THEME III – In vitro testing and integration with epidemiological data
This Theme exploits our collective expertise in mechanisms of toxicity and carcinogenesis of environmental toxicants, their bioavailability, biological consequences of DNA damage and health effects of exposure to ionizing radiation and toxic chemicals. It addresses questions on the origins of mutations in human tumours and the role of the gut microbiome in toxicity of environmental pollutants.
It uses state-of-the-art in vitro mammalian and bacterial cell systems and high throughput analyses, linked to epidemiological studies of radiation-exposed workers and residents near brownfield sites.
Theme III Projects
Project outline: The origins of ~50% of cancer cases remain unknown. Whole genome sequencing has revealed ~49 different patterns of mutations (mutational signatures) in human tumours. Some mutational signatures in human cancers can be replicated experimentally, strengthening epidemiological observations of possible causation by environmental agents. Experimental in vitro systems can shed new light on the origins of mutations in human cancer and the cellular processes and/or environmental agents that give rise to them. A recent development in mammalian cell culture is the isolation and propagation of human tissue organoids. These are grown in specialised 3D culture conditions maintaining the stem cell population and much of the tissue/cell architecture found in vivo. They represent a step change in the ability of in vitro systems to reproduce normal in vivo conditions, providing an important bridge between them. In order to identify in vivo a specific radiation signature in humans we will study genetic and epigenetic changes in leukaemia associated with radiation treatment for a previous cancer.
Overall objectives: To use normal human tissue organoids to explore the mutagenesis and, more broadly, toxicology of environmental toxicants and ionising radiation in vitro in a range of normal human tissues (e.g. gastric, intestine, liver, pancreas, kidney) and to define their modes and mechanisms of action, contributing to their overall risk assessment. Identifying patients who have developed Acute Myeloid Leukaemia (AML) related to a previous radiotherapy (only) treatment for a previous solid tumour such as breast cancer.
Project outline: UKHSA has over many years conducted epidemiological analyses of the health of the UK radiation workforce based on its National Registry for Radiation Workers (NRRW). For a few individuals in the NRRW cohort biological samples have been collected in the context of a study of the ex-BNFL workforce. The suitability of these samples for cytogenetic and genetic biomarker analysis in support of radiation risk assessment and health protection needs to be evaluated.
Overall objectives: This project will scope the feasibility of wider prospective sample collection with a view to identifying and integrating novel prognostic biomarker information to improve health risk estimation. It will also explore the utility of a new protein biomarker developed at MRC Toxicology Unit.
Project outline: To respond to the growing housing need and protect the countryside from development, brownfield sites are increasingly being targeted for housing redevelopment. Depending on their previous use, ex-brownfield sites might pose potential risks to the health of residents in housing developments either in, or in the vicinity of, redeveloped sites. To date, little research has been conducted on the link between brownfield sites and health and the evidence which exists has indicated a potential health concern.
Overall objectives: We will conduct a systematic review of brownfield sites and potential health effects. We will use spatial analysis methods to conduct a detailed exposure assessment of the population living in proximity of brownfield sites to identify potential environmental inequalities by socioeconomic status and ethnicity. In parallel with T2:P3, we will apply spatio-temporal epidemiological methods to quantify any adverse health effects near brownfield sites, with a focus on specific previous uses including gasworks, landfill sites, industrial sites and petrol stations.
Project outline: Pollutants such as pesticides are harmful not only to human cells but also to the commensal microbiota. While the effect on the microbiota could increase the risk of, for example, metabolic diseases, certain bacteria might aid in detoxifying these compounds. This project will use an in vitro microbiomics platform to investigate the potential of gut bacteria to detoxify commonly found environmental pollutants and discover underlying biochemical mechanisms.
Overall objectives: To assess inhibitory effects of commonly encountered environmental pollutants on a representative panel of human gut bacteria; quantify the biochemical capabilities of human gut bacteria to detoxify pollutants; identify enzymatic mechanisms responsible for gut bacteria-pollutant interactions; develop a sequencing-based method to predict detoxication potential of gut bacterial strains.
Respiratory bioavailability Researchers – Ian Mudway (ICL), Ben Forbes (KCL), Zachary Enlo-Scott (KCL)
Project outline: Current regulations assume 100% bioavailability for inhaled pesticides. More realistic estimates are required to enable more rational occupational and environmental health assessments.
Overall objectives: In this project we will test the hypothesis that respiratory bioavailability of inhaled pesticides varies depending on (a) their regional deposition, (b) their physicochemical properties and (c) differences in transepithelial permeability throughout the respiratory tract. Our aim is to develop models that predict the respiratory bioavailability of inhaled pesticides, based on in vitro respiratory transepithelial permeability data, to inform toxicological investigations and integration into health impact assessments.
Unravelling system-wide biomolecular interactions of food-borne pollutants Researchers – Kiran Patil (UC), Anne Willis (UC), Mike Chapman (UC), James Thaventhiran (UC), Ritwick Sarwarkar (UC), Mathew Van de Pette (UC)
Project outline: Several environmental pollutants like pesticides frequently enter the food-chain leading to systemic exposure of the consumers. However, the resulting physiological effects and underlying molecular interactions are only sparsely known.
Overall objectives: The aim is to carry out a large-scale profiling of the effects of hundreds of commonly found environmental pollutants (pesticides, herbicides, and veterinary medicines) using a multi-scale bioassay approach. To this end, the project will bring together different biological systems of toxicity relevance, from liver and immune cells to the gut microbiome, as well as multiple functional readouts, from apoptosis to metabolic aberrations. To identify specific molecular interactions underlying the observed toxic effects, selected interactions identified in the screening phase will be further investigated in molecular detail, especially by using thermal proteome profiling and multi-omic readouts (genomics, epigenomics, transcriptomics, proteomics and metabolomics). Key pathways and mechanisms thus uncovered will be further assessed by using data from published cohort studies to establish their in vivo relevance. Together, the proposed approach will provide a first-of-its-kind view on how environmental pollutants impact cell physiology and suggest potential targets towards mitigation.
Identifying the effects of pesticides on intestinal permeability and gut-bacterial dysbiosis. Researchers – Michael Antoniou (KCL), David Phillips (KCL), Halh Al-Serori (KCL), Robin Mesnage (KCL), Scarlett Ferguson (KCL)
Project outline: Gut microbiome status and integrity can be affected by exposure to environmental chemicals such as pesticides. Exposure to pesticides acting as antibiotics, or fungicides, could generate a stable selection pressure on some microbial communities in the human gut microbiome. This project will provide insight as to whether pesticides commonly found in human food compromise gut well-being, which can lead to serious ill-health, with the ultimate objective of providing evidence to improve regulation of pesticides in the food chain leading to better protection of public health.
Overall objectives: The aim is to investigate whether pesticides can bring about gut microbiome dysbiosis and compromise gut integrity. This PhD project will study the effects of pesticides that are most frequently found in foodstuffs on human gastrointestinal function. It will initially focus on glyphosate, the world’s most widely used herbicide, which inhibits the shikimate pathway in plants leading to their death. It is hypothesised that glyphosate can act as an antibiotic by inhibiting the same shikimate biochemical pathway in microorganisms compromising their viability.