The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity.
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ABSTRACT:
SUBMITTER: Lupu D
PROVIDER: S-EPMC7312023 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity.
Lupu Diana D Andersson Patrik P Bornehag Carl-Gustaf CG Demeneix Barbara B Fritsche Ellen E Gennings Chris C Lichtensteiger Walter W Leist Marcel M Leonards Pim E G PEG Ponsonby Anne-Louise AL Scholze Martin M Testa Giuseppe G Tresguerres Jesus A F JAF Westerink Remco H S RHS Zalc Bernard B Rüegg Joëlle J
International journal of molecular sciences 20200601 11
Ubiquitous exposure to endocrine-disrupting chemicals (EDCs) has caused serious concerns about the ability of these chemicals to affect neurodevelopment, among others. Since endocrine disruption (ED)-induced developmental neurotoxicity (DNT) is hardly covered by the chemical testing tools that are currently in regulatory use, the Horizon 2020 research and innovation action ENDpoiNTs has been launched to fill the scientific and methodological gaps related to the assessment of this type of chemica ...[more]
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Project description:Exposure to chemical substances that can produce endocrine disrupting effects represents one of the most critical public health threats nowadays. In line with the regulatory framework implemented within the European Union (EU) to reduce the levels of endocrine disruptors (EDs) for consumers, new and effective methods for ED testing are needed. The OBERON project will build an integrated testing strategy (ITS) to detect ED-related metabolic disorders by developing, improving and validating a battery of test systems. It will be based on the concept of an integrated approach for testing and assessment (IATA). OBERON will combine (1) experimental methods (in vitro, e.g., using 2D and 3D human-derived cells and tissues, and in vivo, i.e., using zebrafish at different stages), (2) high throughput omics technologies, (3) epidemiology and human biomonitoring studies and (4) advanced computational models (in silico and systems biology) on functional endpoints related to metabolism. Such interdisciplinary framework will help in deciphering EDs based on a mechanistic understanding of toxicity by providing and making available more effective alternative test methods relevant for human health that are in line with regulatory needs. Data generated in OBERON will also allow the development of novel adverse outcome pathways (AOPs). The assays will be pre-validated in order to select the test systems that will show acceptable performance in terms of relevance for the second step of the validation process, i.e., the inter-laboratory validation as ring tests. Therefore, the aim of the OBERON project is to support the organization for economic co-operation and development (OECD) conceptual framework for testing and assessment of single and/or mixture of EDs by developing specific assays not covered by the current tests, and to propose an IATA for ED-related metabolic disorder detection, which will be submitted to the Joint Research Center (JRC) and OECD community.
| S-EPMC7216143 | biostudies-literature
Project description:The use of genomic approaches in toxicological studies has greatly increased our ability to define the molecular profiles of environmental chemicals associated with developmental neurotoxicity (DNT). Integration of these approaches with adverse outcome pathways (AOPs), a framework that translates environmental exposures to adverse developmental phenotypes, can potentially inform DNT testing strategies. Here, using retinoic acid (RA) as a case example, we demonstrate that the integration of toxicogenomic profiles into the AOP framework can be used to establish a paradigm for chemical testing. RA is a critical regulatory signaling molecule involved in multiple aspects of mammalian central nervous system (CNS) development, including hindbrain formation/patterning and neuronal differentiation, and imbalances in RA signaling pathways are linked with DNT. While the mechanisms remain unresolved, environmental chemicals can cause DNT by disrupting the RA signaling pathway. First, we reviewed literature evidence of RA and other retinoid exposures and DNT to define a provisional AOP related to imbalances in RA embryonic bioavailability and hindbrain development. Next, by integrating toxicogenomic datasets, we defined a relevant transcriptomic signature associated with RA-induced developmental neurotoxicity (RA-DNT) in human and rodent models that was tested against zebrafish model data, demonstrating potential for integration into an AOP framework. Finally, we demonstrated how these approaches may be systematically utilized to identify chemical hazards by testing the RA-DNT signature against azoles, a proposed class of compounds that alters RA-signaling. The provisional AOP from this study can be expanded in the future to better define DNT biomarkers relevant to RA signaling and toxicity.
| S-EPMC7736340 | biostudies-literature
Project description:Environmental health promotion interventions may reduce endocrine disruptor (ED) exposure. The PREVED (PREgnancy, preVention, Endocrine Disruptors) project was developed to improve knowledge, to enhance risk perception, and to change exposure behavior. Our objective was to present the phases of the PREVED project using the RE-AIM method. PREVED intervention consisted of three workshops during pregnancy. Reach, adoption, and implementation phases were assessed with qualitative studies. Efficacy study consisted of a three-arm randomized controlled trial (RCT) on 268 pregnant women: (i) control group (leaflet), (ii) intervention group in neutral location, (iii) intervention group in contextualized location. The main outcome was the percentage evolution of participants who reported consuming canned food. Secondary outcomes were evolution of psycho-social scores, evolution of ED presence in urine, and ED presence in colostrum. The intervention adoption was centered on upper-privileged women, but implementation assessment showed that key features (highly practical intervention) seemed to be carried out and had initiated some behavior changes. A total of 268 pregnant women participated in the intervention and 230 in a randomized controlled trial (control group: 86 and intervention groups: 172). We found no significant differences in consumption of canned food and in percentage of women having a decrease of bisphenol A or parabens in urine, but we found a significant increase in the evolution of risk perception score and overall psychosocial score in intervention groups (respectively: +15.73 control versus +21.03 intervention, p = 0.003 and +12.39 versus +16.20, p = 0.02). We found a significant difference in percentage of women with butylparaben detection between control group and intervention groups (13% versus 3%, p = 0.03). PREVED intervention is the first intervention research dedicated to perinatal environmental health education in France. By sharing know-how/experience in a positive non-alarmist approach, it improved risk perception, which is key to behavior change, aiming to reduce perinatal ED exposure. Including women in precarious situations remains a major issue.
| S-EPMC8750995 | biostudies-literature
Project description:Environmental reproductive health focuses on the effect of exposure to contaminants considered as endocrine disruptors. Developmental testis is considered as target of these compounds affecting testicular functions in adults and suspected implications in tumor etiology. Comparative analysis of gene expression in mouse testis exposed to five disruptors, three different dosages and three accumulative developmental stages shown defined signature profiles of gene deregulation for MEHP (monoethyl phthalate) and zearalenone (a phytoestrogen) and different to 17β-estradiol exposure. The effects are even detected in postpuberal male offspring from premating exposed mothers. Oxidative stress response, protein ubiquitination and oxidative phosphorylation are the most representative pathways affected.
2010-06-01 | GSE14774 | GEO
Project description:Environmental reproductive health focuses on the effect of exposure to contaminants considered as endocrine disruptors. Developmental testis is considered as target of these compounds affecting testicular functions in adults and suspected implications in tumor etiology. Comparative analysis of gene expression in mouse testis exposed to five disruptors, three different dosages and three accumulative developmental stages shown defined signature profiles of gene deregulation for MEHP (monoethyl phthalate) and zearalenone (a phytoestrogen) and different to 17β-estradiol exposure. The effects are even detected in postpuberal male offspring from premating exposed mothers. Oxidative stress response, protein ubiquitination and oxidative phosphorylation are the most representative pathways affected. Animal Exposure CD-1 mice were in vivo exposed to several doses of EDs following a defined protocol: mothers were exposed two weeks before mating (exposure A); the same exposure and dose were maintained during pregnancy (exposure B) and four weeks after birth (exposure C). In all exposures, male offspring were sacrificed to obtain the testes. The compounds were administrated in drinking water to a final concentration of: E2(mg/l) BPA(mg/l) Zea(mg/l) MEHP(mg/l) Lindane(mg/l) Dose (1) 0.02 0.5 4 27.85 50 Dose (2) 0.04 50 12 139.17 100 Dose (3) 0.16 200 20 278.34 200 Ethanol was used as vehicle for E2, BPA and Zea and DMSO was for MEHP and Lindane. Control testes were obtained from animals exposed to solvents of EDs: Ethanol and DMSO. Animal care and sacrifice were made following regulations from the CSIC Bioethics Committee. RNA preparation Total RNA from testes of exposed animals and controls was extracted using TRIzol reagent (Invitrogen), according to the manufacturer’s standard protocol. RNA samples were spectrophotometrically quantified using NanoDrop (NanoDrop Technologies). To minimize the effect of inter-individual expression variability we made pools of RNA from at least 3 individual RNA samples from each experimental condition (same quantity of total RNA per sample). Pools of RNA were checked for quality performing Experion analysis (Bio-Rad Laboratories). Total RNA from testes of unexposed four weeks old animals was also extracted with the purpose of making pools to assess the variability at the expression level of the mouse strain used (Ctr). Microarray Processing Starting with total RNA from pools described above, full length cDNAs were synthesized from oligo(dT) primers bearing a T7 promoter. These cDNAs were used as template for in vitro transcription by T7-RNA-Polymerase to amplify the mRNAs; following the Amino Allyl MessageAmp™ aRNA Kit (Ambion, Inc.) protocol. The amplified mRNAs (aRNA) were labeled either with Cy3 or Cy5 dyes, using Amersham CyDye Post-Labeling Reactive Dyes (Amersham Biosciences). The incorporated dye was spectrophotometrically quantified using NanoDrop (NanoDrop Technologies). The same dye signal quantities of labeled experimental and control aRNAs were mixed and hybridized to Mouse Oligoset v3 (OPERON) arrays from Genomics facility-University of Cincinnati (USA). The slides contained 31,769 spotted probes (70 mer oligonucleotides) corresponding to 24,878 expressed or predicted mouse genes. Hybridization and washes of microarrays were performed according to Genomics facility-University of Cincinnati instructions. Dye-Swap replicates were performed: one slide hybridized with experimental and control targets labeled with Cy3 and Cy5, respectively; and the second slide with the same type of targets but inversely labeled. Target refers to labeled aRNA while probe refers to the oligonucleotides spotted on the microarray platform. Imaging and data generation were carried out using a GenePix 4000B (Axon Instruments) and associated software from Axon Instruments, Inc. The microarray slides were scanned with dual lasers with wavelength frequencies to excite Cy3 and Cy5. Images were captured in TIFF files. Information extraction for a given spot was based on the median value for the signal pixels minus the median value for the background pixels to produce a gene set data file for all the DNA spots. The Cy3 and Cy5 fluorescence signal intensities were normalized.
2010-06-01 | E-GEOD-14774 | biostudies-arrayexpress
Project description:BackgroundProstaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics.Objectives and methodsUsing cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption.ResultsWe found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator-activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes.ConclusionOur findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades.
| S-EPMC3080937 | biostudies-literature
Project description:The placenta and its myriad functions are central to successful reproductive outcomes. These functions can be influenced by the environment encountered throughout pregnancy, thereby altering the appropriate genetic programming needed to allow for sustained pregnancy and appropriate fetal development. This altered programming may result from epigenetic alterations related to environmental exposures. Epigenetic alterations are now being linked to several important reproductive outcomes, including early pregnancy loss, intrauterine growth restriction, congenital syndromes, preterm birth, and preeclampsia. The diversity of environmental exposures linked to adverse reproductive effects continues to grow. Much attention has focused on the role of endocrine disruptors in infertility, but recent work suggests that these chemicals may also have adverse effects in pregnancy and development. Environmental oxygen is also critical in pregnancy success. There are clear links between altered oxygen levels and placentation amongst other effects. As research continues to enhance our understanding of the molecular processes including epigenetic regulation that influence pregnancy, it will be critical to specifically examine how the environment, broadly defined, may play a role in altering these critical functions.
| S-EPMC3050574 | biostudies-literature
Project description:Introduction: Data from last years suggested that early exposure to endocrine disruptors (EDs) can predispose newborns to endocrine dysfunction of adipocytes, obesity, and associated disorders. The implication of EDs at low doses on adipocyte development has been poorly investigated. For instance, vinclozolin (V) is a dicarboximide fungicide widely used in agriculture since the 90's, alone or in mixture with genistein (G), an isoflavonoid from Leguminosae. This study aims to identify the effect of vinclozolin alone or with genistein, on adipose tissue properties using cell culture. Methods: In steroid-free conditions, 3T3-L1 pre-adipocytes were induced to differentiate in the presence of EDs, singularly or in mixtures, for 2 days. DNA and triglyceride (TG) levels were measured on days 0, 2 and 8 of differentiation. Leptin secretion was measured only on the eighth day. Results: We show that low doses of G (25 µM) and V (0.1 µM) inhibit pre-adipocytes differentiation. This inhibition has been represented by a decreasing in DNA content (µg/well) and decreasing in TG accumulation (mg/mL) in 3T3-L1 cells. Nevertheless, V increased the anti-adipogenic properties of G. Conclusion: This study confirms that EDs singularly or in mixtures, introduced during early stages of life, could affect the differentiation and the endocrine activity of adipocytes, and can act as potential factors for obesity.
| S-EPMC5524989 | biostudies-literature
Project description:Evaluation of carcinogenic substances from the environment is a challenge for scientists. Recently, a novel approach based on 10 key characteristics of human carcinogens classified by the International Agency for Research on Cancer (IARC) has emerged. Carcinogenesis depends on different mechanisms and factors, including genetic, infectious (bacteria, viruses) and environmental (chemicals) factors. Endocrine disruptors are exogenous chemicals that can interfere and impair the function of the endocrine system due to their interaction with estrogen receptors or their estrogen signaling pathways inducing adverse effects in the normal mammary development, originating cancer. They are heterogeneous chemicals and include numerous synthetic substances used worldwide in agriculture, industry and consumer products. The most common are plasticizers, such as bisphenol A (BPA), pesticides, such as dichlorodiphenyltrichloroethane, and polychlorinated biphenyls (PCBs). Xenoestrogens appear to serve an important role in the increased incidence of breast cancer in the United States and numerous other countries. Several studies have demonstrated the role of organochlorine xenoestrogens in breast cancer. Therefore, the overall cumulative exposure of women to estrogens results in an increased risk for this type of cancer. Factors like lifestyle and diet also serve a role in the increased incidence of this disease. The aim of the present study was to analyze these chemical compounds based on the key characteristics given by the IARC, with a special focus on breast cancer, to establish whether these compounds are carcinogens, and to create a model for future analysis of other endocrine disruptors.
| S-EPMC7286136 | biostudies-literature
Project description:Introduction According to the World Health Organization, infertility is a public health problem that affects around 48 million couples and 186 million individuals worldwide. Endocrine disruptors are one of the causes that raise more concern, given that it is a problem that has evolved with the progress of society. Many chemicals are used by food industry, entering food chain, and directly affecting human health. Endocrine disruptors have the capacity of interfering with the normal hormonal action, metabolism, and biosynthesis, which can lead to a variation of the normal hormonal homeostasis. Some of these endocrine disruptors are highly associated with diseases that are positively correlated with female infertility, such as polycystic ovary syndrome, endometriosis, irregular menstrual cycle and also disturbances on processes as steroidogenesis and development of the ovarian follicles.ResultsThe present literature review covers various aspects of the possible relationship between endocrine disruptors and female infertility. Bisphenol A and its metabolites, phthalates, dioxins, organochlorine, and organophosphate compounds are groups of chemicals considered to have the capacity to disrupt endocrine activity and herein addressed. The results reported in in vivo studies and in clinical trials addressing endocrine disruptors and female infertility were discussed as well as their possible mechanism of action.ConclusionsLarge, double-blind, placebo-controlled randomized clinical trials are needed to better understand the mechanisms of action of endocrine disruptors in female infertility, as well as the doses and frequency of exposure responsible for it.
| S-EPMC10374778 | biostudies-literature