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Novel approaches for testing metabolism disrupting chemicals

GOLIATH - Generation Of Novel, Integrated and Internationally Harmonised Approaches for Testing Metabolism Disrupting Chemicals

GOLIATH focusses on one of the most urgent regulatory needs in the field of endocrine disrupting chemicals, namely the lack of methods for testing EDCs that disrupt metabolism – chemicals collectively referred to as ‘metabolism disrupting chemicals’ (MDCs). MDCs are natural and anthropogenic chemicals that have the ability to promote metabolic changes that can ultimately result in obesity, diabetes and/or fatty liver in humans. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs.

With a focus on the main cellular targets of metabolic disruption – hepatocytes, pancreatic endocrine cells, myocytes and adipocytes – GOLIATH will develop new methods and optimise existing methods that span the entire adverse outcome pathway (AOP) spectrum, using in silico predictive modelling and high throughput screening, (pre-)validated ready-to use in vitro assays and optimised in vivo toxicity testing guidelines.

GOLIATH will provide key information on the endocrine mode of action by which MDCs disrupt metabolic pathways and induce adverse effects on human health by incorporating multi-omics technologies, and translating results from in vitro and in vivo assays to adverse metabolic health outcomes in humans at real life exposures.

Meet the Principal Investigator(s) for the project

Dr Luigi Margiotta-Casaluci - Luigi is a Lecturer in Pharmacology and Toxicology, and Group Leader in the Department of Life Sciences, Centre of Inflammation Research and Translational Medicine. He is specialised in the quantitative bi-directional extrapolation of complex biological processes between zebrafish, pre-clinical mammalian species, and humans. His research focuses on understanding the multi-scale effects of pharmaceuticals, alone and in combination, and developing predictive models able to support drug safety assessment. In parallel with the drug safety research, Luigi is also interested in understanding the molecular mechanisms underlying specific behavioural phenotypes. The Margiotta-Casaluci Lab is currently using the zebrafish model to study the effects of chronic inflammation on brain and behaviour. This research aims at generating novel mechanistic understanding that can potentially support the identification of more effective therapeutic strategies for patients affected by behavioural disorders. Since starting his independent group in 2015, Luigi secured external research funding as Principal Investigator from several public research councils (e.g. BBSRC, NC3Rs, European Commission) as well as industrial partners (e.g. AstraZeneca). His current research includes the following projects:  (2017-2021; BBSRC/AstraZeneca): Understanding molecular and phenotypic effects of cyclo-oxygenase inhibition in the zebrafish model.  (2017-2018; NC3Rs): Development of an Adverse Outcome Pathway for cardiotoxicity mediated by the blockade of L-type calcium channels.  (2018-2021; Brunel Isambard Award): Understanding the effects of chronic inflammation on brain and behaviour.  (2019-2022; H2020 European Commission): GOLIATH: Generation of novel, integrated and internationally harmonised approaches for testing chemical-induced metabolic disruption. Career 2020-to date: Group Leader & Lecturer, Pharmacology & Toxicology, College of Health and Life Sciences, Brunel University London, UK 2018-2020: Group Leader & Research Fellow II, Comparative Pharmacology & Toxicology, College of Health and Life Sciences, Brunel University London, UK 2015-2018: Group Leader & Research Fellow, Comparative Pharmacology & Toxicology, College of Health and Life Sciences, Brunel University London, UK 2011-2013: Visiting Scientist, AstraZeneca, UK 2011-2015: Post-doctoral Research Fellow, AstraZenenca/Brunel University London, London, UK (funded by BBSRC/AstraZeneca). Education 2007–2011: Ph.D. in Environmental Toxicology, Brunel University London, London, UK (supported by GlaxoSmithKline) 2003-2005: MSc Marine Biology, Universita’ Politecnica delle Marche, Ancona, Italy 2000-2003: BSc Biological Sciences, Universita’ Politecnica delle Marche, Ancona, Italy
Professor Andreas Kortenkamp - Traditional chemicals risk assessment has a quite artificial orientation: It treats chemicals as if they act in isolation, when in reality there is exposure to multiple substances. For more than 15 years, our team have been engaged in efforts to find ways of improving risk assessment by taking “cocktail effects” into account. This work has proceeded in stages: Firstly, when we have information about the toxicity of individual mixture components, is it possible to predict the effects of the combination? Working with mixtures of endocrine disrupting chemicals we have shown that this is achievable. Secondly, what is the composition of mixtures of environmental relevance, and what effects do they produce? Work on this aspect of the mixtures issue is currently proceeding in our group. We are also interested in making an impact on chemical regulation by addressing the questions: Which chemicals should be grouped together for mixtures risk assessment? What are scientifically sound grouping criteria? We have prepared scientific reports for the European Commission, including the State of the Art Report on Mixture Toxicology. Currently we are writing a State of the Art Assessment for Endocrine Disrupters, a project also commissioned by the European Commission. Another research interest is in unravelling the details of estrogen signalling and estrogen-mediated effects with a view to understanding hormonal cancers, especially breast cancer. Here, I closely collaborate with Dr Elisabete Silva. Qualifications1983: Degree in Chemistry, Philosophy and Educational Sciences from University of Muenster, Germany 1989: PhD (with distinction) from Bremen University, Bremen, Germany Career 1990-1991: Post-doctoral Fellow at Queen Mary London, University of London. 1991-2000: Lecturer in Environmental Toxicology, School of Pharmacy, University of London, London. 2000-2005: Senior Lecturer, School of Pharmacy, University of London, London. 2005-2007: Reader and Head of Centre for Toxicology, School of Pharmacy, University of London, London. 2007-2011: Professor for Molecular Toxicology, Head of Centre for Toxicology, School of Pharmacy, University of London, London. 2011-present: Professor in the Institute for the Environment, Brunel University.

Related Research Group(s)

Inflammation Research and Translational Medicine

Inflammation Research and Translational Medicine - Driving scientific innovation and discovery for diagnosis, treatment, and management of cardiovascular disease, inflammatory and immune disorders, microbial resistance, and cancer.

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Project last modified 18/06/2021