Chemical exposures often occur in mixtures and exposures during pregnancy may lead to adverse effects on the fetal brain, potentially reducing lower cognitive abilities and fine motor function of the child. We investigated the association of motheŕs exposure to a mixture of chemicals during pregnancy (i.e., organochlorine compounds, per- and polyfluoroalkyl substances, phenols, phthalates, organophosphate pesticides) with cognitive abilties and fine motor function in their children. We studied 1097 mother-child pairs from five European cohorts participating in the Human Early Life Exposome study (HELIX). Measurement of 26 biomarkers of exposure to chemicals was performed on urine or blood samples of pregnant women (mean age 31 years). Cognitive abilities and fine motor function were assessed in their children (mean age 8 years) with a battery of computerized tests administered in person (Raveńs Coloured Progressive Matrices, Attention Network Test, N-back Test, Trail Making Test, Finger Tapping Test). We estimated the joint effect of prenatal exposure to chemicals on cognitive abilities and fine motor function using the quantile-based g-computation method, adjusting for sociodemographic characteristics. A quartile increase in all the chemicals in the overall mixture was associated with worse fine motor function, specifically lower scores in the Finger Tapping Test [-8.5 points, 95 % confidence interval (CI) -13.6 to -3.4; -14.5 points, 95 % CI -22.4 to -6.6, and -18.0 points, 95 % CI -28.6 to -7.4) for the second, third and fourth quartile of the overal mixture, respectively, when compared to the first quartile]. Organochlorine compounds, phthalates, and per- and polyfluoroalkyl substances contributed most to this association. We did not find a relationship with cognitive abilities. We conclude that exposure to chemical mixtures during pregnancy may influence neurodevelopment, impacting fine motor function of the offspring.
- MeSH
- chlorované uhlovodíky * MeSH
- dítě MeSH
- dospělí MeSH
- fluorokarbony * MeSH
- kognice MeSH
- kyseliny ftalové * MeSH
- látky znečišťující životní prostředí * toxicita MeSH
- lidé MeSH
- matka - expozice noxám škodlivé účinky MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Z endokrinních disruptorů, látek, které zasahují do endokrinní regulace, některé významně ovlivňují tvorbu a distribuci bílého tuku. Označujeme je za obesogeny. Obesogenní vlastnosti byly dosud detailněji testovány různými metodami in vivo a in vitro jen na malém počtu několika desítek látek, většinou aditiv do potravin, jako jsou konzervační prostředky, ochucovadla včetně umělých sladidel, fruktóza, emulzifikátory a barviva. K jejich účinku vedou různé mechanismy stručně uvedené s příklady v této práci.
Some of the endocrine disruptors, compounds that affect endocrine regulations, greatly influence the formation and distribution of white fat. We name them obesogens. The obesogenic characteristics were tested until now by various detailed methods in vitro and in vivo only on a small scale for dozens of compounds, mainly additives to food: preservatives or flavours including artificial sweeteners, fructose, emulsifiers, and colours. Various mechanisms effect the functioning of obesogens; those mechanisms are briefly presented in this article.
- Klíčová slova
- obesogeny,
- MeSH
- adipogeneze MeSH
- endokrinní disruptory analýza škodlivé účinky toxicita MeSH
- látky znečišťující životní prostředí * analýza škodlivé účinky toxicita MeSH
- lidé MeSH
- obezita chemicky indukované etiologie MeSH
- potraviny škodlivé účinky MeSH
- techniky in vitro metody MeSH
- vystavení vlivu životního prostředí škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Cell-based bioassays are very sensitive and allow integrative effect screening of the whole environmental sample, which is usually composed of a mixture of agonists and antagonists. Measured toxicity is usually expressed as a bioanalytical equivalent concentration. So far, it is not possible to distinguish which part of this value is caused by the agonists and which by the antagonists. In this article, we present a simple method to analyze the dose-response curve of a mixture and to determine an agonistic bioanalytical equivalent concentration: a concentration of a reference chemical that would elicit the same effect as do only agonists in an unknown mixture. The method has been validated using several artificially prepared mixtures of agonists and competitive antagonists measured in a recombinant yeast assay. No difference was observed between the calculated equivalent concentrations and the used concentrations of the agonist in the mixture.
- MeSH
- biotest metody MeSH
- endokrinní disruptory * MeSH
- estradiol farmakologie MeSH
- estriol farmakologie MeSH
- fulvestrant farmakologie MeSH
- látky znečišťující životní prostředí toxicita MeSH
- lékové interakce MeSH
- receptory pro estrogeny antagonisté a inhibitory MeSH
- Saccharomyces cerevisiae účinky léků MeSH
- teoretické modely MeSH
- Publikační typ
- časopisecké články MeSH
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.
Sphingolipids (SLs) are important signaling molecules and functional components of cellular membranes. Although SLs are known as crucial regulators of neural cell physiology and differentiation, modulations of SLs by environmental neurotoxicants in neural cells and their neuronal progeny have not yet been explored. In this study, we used in vitro models of differentiated neuron-like cells, which were repeatedly exposed during differentiation to model environmental toxicants, and we analyzed changes in sphingolipidome, cellular morphology and gene expression related to SL metabolism or neuronal differentiation. We compared these data with the results obtained in undifferentiated neural cells with progenitor-like features. As model polychlorinated organic pollutants, we used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3'-dichlorobiphenyl (PCB11) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153). PCB153 revealed itself as the most prominent deregulator of SL metabolism and as potent toxicant during early phases of in vitro neurogenesis. TCDD exerted only minor changes in the levels of analysed lipid species, however, it significantly changed the rate of pro-neuronal differentiation and deregulated expression of neuronal markers during neurogenesis. PCB11 acted as a potent disruptor of in vitro neurogenesis, which induced significant alterations in SL metabolism and cellular morphology in both differentiated neuron-like models (differentiated NE4C and NG108-15 cells). We identified ceramide-1-phosphate, lactosylceramides and several glycosphingolipids to be the most sensitive SL species to exposure to polychlorinated pollutants. Additionally, we identified deregulation of several genes related to SL metabolism, which may be explored in future as potential markers of developmental neurotoxicity.
- MeSH
- buněčná diferenciace účinky léků MeSH
- buněčné linie MeSH
- látky znečišťující životní prostředí toxicita MeSH
- neurogeneze účinky léků MeSH
- neurony účinky léků metabolismus MeSH
- neurotoxické syndromy etiologie genetika MeSH
- polychlorované bifenyly farmakologie toxicita MeSH
- polychlorované dibenzodioxiny toxicita MeSH
- sfingolipidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The contribution of environmental pollutants to the obesity pandemic is still not yet fully recognized. Elucidating possible cellular and molecular mechanisms of their effects is of high importance. Our study aimed to evaluate the effect of chronic, 21-day-long, 2,2-bis (4-chlorophenyl)-1,1-dichlorethylenedichlorodiphenyldichloroethylene (p,p'-DDE) exposure of human adipose-derived mesenchymal stem cells committed to adipogenesis on mitochondrial oxygen consumption on days 4, 10, and 21. In addition, the mitochondrial membrane potential (MMP), the quality of the mitochondrial network, and lipid accumulation in maturing cells were evaluated. Compared to control differentiating adipocytes, exposure to p,p'-DDE at 1 μM concentration significantly increased basal (routine) mitochondrial respiration, ATP-linked oxygen consumption and MMP of intact cells on day 21 of adipogenesis. In contrast, higher pollutant concentration seemed to slow down the gradual increase in ATP-linked oxygen consumption typical for normal adipogenesis. Organochlorine p,p'-DDE did not alter citrate synthase activity. In conclusion, in vitro 1 μM p,p'-DDE corresponding to human exposure is able to increase the mitochondrial respiration per individual mitochondrion at the end of adipocyte maturation. Our data reveal that long-lasting exposure to p,p'-DDE could interfere with the metabolic programming of mature adipocytes.
- MeSH
- adipogeneze účinky léků MeSH
- buněčná diferenciace účinky léků MeSH
- dichlordifenyldichlorethylen toxicita MeSH
- kultivované buňky MeSH
- látky znečišťující životní prostředí toxicita MeSH
- lidé MeSH
- membránový potenciál mitochondrií MeSH
- mezenchymální kmenové buňky cytologie účinky léků MeSH
- mitochondrie účinky léků MeSH
- obezita metabolismus MeSH
- tukové buňky cytologie účinky léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Polycyclic aromatic hydrocarbons (PAHs) represent a class of widely distributed environmental pollutants that have been primarily studied as genotoxic compounds. Their mutagenicity/genotoxicity largely depends on their oxidative metabolism leading to the production of dihydrodiol epoxide metabolites, as well as additional metabolites contributing to oxidative DNA damage, such as PAH quinones. However, both parental PAHs and their metabolites, including PAH quinones or hydroxylated PAHs, have been shown to produce various types of non-genotoxic effects. These include e.g., activation of the aryl hydrocarbon receptor and/or additional nuclear receptors, activation of membrane receptors, including tyrosine kinases and G-protein coupled receptors, or activation of intracellular signaling pathways, such as mitogen-activated protein kinases, Akt kinase and Ca2+-dependent signaling. These pathways may, together with the cellular DNA damage responses, modulate cell proliferation, cell survival or cell-to-cell communication, thus contributing to the known carcinogenic effects of PAHs. In the present review, we summarize some of the known non-genotoxic effects of PAHs, focusing primarily on those that have also been shown to be modulated by PAH metabolites. Despite the limitations of the available data, it seems evident that more attention should be paid to the discrimination between the potential non-genotoxic effects of parental PAHs and those of their metabolites. This may provide further insight into the mechanisms of toxicity of this large and diverse group of environmental pollutants.
- MeSH
- látky znečišťující životní prostředí farmakokinetika toxicita MeSH
- lidé MeSH
- metabolická aktivace MeSH
- mutageny farmakokinetika toxicita MeSH
- oxidační stres MeSH
- polycyklické aromatické uhlovodíky farmakokinetika toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
