N-cadherin promoter polymorphisms and risk of osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis. It is characterized by cartilage destruction and bone remodeling, mediated in part by synovial fibroblasts (SFs). Given the functional significance of cadherins in these cells, we aimed at determining the role of genetic variants of N-cadherin (CDH2) in OA of the knee and hip. Six single-nucleotide polymorphisms in the genomic region of the CDH2 gene were genotyped in 312 patients with OA and 259 healthy control subjects. Gene expression of CDH2 was analyzed by qRT-PCR. Liquid chromatography-mass spectrometry was used to identify a transcription factor isolated by DNA pulldown. Its potential for binding to gene variants was examined by electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, and chromatin immunoprecipitation. Genetic analysis identified a polymorphism located in the CDH2 promoter region to be associated with risk of OA. The minor allele of rs11564299 had a protective effect against OA. Compared to carriers of the major allele, carriers of the minor allele of rs11564299 displayed increased N-cadherin levels in SFs. Based on in silico analysis, the minor allele was predicted to generate a novel transcription factor binding site, Direct-binding assays and mass spectrometric analysis identified hnRNP K as binding selectively to the minor allele. In summary, a CDH2 promoter polymorphism influences the risk of OA, and hnRNP K was found to be involved in the regulation of elevated N-cadherin expression in patients with OA carrying the minor allele of rs11564299

The NORMAN Association and the European Partnership for Chemicals Risk Assessment (PARC): let’s cooperate! [Commentary]

The Partnership for Chemicals Risk Assessment (PARC) is currently under development as a joint research and innovation programme to strengthen the scientific basis for chemical risk assessment in the EU. The plan is to bring chemical risk assessors and managers together with scientists to accelerate method development and the production of necessary data and knowledge, and to facilitate the transition to next-generation evidence-based risk assessment, a non-toxic environment and the European Green Deal. The NORMAN Network is an independent, well-established and competent network of more than 80 organisations in the field of emerging substances and has enormous potential to contribute to the implementation of the PARC partnership. NORMAN stands ready to provide expert advice to PARC, drawing on its long experience in the development, harmonisation and testing of advanced tools in relation to chemicals of emerging concern and in support of a European Early Warning System to unravel the risks of contaminants of emerging concern (CECs) and close the gap between research and innovation and regulatory processes. In this commentary we highlight the tools developed by NORMAN that we consider most relevant to supporting the PARC initiative: (i) joint data space and cutting-edge research tools for risk assessment of contaminants of emerging concern; (ii) collaborative European framework to improve data quality and comparability; (iii) advanced data analysis tools for a European early warning system and (iv) support to national and European chemical risk assessment thanks to harnessing, combining and sharing evidence and expertise on CECs. By combining the extensive knowledge and experience of the NORMAN network with the financial and policy-related strengths of the PARC initiative, a large step towards the goal of a non-toxic environment can be taken

The NORMAN Suspect List Exchange (NORMAN-SLE): facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry

Background: The NORMAN Association (https://www.norman-.network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-.network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for "suspect screening" lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide.Results: The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https:// zenodo.org/communities/norman-.sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https://pubchem.ncbi.nlm.nih.gov/) and the US EPA's CompTox Chemicals Dashboard (https://comptox. epa.gov/dashboard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101).Conclusions: The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the "one substance, one assessment" approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https://www.norman-.network.com/nds/SLE/)

Verfolgung von Umweltbelastungen durch Alkylphenole, Bisphenol A und organische Zinnverbindungen repraesentativen Umweltproben: Methodische Entwicklungen und aktuelles sowie retrospektives Monitoring. Bd. 1: Organische Zinnverbindungen. Bd. 2: Alkylphenole, Bisphenol A Abschlussbericht

Im Rahmen dieses Forschungsvorhabens wurden analytische Methoden zur quantitativen Bestimmung von Alkylphenolen (4-Nonylphenol, 4NP; 4-tert.-Octylphenol, 4tOP) und Alkylphenolethoxylaten (4-Nonylphenolmonoethoxylat, 4NP1EO; 4-tert.-Octylphenolmonoethoxylat, 4tOP1EO), Bisphenol A (BPhA) sowie organischen Zinnverbindungen (Tributylzinn, TBT; Dibutylzinn, DBT, Monobutylzinn, MBT; Triphenylzinn, TPhT) in verschiedenen biologischen Matrices adaptiert und weiterentwickelt. Die Methoden wurden in Form von Standardarbeitsanweisungen (SOP) dokumentiert. Mit diesen Methoden wurden Proben aus der Umweltprobenbank des Bundes analysiert. Aus marinen Oekosystemen der Nord- und Ostsee wurden Blasentang, Miesmuschel, Aalmuttermuskulatur, Silbermoewenei und aus limnischen Oekosystemen (Elbe, Mulde, Saale, Rhein, Saar, Bornhoeveder Seengebiet) Dreikantmuschel und Brassenmuskulatur verschiedener Jahrgaenge analysiert. Alkylphenole: In der Regel lagen die Gehalte an 4NP und 4NP1EO sowohl in den marinen, als auch in den limnischen Oekosystemen oberhalb der Gehalte von 4tOP und 4tOP1EO. In den marinen Proben war die Miesmuschel hoeher belastet als die anderen Matrices. Die Gehalte in den Proben aus limnischen Oekosystemen lagen deutlich hoeher als die der Proben aus den marinen Oekosystemen. Die hoechste Konzentration wurde mit 324 #mu#g/kg Frischgewicht fuer 4NP1EO in Brassenmuskulatur in der Saar bei Guedingen gemessen. Bisphenol A: Der Gehalt an BPhA in den untersuchten Proben war durchweg gering. Die Analysen ergaben in Dreikantmuschel Konzentrationen von 1-2,5 #mu#g BPhA/kg; nur am Standort Rehlingen (Saar) wurde ein deutlich hoeherer Wert von ca. 5 #mu#g/kg nachgewiesen. Die BPhA-Konzentration in Brassenmuskulatur lag ueberwiegend unterhalb der Bestimmungsgrenze (BG). Der geringste Gehalt an BPhA im marinen System fand sich in der Miesmuschel (Konzentration<BG); im Blasentang wurden ca. 1-2 #mu#g/kg nachgewiesen. Die Konzentrationen im Silbermoewenei und in der Aalmuttermuskulatur lagen bei ca. 2,5 #mu#g/kg. Zinnorganische Verbindungen: Als Hauptkontaminanten wurden TBT und TPhT (max. 385 bzw. 86 #mu#g Sn/kg Matrix) detektiert. Die Werte fuer DBT und MBT lagen bei maximal 14 bzw. 9 #mu#g Sn/kg. Die hoechsten Werte fuer DPhT wurden mit 13 #mu#g Sn/kg gemessen. Am hoechsten belastet waren Brassenmuskulatur und Dreikantmuschel aus der Elbe. (orig.)In the context of this research project analytic methods for the quantitative determination of alkylphenols (4-nonylphenol, 4NP; 4-tert.-octylphenol, 4tOP) and alkylphenol ethoxylates (4-nonlyphenol monoethoxylate, 4NP1EO; 4-tert.-octylphenol monoethoxylate, 4tOP1EO), bisphenol A (BPhA) as well as tin-organic compounds (tributyl tin, TBT; dibutyl tin, DBT, monobutyl tin, MBT; triphenyl tin, TPhT) in different biological matrices were adapted and optimised. The methods were documented in form of standard operating procedures (SOP). Following these methods samples from the German federal environmental specimen bank were investigated. Brown algae, (bay) mussels, eel pouts, sea gull eggs from the marine ecological systems of the North Sea and Baltic Sea and zebra mussels and bream muscles from fresh water ecological systems (Elbe, Mulde, Saale, Thine, Saar, Bornhoeveder lake district) of different years were analysed. Alkylphenols: The contents of 4NP and 4NP1EO mostly were in both, the marine and the fresh water, ecological systems above the contents of 4tOP and 4tOP1EO. In the marine samples the mussels were higher loaded than the other matrices. The contents in the samples from fresh water ecological systems were clearly higher than those of the samples from the marine ecological systems. The highest concentration for 4NP1EO with 324 #mu#g/kg fresh weight was measured in bream muscles from the Saar near Guedingen. Bisphenol A: the content of BPhA in the examined samples generally was low. The analyses resulted in concentrations of 1-2.5 #mu#g/ BPhA/kg in zebra mussel; only in zebra mussels from the river Saar near Rehlingen a higher value of approx. 5 #mu#g/kg was detected. The BPhA concentration in bream muscles was always below the limit of determination (LOD). The lowest content of BPhA in marine samples was found for mussels (concentration<LOD); in the brown algae approx. 1-2 #mu#gBPhA/kg were detected. The concentrations in seagull eggs and eel pout muscles were approx. 2.5 #mu#g/kg. Tin-organic compounds: TBT and TPhT were detected as major contaminants (max. 385 and 86 #mu#g Sn/kg of matrix, respectively). The maximum values for DBT and MBT were 14 and 9 #mu# Sn/kg, respectively. The highest values detected for DPhT were 13 #mu#g Sn/kg. The most highly loaded samples were bream muscles and zebra mussels from the river Elbe. (orig.)Published in two volumesSIGLEAvailable from TIB Hannover: RN 8908(2000,20,1): RN 8908(2000,20,2) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Organische Zinnverbindungen, Alkylphenole und Bisphenol A in marinen und limnischen Biota der Umweltprobenbank. Methodische Entwicklungen sowie aktuelles und retrospektives Monitoring. Teilberichte 1 - 3: Organische Zinnverbindungen. Alkylphenole und Alkylphenolethoxylate. Biosphenol A

In the context of this research project analytic methods for the quantitative determination of tinorganic compounds (tributyl tin, TBT; dibutyl tin, DBT, monobutyl tin, MBT; triphenyl tin, TPhT), alkylphenols (4-nonylphenol, 4NP; 4-tert.-octylphenol, 4tOP) and alkylphenol ethoxylates (4-nonylphenol monoethoxylate, 4NP1EO; 4-tert.-octylphenol monoethoxylate, 4tOP1EO) as well as bisphenol A (BPhA) in different biological matrices were adapted and optimised. The methods were documented in form of standard operating procedures (SOP). Following these methods samples from the German federal environmental specimen bank were investigated. Brown algae, (bay) mussels, eel pouts, sea gull eggs from the marine ecological systems of the North Sea and Baltic Sea and zebra mussels and bream muscles from fresh water ecological systems (Elbe, Mulde, Saale, Rhine, Saar, Bornhoeveder lake district) of different years were analysed. Tin-organic compounds: TBT and TPhT were detected as major contaminants (max. 385 and 86 #mu#g Sn/kg of matrix, respectively). The maximum values for DBT and MBT were 14 and 9 #mu#g Sn/kg, respectively. The highest values detected for DPhT were 13 #mu#g Sn/kg. The most highly loaded samples were bream muscles and zebra mussels from the river Elbe. Alkylphenols: The contents of 4NP and 4NP1EO mostly were in both, the marine and the fresh water, ecological systems above the contents of 4tOP and 4tOP1EO. In the marine samples the mussels were higher loaded than the other matrices. The contents in the samples from fresh water ecological systems were clearly higher than those of the samples from the marine ecological systems. The highest concentration for 4NP1EO with 324 #mu#g/kg fresh weight was measured in bream muscles from the Saar near Guedingen. Bisphenol A: The content of BPhA in the examined samples generally was low. The analyses resulted in concentrations of 1-2.5 #mu#g BPhA/kg in zebra mussel; only in zebra mussels from the river Saar near Rehlingen a higher value of approx. 5 #mu#g/kg was detected. The BPhA concentration in bream muscles was always below the limit of determination (LOD). The lowest content of BPhA in marine samples was found for mussels (concentration<LOD); in the brown algae approx. 1-2 #mu#g BPhA/kg were detected. The concentrations in seagull eggs and eel pout muscles were approx. 2.5 #mu#g/kg. (orig.)Im Rahmen dieses Forschungsvorhabens wurden analytische Methoden zur quantitativen Bestimmung von organischen Zinnverbindungen (Tributylzinn, TBT; Dibutylzinn, DBT, Monobutylzinn, MBT; Triphenylzinn, TPhT), Alkylphenolen (4-Nonylphenol, 4NP; 4-tert.-Octylphenol, 4tOP) und Alkylphenolethoxylaten (4-Nonylphenolmonoethoxylat, 4-tert.-Octylphenolmonoethoxylat) sowie Bisphenol A (BPhA) in biologischen Matrices adaptiert und weiterentwickelt. Die Methoden wurden in Form von Standardarbeitsanweisungen (SOP) dokumentiert. Mit diesen Methoden wurden Proben aus der Umweltprobenbank des Bundes analysiert. Aus marinen Oekosystemen der Nord- und Ostsee wurden Blasentang, Miesmuschel, Aalmuttermuskulatur, Silbermoewenei und aus limnischen Oekosystemen (Elbe, Mulde, Saale, Rhein, Saar, Bornhoeveder Seengebiet) Dreikantmuschel und Brassenmuskulatur verschiedener Jahrgaenge analysiert. Zinnorganische Verbindungen: Als Hauptkontaminanten wurden TBT und TPhT (max. 385 bzw. 86 #mu#g Sn/kg Matrix) detektiert. Die Werte fuer DBT und MBT lagen bei maximal 14 bzw. 9 #mu#g Sn/kg. Die hoechsten Werte fuer DPhT wurden mit 13 #mu#g Sn/kg gemessen. Am hoechsten belastet waren Brassenmuskulatur und Dreikantmuschel aus der Elbe. Alkylphenole: In der Regel lagen die Gehalte an 4NP und 4NP1EO sowohl in den marinen, als auch in den limnischen Oekosystemen oberhalb der Gehalte von 4tOP und 4tOP1EO. In den marinen Proben war die Miesmuschel hoeher belastet als die anderen Matrices. Die Gehalte in den Proben aus limnischen Oekosystemen lagen deutlich hoeher als die der Proben aus den marinen Oekosystemen. Die hoechste Konzentration wurde mit 324 #mu#g/kg Frischgewicht fuer 4NP1EO in Brassenmuskulatur in der Saar bei Guedingen gemessen. Bisphenol A: Der Gehalt an BPhA in den untersuchten Proben war durchweg gering. Die Analysen ergaben in Dreikantmuschel Konzentrationen von 1-2,5 #mu#g BPhA/kg; nur am Standort Rehlingen (Saar) wurde ein deutlich hoeherer Wert von ca. 5 #mu#g/kg nachgewiesen. Die BPhA-Konzentration in Brassenmuskulatur lag ueberwiegend unterhalb der Bestimmungsgrenze (BG). Der geringste Gehalt an BPhA im marinen System fand sich in der Miesmuschel (Konzentration<BG); im Blasentang wurden ca. 1-2 #mu#g/kg nachgewiesen. Die Konzentrationen im Silbermoewenei und in der Aalmuttermuskulatur lagen bei ca. 2,5 #mu#g/kg. (orig.)SIGLEAvailable from TIB Hannover: RN 8422(2001,6) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman