The research performed in EDC-MixRisk helps to expand our knowledge on mixtures of endocrine disrupting chemicals. Meet our EDC-MixRisk scientists and hear their story on what they are doing and why it is important. This time in line is Efthymia Kitraki (PhD), professor of Biology and Head of the Laboratory of Basic Biomedical Sciences, in the School of Health Sciences University of Athens, Greece. Her experimental approaches include in vivo manipulations and behavioural testing of small rodents, followed by in vitro analysis of the tissues using cellular and molecular techniques.
What is the focus of your research group in EDC-MixRisk?
Our research group is studying the effects of in utero exposure of mice to mixtures of EDCs. The exposed offspring of both sexes are tested at postnatal days 21(weaning) and 90 (adulthood).
We are mainly interested in the potential effects of Mixture N1 (neurodevelopment) on the neuroendocrine axis of stress response.
Additional goals are: investigation of the potential effects of Mixture G1 (growth and metabolism) on the development of brain areas implicated in cognition and of Mixture S (sexual development) on the gonadal function.
What have you discovered so far?
We had a first set of mixtures, mixtures G0 (growth and metabolism), N0 (neurodevelopment), and S0 (sexual development) as they, in the respective dilution, reflect a “typically-measured” mixture of EDCs in the SELMA mothers. Given the inability to use Mixtures N0 and G0 (due to different kinetics of persistent and non-persistent compounds in the same mixture) we are presently studying the effects of Mix S0. Anogenital distance (AGD) is used as a measurement of genital development. Preliminary results show alterations in AGD and AGD/bw (AGD index), especially in male offspring at concentrations 0.4mM and 4mM of Mix S0 (stock 1M), but not at 20mM. Experiments are ongoing by exposing animals at 0.02mM (corresponds to SELMA levels). Analyses of gonadal histology and expression of steroidogenesis- and differentiation-related genes are in process.
What are the potential implications of your findings?
The detected alterations in AGD index are in line with those observed in the SELMA study for the boys exposed in utero to a mixture comprised mainly by the same ‘bad’ chemicals. Our preliminary data are also in compliance with the literature on the effects of individual components of our Mixture S0 in rodents. The observed alterations of AGD index, a biomarker of prenatal exposure to endocrine disruptors, if linked to molecular/hormonal indices of gonadal dysfunction in our study, could provide a pathway of adversity due to exposure to this mixture.
2nd International Fresenius MIXTOX Conference “Toxicity of Chemical Mixtures: Risk, Hazard and Exposure Assessment” will be organized in Cologne, Germany 8‐9 June 2017. Prof. Åke Bergman, EDC-MixRisk Coordinator, will give some insights and provide an overview of EDC-MixRisk at the conference. The title of his talk is EDC-MixRisk – a novel approach for assessing EDCs.
More information and programme of the conferece is available here.
A very recently published study carried out by CNRS flags that exposure to endocrine disrupting chemicals (EDCs) causes changes in thyroid hormone signalling, which may disturb brain development. Frog embryos were exposed to a mixture of 15 chemicals commonly present in the fluid of a human mother’s womb.
The results of the study demonstrate that a short exposure to the mixture (3 days) affected thryoid hormone signalling, but also altered brain gene expression, reduced neuron volume and inhibited tadpole movement. Furthermore, these findings can be placed in the context of recent epidemiological studies showing that small variations in maternal thyroid hormone during early pregnancy impact children’s IQ.
Professor Barbara Demeneix, an author of the paper and work package leader in EDC-MixRisk, says:
“Undisturbed thyroid signalling is essential for normal brain development in all vertebrates. Since thyroid hormone is exactly the same in frogs and humans, these findings should prompt rapid action to remove these harmful chemicals from the market.”
The results are published by Nature in a peer-reviewed paper in Scientific Reports entitled “Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos”. The full article is available here.
9th Copenhagen Workshop on Endocrine Disrupters – COW2017 will take place May 2-5, 2017 In Copenhagen, Denmark. The scientific programme will focus on reproduction and child health, which are both fundamental aspects of human health and more relevant than ever.
Several EDC-MixRisk researchers will participate in the workshop and present results of their research.
Dr. Pauliina Damdimopoulou’s group focuses on reproductive toxicology and recently, they have been working on a new technique obtained from Dr. Claus Andersen’s laboratory in Copenhagen. They have been isolating structures from within the ovary called follicles, which consist of supporting and nourishing cells surrounding the growing egg.
The group has successfully modified the technique learned in Copenhagen to isolate follicles from bovine and human ovaries, specifically focusing on an area of tissue called the cortex which contains the most follicles. The next step is culturing follicles for long periods of time, such as several days or weeks, so that the effects of chemical mixtures on egg development and health can be tested. The research will increase our understanding on whether chemicals can affect women’s fertility.
A growing follicle after 5 days of culture. The egg can be seen in the centre of several layers of supporting cells.
For more information on the research team:
The position is linked to EDC-MixRisk project and it is open at the Department of Environmental Science and Analytical Chemistry, Stockholm University. The Postdoctoral Fellow will contribute to the work package that concerns the development of a transparent and systematic risk assessment procedure that can integrate epidemiological and experimental research to facilitate the assessment of risk for EDCs and their mixtures.
Main responsibilities will include:
(1) To perform a risk assessment case study with a single chemical, using the recently proposed SYRINA framework for EDC risk assessment. SYRINA is described here: http://ehjournal.biomedcentral.com/articles/10.1186/s12940-016-0156-6. The case study includes performing all the steps outlined in SYRINA for a selected case chemical. The process will also be presented and discussed with all other scientists involved in the project.
(2) Together with other scientists in EDC-MixRisk, further develop the SYRINA framework to encompass also mixtures.
For more information, click here.
Meet our EDC-MixRisk scientists working behind the scenes. Prof. Chris Gennings shares her insights into the project. She is Professor of Biostatistics at the Icahn School of Medicine at Mount Sinai, NY, USA and her research focuses particularly on the design and statistical analysis methodologies for studies of chemical mixtures.
Hi Chris – What are you researching in EDC-MixRisk?
We are using the SELMA pregnancy cohort data to identify mixtures of endocrine disrupting chemicals (EDCs) measured in early pregnancy that are associated with health effects in each of three health domains for the children: neurodevelopment, metabolism and growth, and sexual development. Our strategy includes evaluation of chemicals across a wide range of chemical classes. Once the sets of ‘bad actors’ are identified, we calculate a ‘typical mixture’ from the SELMA cohort data for each health domain using pharmacokinetic modeling. These mixtures are then constructed and experimentally evaluated across the consortium.
What are the key results so far?
Important results so far include the identification of bad actors that are detected in all or nearly all of the pregnant women in the SELMA cohort. Second, these identified chemicals come from multiple chemical classes, indicating that focusing on single chemical classes may underestimate risk. Further, we have detected health effects from each of the three health domains, indicating the potential comorbidity associated with exposures to EDCs.
What these findings could implicate?
The strategy we use for identifying bad actors is based on the simultaneous evaluation of mixtures of chemicals related to a health effect, i.e., the so-called ‘mixture effect’. An advantage of this strategy is the inference is focused towards detecting the mixture effect and thereby has more power to find it. Single chemical analyses may not indicate statistically significant associations; but combining across components we detect higher signal. The potential consequences are that we may identify that current regulatory guidelines, which generally focus on single chemicals or single chemical classes, are not adequately protective.
The annual Consortium meeting will be organized in Stockholm, 15-17 May 2017. The first day of the meeting will focus on presenting some of the key results of EDC-MixRisk project as well as of EDC-2020 project. Also a workshop on Adverse Outcome Pathways will take place in the context of the meeting. The following days aim at discussing and reviewing the progress of the project and future plans.
Meet our EDC-MixRisk scientists working behind the scenes.
This time Dr. Hannu Kiviranta is in the spotlight: He is head of the Chemicals and Health Unit at the National Institute for Health and Welfare (THL), located in Kuopio, Finland. In EDC-MixRisk Project, Dr. Kiviranta is Work Package Leader in WP3 that focuses on chemical and biological analyses.
Hi Hannu – What is your research group investigating in EDC-MixRisk?
Our task is to measure persistent organic pollutant (PCBs, organochlorine pesticides, and polybrominated flame retardants) in two large European pregnancy cohort, namely SELMA and LIFE Child Study. These results will be utilized to identify critical EDC mixtures which will then be tested in various animal and cell models. In addition, these exposure estimates will be used in traditional epidemiological studies in order to find associations between exposure and health endpoints in focus in EDC-MixRisk Project.
What have you discovered so far?
We have so far analyzed all SELMA cohort serum samples from mothers and these results have been used for determining the next set of critical mixture, Mixture I, to be used by other partners in experimental studies.
What are the potential implications of your findings?
We will have interesting data of the exposure of fetus to persistent organic pollutants in two large birth cohorts and enhance our understanding of the total exposure fetus is facing during sensitive developing stage at early life. If these exposures, both with persistent and non-persistent chemicals, will be associated to those health endpoints studied in EDC-MixRisk (either through mixture studies or in epidemiological studies), the project will provide crucial data for risk assessment and to risk managers to take actions to reduce the exposures in the future.
The overall concept underpinning EDC-MixRisk is that early life exposure to EDC mixtures induces changes in the organism that underlie increased susceptibility to diseases during the entire life span. Three health domains will be addressed in the project: growth and metabolism, neurodevelopment, and sexual development. Furthermore, the project integrates research from three relevant scientific modules: 1) epidemiology, 2) experimental systems and 3) risk assessment and societal impact. In the epidemiological module, mixtures of EDCs are identified, through associations between exposure and health outcomes in the three domains. These mixtures are tested in different experimental systems relevant for the respective health outcomes, whereas the experimental data are integrated into the risk assessment methods developed in module 3.
In contrast to the vast majority of studies that focus on one chemical and one physiological outcome at the time, EDC-MixRisk has developed a multiple-exposure-to-multiple-outcome approach, which mimics the real life exposure situation. Our first results demonstrate that EDC mixtures associated with adverse health outcomes in population based epidemiology evoke relevant molecular and physiological effects in experimental systems in cells and animals, even at low concentrations. This demonstrates the validity of our approach in interacting between epidemiology and experimental toxicology and the need to take mixture effects into account for risk assessment. The major innovative potential of EDC-MixRisk lies within the improved risk assessment methodologies directly linked to the data obtained in the project, and strategies to systematically engage policy-relevant stakeholders. Improved regulatory processes will be important for the general populations globally, for national regulatory agencies and organizations; for chemicals manufacturing industry and down-stream users of these chemicals.
Read the full summary here