THEME II – Biomarkers of exposure, effect and susceptibility to chemical and radiation exposures
The aim of this Theme is to produce new insights into the molecular effects of exposures to chemicals and radiation that will allow us to (i) identify and validate biomarkers of exposure, early and long-term effects (such as toxicity and carcinogenesis) and susceptibility; (ii) identify potential mechanisms involved; and (iii) improve our understanding of causal pathways to evaluate their subsequent effects on health and ageing.
Using data from existing large and well-established population, patient and occupational cohort studies, as well as de novo collected biosamples, in vitro cell lines and blood samples exposed ex vivo, these studies will apply state-of-the-art 'omics' technologies and develop new statistical approaches to mine these large datasets for biomarkers of chemical and radiation exposures. Further mechanistic investigations will be carried out using causal modelling approaches, as well as cell line experiments.
Theme II Projects
Project outline: This project will study in vitro, and in vivo biomarkers of ionising radiation relevant to healthcare (e.g. CT scans, radiotherapy and man-made radioactive isotopes). Studies will be undertaken to characterise biomarkers in the context of radiotherapy patients (in collaboration with the Institute for Cancer Research), vascular operators, nuclear medicine patients and practitioners using human cell model systems and a range of therapeutic and diagnostic radionuclides and radiopharmaceuticals to develop new treatment protocols with lower toxicity. Ultimately, this knowledge will be used to support health decisions by the public and policy-makers and will allow individual differences in sensitivity to be considered to better protect those at higher risk by regularly monitoring them, to decrease the risk and intervene to treat cancer earlier.
Overall objectives: We will develop and validate novel biomarkers of radiation exposure, effect and susceptibility, notably exploiting existing cytogenetics techniques and developing markers such as expression of splice variants, microRNAs, RNA modification and mitochondrial DNA mutations. These and other markers will be applied to samples obtained from practitioners delivering X-ray guided endovascular procedures and their patients. This will contribute to a better understanding of the radiation doses delivered to specific tissues such as bone marrow and blood following radioactive isotopes injected for nuclear medicine purposes. We will evaluate DNA damage and activated pathways associated with low dose exposures from an intracellular radiation source in vivo. We aim to assess multiple existing and new sensitive biomarkers for reliable estimation of the low doses delivered internally in vitro and in vivo by radionuclides, respectively to blood and bone marrow, to develop calibration curves to compare external X-ray doses and internal exposure.
Project outline: This project aims at developing statistical approaches to analyse mixtures of chemical exposures and their biological response and ultimately to identify biomarkers of these complex exposures. The project comprises a strong methodological component focusing on the development and the application of novel statistical models and machine learning algorithms accommodating multiple and interacting compounds. The project will be based on the re-analysis of existing data as proof-of-principle and the resulting approach will be used for the analysis of new data to identify validated biomarkers of exposure mixtures.
Overall objectives: The main objectives are two-fold (i) to identify from existing data the biological imprint of chemical mixtures using exposure to chlorination by-products as an exemplar; (ii) to investigate the molecular signatures associated with these complex exposures. Adopting a xenobiotic approach, we will use clustering algorithms to define co-occurring sets of exposures and/or markers of exposure. Resulting cluster memberships will be used as a proxy to define discrete (multiple) exposure profiles. Their interpretation will rely on regression models or classification approaches quantifying the factors (and/or individual exposures) driving the cluster membership. To explore the internal response to these exposures we will perform (multi) omic profiling using penalised regression and Partial Least Square models and will visualise complex correlation patterns across omic signals and/or exposures via network inference.
Project outline: The urgent need for affordable and social housing in the UK has driven the exploitation of ex-brownfield sites. This has resulted in considerable public concern, but to date there is limited data on the likely residual chemical exposures of populations at these locations. These issues are compounded by the fact that many of the developments are in inner city areas with high air pollution levels. In this project we aim to address this knowledge gap by monitoring a broad range of pollutants at selected brownfield sites where there is significant or planned housing development. This surveillance work will be complemented by personal monitoring of populations living at varying distance from these locations using novel passive absorption badges to capture exposures to volatile organic compounds (VOC) and semi-volatile organic compounds (SVOC), with a focus on vulnerable groups: pregnant mothers, children and aged-individuals with chronic disease.
Overall objectives: We will conduct residential, ambient and personal VOC and SVOC exposure assessments of populations at ex-brownfields sites, beginning with residential developments built on ex-gas works (identified as an area of public concern through PCIEP activities), before expanding consideration to other types of brownfield sites. We will explore the feasibility of examining internal biomarkers of exposure and response in vulnerable populations living at these locations. This project will complement the activities outlined in T3:P3, as well as providing samples relevant to the activities outlined in T4:P3.
Project outline: This project will analyse questionnaire and biomarker data collected from women in the Breast Milk, Environment, and Early-life Development (BEED) study and follow up neurodevelopmental outcomes in their children. The BEED study was set up around 3 municipal waste incinerators (MWIs) across England and includes ~600 women and approximately ~1500 breast milk samples. The number of MWIs in the UK has increased due to EU restrictions on landfill, but there is ongoing public concern about the possible health effects of MWIs and resistance to their construction. BEED has gathered personal exposure profiles using biomarkers in breast milk, including persistent organic pollutants such as polychlorinated dibenzodioxins, polychlorinated dibenzofurans, dioxin-like polychlorinated biphenyls (PCBs), heavy metals, brominated flame retardants. The breast milk metabolome has also been analysed using liquid chromatography-mass spectrometry (LC-MS).
Overall objectives: The main objectives are: (i) to analyse a large range of breast milk biomarker data to determine background population levels of these environmental chemicals; (ii) to investigate personal exposure levels to these environmental chemicals in relation to both distance and particulate matter exposures from an MWI; (iii) to investigate personal exposure levels to these environmental chemicals in relation to pregnancy, lifestyle and dietary questionnaire data.