulatory approach, limiting the use of these preservatives.

• Klíčová slova
• Ames test, Comet assay, chromosome aberrations, endocrine disruption, genotoxicity/mutagenicity, preservatives,
• Publikační typ
• časopisecké články MeSH

Ambient air pollution and smoking are well-documented risk factors for male infertility. Prevalent air pollutants and cigarette smoke components, polycyclic aromatic hydrocarbons (PAHs), are environmental and occupational toxicants that act as chemicals disrupting endocrine regulation and reproductive potential in males. Testicular gap junctional intercellular communication (GJIC) is critical for normal development and function of testicular tissue, thus we assessed GJIC as a process potentially targeted by PAHs in testes. Lower MW PAHs with a bay or bay-like region rapidly dysregulated GJIC in Leydig TM3 cells by relocalization of major testicular gap junctional protein connexin 43 (Cx43) from plasma membrane to cytoplasm. This was associated with colocalization between Cx43 and ubiquitin in intracellular compartments, but without any effect on Cx43 degradation rate or steady-state Cx43 mRNA levels. A longer exposure to active PAHs decreased steady-state levels of full-length Cx43 protein and its 2 N-truncated isoforms. Inhibition of GJIC by PAHs, similarly to a prototypic GJIC-inhibitor TPA, was mediated via the MAP kinase-Erk1/2 and PKC pathways. Polycyclic aromatic hydrocarbon-induced GJIC dysregulation in testes was cell-type-specific because neither PAH dysregulated GJIC in Sertoli TM4 cells, despite PAHs were rapidly taken up by both Leydig TM3 as well as Sertoli TM4 cells. Because TPA effectively dysregulated GJIC in both testicular cell types, a unique regulator of GJIC targeted by PAHs might exist in Leydig TM3 cells. Our results indicate that PAHs could be a potential etiological agent contributing to reproductive dysfunctions in males through an impairment of testicular GJIC and junctional and/or nonjunctional functions of Cx43.

• Klíčová slova
• Cx43 truncated isoforms, connexins, endocrine disruptors, gap junctional intercellular communication, polycyclic aromatic hydrocarbons, testicular cells,
• MeSH
• buněčné linie MeSH
• endokrinní disruptory chemie   toxicita   MeSH
• fosforylace MeSH
• konexin 43 genetika   metabolismus   MeSH
• Leydigovy buňky účinky léků   metabolismus   patologie   MeSH
• mezerový spoj účinky léků   metabolismus   patologie   MeSH
• mezibuněčná komunikace účinky léků   MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• myši MeSH
• polycyklické aromatické uhlovodíky chemie   toxicita   MeSH
• Sertoliho buňky účinky léků   metabolismus   patologie   MeSH
• signální transdukce MeSH
• viabilita buněk účinky léků   MeSH
• zátoková oblast polycyklických aromatických uhlovodíků MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endokrinní disruptory MeSH
• GJA1 protein, mouse MeSH Prohlížeč
• konexin 43 MeSH
• mitogenem aktivované proteinkinasy MeSH
• polycyklické aromatické uhlovodíky MeSH

BACKGROUND AND AIM: Endocrine disrupting chemicals (EDCs) constitute a major public health concern because they can induce a large spectrum of adverse effects by interfering with the hormonal system. Rapid identification of potential EDCs using in vitro screenings is therefore critical, particularly for chemicals of emerging concerns such as replacement flame retardants (FRs). The review aimed at identifying (1) data gaps and research needs regarding endocrine disrupting (ED) properties of replacement FRs and (2) potential EDCs among these emerging chemicals. METHODS: A systematic search was performed from open literature and ToxCast/Tox21 programs, and results from in vitro tests on the activities of 52 replacement FRs towards five hormone nuclear receptors (NRs) associated with reproductive outcomes (estrogen, androgen, glucocorticoid, progesterone, and aryl hydrocarbon receptors) were compiled and organized into tables. Findings were complemented with information from structure-based in silico model predictions and in vivo information when relevant. RESULTS: For the majority of the 52 replacement FRs, experimental in vitro data on activities towards these five NRs were either incomplete (15 FRs) or not found (24 FRs). Within the replacement FRs for which effect data were found, some appeared as candidate EDCs, such as triphenyl phosphate (TPhP) and tris(1,3-dichloropropyl)phosphate (TDCIPP). The search also revealed shared ED profiles. For example, anti-androgenic activity was reported for 19 FRs and predicted for another 21 FRs. DISCUSSION: This comprehensive review points to critical gaps in knowledge on ED potential for many replacement FRs, including chemicals to which the general population is likely exposed. Although this review does not cover all possible characteristics of ED, it allowed the identification of potential EDCs associated with reproductive outcomes, calling for deeper evaluation and possibly future regulation of these chemicals. By identifying shared ED profiles, this work also raises concerns for mixture effects since the population is co-exposed to several FRs and other chemicals.

• Klíčová slova
• Emerging contaminants, Endocrine disruption, Flame retardants, Nuclear receptors, Steroid hormones, ToxCast,
• MeSH
• endokrinní disruptory * toxicita   MeSH
• fosfáty MeSH
• lidé MeSH
• receptory cytoplazmatické a nukleární MeSH
• retardanty hoření * toxicita   MeSH
• rozmnožování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• endokrinní disruptory * MeSH
• fosfáty MeSH
• receptory cytoplazmatické a nukleární MeSH
• retardanty hoření * MeSH

A decline in male fertility possibly caused by environmental contaminants, namely endocrine-disrupting chemicals (EDCs), is a topic of public concern and scientific interest. This study addresses a specific role of testicular gap junctional intercellular communication (GJIC) between adjacent prepubertal Leydig cells in endocrine disruption and male reproductive toxicity. Organochlorine pesticides (lindane, methoxychlor, DDT), industrial chemicals (PCB153, bisphenol A, nonylphenol and octylphenol) as well as personal care product components (triclosan, triclocarban) rapidly dysregulated GJIC in murine Leydig TM3 cells. The selected GJIC-inhibiting EDCs (methoxychlor, triclosan, triclocarban, lindane, DDT) caused the immediate GJIC disruption by the relocation of gap junctional protein connexin 43 (Cx43) from the plasma membrane and the alternation of Cx43 phosphorylation pattern (Ser368, Ser279, Ser282) of its full-length and two N-truncated isoforms. After more prolonged exposure (24 h), EDCs decreased steady-state levels of full-length Cx43 protein and its two N-truncated isoforms, and eventually (triclosan, triclocarban) also tight junction protein Tjp-1. The disturbance of GJIC was accompanied by altered activity of mitogen-activated protein kinases MAPK-Erk1/2 and MAPK-p38, and a decrease in stimulated progesterone production. Our results indicate that EDCs might disrupt testicular homeostasis and development via disruption of testicular GJIC, a dysregulation of junctional and non-junctional functions of Cx43, activation of MAPKs, and disruption of an early stage of steroidogenesis in prepubertal Leydig cells. These critical disturbances of Leydig cell development and functions during a prepubertal period might be contributing to impaired male reproduction health later on.

• Klíčová slova
• Connexins, Endocrine-disrupting chemicals, Gap junctional intercellular communication, Leydig cells, Reproductive toxicants, Steroidogenesis,
• MeSH
• endokrinní disruptory toxicita   MeSH
• fenoly toxicita   MeSH
• konexin 43 genetika   metabolismus   MeSH
• Leydigovy buňky účinky léků   MeSH
• mezibuněčná komunikace účinky léků   MeSH
• myši MeSH
• signální transdukce účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endokrinní disruptory MeSH
• fenoly MeSH
• GJA1 protein, mouse MeSH Prohlížeč
• konexin 43 MeSH
• nonylphenol MeSH Prohlížeč

Many xenobiotic compounds with endocrine disrupting activity have been described since the late eighties. These compounds are able to interact with natural hormone systems and potentially induce deleterious effects in wildlife, notably piscine species. However, while the characterization of endocrine disruptors with "dioxin-like", estrogenic or androgenic activities is relatively well established, little is known about environmentally relevant pollutants that may act at thyroid system level. Iodothyronine deiodinases, the key enzymes in the activation and inactivation of thyroid hormones, have been suggested as suitable biomarkers for thyroid metabolism disruption. The present article reviews the biotic and abiotic factors that are able to modulate deiodinases in teleosts, a representative model organism for vertebrates. Data show that deiodinases are highly sensitive to several physiological and physical variables, so they should be taken into account to establish natural basal deiodination patterns to further understand responses under chemical exposure. Among xenobiotic compounds, brominated flame retardants are postulated as chemicals of major concern because of their similar structure shared with thyroid hormones. More ambiguous results are shown for the rest of compounds, i.e. polychlorinated biphenyls, perfluorinated chemicals, pesticides, metals and synthetic drugs, in part due to the limited information available. The different mechanisms of action still remain unknown for most of those compounds, although several hypothesis based on observed effects are discussed. Future tasks are also suggested with the aim of moving forward in the full characterization of chemical compounds with thyroid disrupting activity.

• Klíčová slova
• Environmental pollutants, Iodothyronine deiodinases, Physical factors, Teleosts, Thyroid disruption,
• MeSH
• biologické markery metabolismus   MeSH
• biologické modely MeSH
• endokrinní disruptory škodlivé účinky   MeSH
• hormony štítné žlázy chemie   metabolismus   MeSH
• jodidperoxidasa chemie   metabolismus   MeSH
• látky znečišťující životní prostředí škodlivé účinky   MeSH
• molekulární struktura MeSH
• referenční hodnoty MeSH
• retardanty hoření škodlivé účinky   MeSH
• ryby metabolismus   MeSH
• štítná žláza účinky léků   metabolismus   MeSH
• xenobiotika škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• endokrinní disruptory MeSH
• hormony štítné žlázy MeSH
• jodidperoxidasa MeSH
• látky znečišťující životní prostředí MeSH
• retardanty hoření MeSH
• xenobiotika MeSH