Learning from previous work and finding synergies in the domains of public and environmental health: EU-funded projects BRIDGE Health and HBM4EU.

During the last decade, the European Union initiated several projects in the domains of public and environmental health. Within this framework, BRIDGE Health (Bridging Information and Data Generation for Evidence-based Health policy and Research) and HBM4EU (European human biomonitoring initiative) have been implemented. Whereas, the focus of BRIDGE Health was towards a sustainable and integrated health information system (HIS), the aim of HBM4EU is to improve evidence of the internal exposure of European citizens to environmental chemicals by human biomonitoring (HBM) and the impact of internal exposure on health. As both, environmental and public health determinants are important for health promotion, disease prevention and policy, BRIDGE Health and HBM4EU have overlapping aims and outcomes. In order to improve health information regarding public health and environmental health issues, best use and exchange of respective networks and project results is necessary. Both projects have implemented health information (HI) and HBM tasks in order to provide adequate environmental and public health information of the European population. Synergies of the projects were identified in the working progress and because of overlapping networks and experts a focused analysis of both projects was envisaged. This paper elaborates on the aims and outcomes of both projects and the benefit of merging and channelling research results for the use of better health information and policy making that may be of relevance for any other project in these research fields. The need for focused exchanges and collaborations between the projects were identified and benefits of exchanges were highlighted for the specific areas of indicator development, linkage of data repositories and the combination of HBM studies and health examination surveys (HES). Further recommendations for a European wide harmonisation among different tasks in the fields of public health and environmental health are being developed. Lessons learned from HBM4EU and BRIDGE Health show that continuous efforts must be undertaken, also by succeeding projects, to guarantee the exchange between public health and environmental health issues. Networks covering both are essential to provide better evidence of knowledge. The experiences from BRIDGE Health and HBM4EU give a valuable input for any future activity in these domains. Avoiding overlaps and streamlining further exchange of public health and environmental health contributes to best use of research results and allows to develop new strategies and tools for improvement of health information and thus enhances people's health and well-being.This publication is funded from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 733032 (HBM4EU) and from the Federal Ministry for the Environment, Nature Conservation and Nuclear Safety of Germany (BMU) under FKZ 3716622000. Open Access funding provided by Projekt DEAL.S

Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers

The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols are widespread in modern life because of their industrial application as plasticisers. Bisphenol A (BPA) is the best-known member and has gained significant scientific as well as public attention as an endocrine disrupting chemical, a fact that eventually led to its replacement. However, compounds used to replace BPA still contain the molecular scaffold of bisphenols. BPA, BPAF, BPB, BPE, BPF, and an amine-substituted BPAF-derivate all interact with all GDP-bound Ras-Isoforms through binding to a common site on these proteins. NMR-, SOScat-, and GDI- assay-based data revealed a new bisphenol-induced, allosterically activated GDP-bound Ras conformation that define these plasticisers as Ras allosteric agonists

Comprehensive multidimensional NMR studies on the interaction between Ras-like GTPases and bisphenols

Die Interaktion von Proteinen mit organischen Molekülen ist essentiell für die Zell-Signaltransduktion, da diese auf eine dynamische Anpassung an Umweltfaktoren angewiesen ist. Zusätzlich bieten Protein-Ligand-Interaktionen die Möglichkeit medizinischer Intervention. In dieser Dissertation wird die Interaktion verschiedener Bisphenol-Liganden mit Ras-Proteinen, inklusive der Ras Isoformen (K-Ras4B, H-Ras, N-Ras) und Rap1A, mittels NMR-Spektroskopie untersucht. Es wurden ligandeninduzierte chemische Resonanzänderungen mittels 2D-HSQC-Spektren detektiert. Die genannten Ras-Isoformen weisen in ca. 15 % aller Krebsformen eine mutierte Aminosäure auf und gelten daher als Proto-Onkogene. Die untersuchten Bisphenole variieren in der Substituierung des zentralen Kohlenstoff-Atoms, sodass eine Struktur-Aktivitäts-Beziehung etabliert wurde, inklusive der Affinitätskonstante (K$_D$). Schlussendlich wird eine sog. Pseudoaktivierung der kleinen GTPasen durch die Bisphenole diskutiert

Analytical Methods for PFAS in Products and the Environment

Per- and polyfluoroalkyl substances (PFASs) are a large group of substances that have been widely used in articles since many years. They are found wherever extreme conditions prevail and particularly high demands are placed on materials. Their use spans over many different sectors ranging from fire-fighting foams to the manufacture of everyday articles like water-repellent outdoor jackets or stain-proofing agents.On the other side, PFASs are not easily degradable and can remain in the environment for decades. In addition, the use of PFASs has raised human and environmental concerns. In Europe, some PFASs are therefore classified as persistent, bioaccumulative and toxic (PBT) and very persistent and very bioaccumulative (vPvB) under the REACH Regulation. The following report provides an overview of currently available analytical methods for PFASs in different matrices.

Design, Synthesis, and Cytotoxicity of 5-Fluoro-2-methyl-6-(4-aryl-piperazin-1-yl) Benzoxazoles

To design new compounds suitable as starting points for anticancer drug development, we have synthesized a novel series of benzoxazoles with pharmaceutically advantageous piperazine and fluorine moieties attached to them. The newly synthesized benzoxazoles and their corresponding precursors were evaluated for cytotoxicity on human A-549 lung carcinoma cells and non-cancer HepaRG hepatocyes. Some of these new benzoxazoles show potential anticancer activity, while two of the intermediates show lung cancer selective properties at low concentrations where healthy cells are unaffected, indicating a selectivity window for anticancer compounds

Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers

The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols are widespread in modern life because of their industrial application as plasticisers. Bisphenol A (BPA) is the best-known member and has gained significant scientific as well as public attention as an endocrine disrupting chemical, a fact that eventually led to its replacement. However, compounds used to replace BPA still contain the molecular scaffold of bisphenols. BPA, BPAF, BPB, BPE, BPF, and an amine-substituted BPAF-derivate all interact with all GDP-bound Ras-Isoforms through binding to a common site on these proteins. NMR-, SOScat-, and GDI- assay-based data revealed a new bisphenol-induced, allosterically activated GDP-bound Ras conformation that define these plasticisers as Ras allosteric agonists

Environmental health surveillance in a future European health information system

Background: To date Health information (HI) in the European Union does not comprise indicators or other information related to impacts of hazardous chemicals in consumer products, food, drinking water or air on the health status of the population. Therefore, we inventorised and evaluated the potential of environmental health surveillance and research data sources in the European population to provide HBM-based indicators of internal human exposure and health impact of relevant chemicals. Methods: We established an up-dated inventory of European cross-sectional Human Biomonitoring (HBM) surveys and of birth cohorts, and compared chemicals and chemical groups addressed by HBM with indicators and health end points collected via European Core Health Indicators (ECHI), in birth registries, as well as in environmental and food data bases and health registries to see on how data collection could be aligned. Finally, we investigated study designs of HBM survey and health examination surveys for potential synergies. Results: The inventory covers a total of 11 European cross-sectional national programmes and a large number of birth cohorts and includes information on study population, age groups, covered substances, sampled matrices, and frequency. The comparison of data collections shows that there are many overlaps between environmental chemicals with environmental and health reporting. HBM data could be linked with ECHI indicators for work-related risks, body mass index (BMI), and low birth weight, with perinatal disease, neurologic disorders, and some chronic diseases, or with data bases for e.g. indoor air, food, or consumer products. Existing initiatives to link data collections at European Environment Agency (EEA) and Joint Research Center (JRC) or at World Health Organization (WHO) are good options to further develop linkage of HBM with exposures sources and health end points. Conclusions: There is potential to use HBM based information in a number of public health policies, and this would help to align reporting to international commitments. Environmental health surveillance based on HBM and HBM-based indicators, is an excellent tool to inform public health policies about risks from environmental chemicals, and the EU health information system would benefit from additional HBM-based indicators for monitoring exposure burden from environmental chemicals. Considerable efforts are needed to align and establish routine data collections and to develop a surveillance system and indicators which may inform public health policies

Allosteric activation of GDP-bound ras isoforms by bisphenol derivative plasticisers

The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols are widespread in modern life because of their industrial application as plasticisers. Bisphenol A (BPA) is the best-known member and has gained significant scientific as well as public attention as an endocrine disrupting chemical, a fact that eventually led to its replacement. However, compounds used to replace BPA still contain the molecular scaffold of bisphenols. BPA, BPAF, BPB, BPE, BPF, and an amine-substituted BPAF-derivate all interact with all GDP-bound Ras-Isoforms through binding to a common site on these proteins. NMR-, $SOS^{cat_{-}}$, and GDI- assay-based data revealed a new bisphenol-induced, allosterically activated GDP-bound Ras conformation that define these plasticisers as Ras allosteric agonists