Theme III - Biomarkers of exposure and effect
Overview
Theme III will use a 'whole systems' approach to study the mechanistic pathways linking ambient air pollution exposure to disease outcomes. This Theme will involve metabolic phenotyping technologies (metabolomics) that are powerful tools to capture information on a range of toxicological and disease processes. As exhaust emission controls take effect, non-exhaust emissions from brakes and tyres are drawing increasing attention. Research on the health impacts of these emissions will provide information requested by the Committee on the Medical Effectives of Air Pollutants (COMEAP). Our work on asthma aims to identify the components and sources of ambient PM that contribute most to negative impacts in this condition. Finally, our work on e-cigarettes will fulfil the UK Health Security Agency requirements in this important area.
Theme Leads
Professor Catherine Hawrylowicz
Theme III Co-Lead
King’s College London
EEH Themes:
Theme III Project 3: The role of AhR in Asthma
Publications:
Dr Martin Leonard
Theme III Co-Lead
UK Health Security Agency
Dr Martin Leonard obtained his PhD in Pharmacology in 2000 from University College Dublin, Ireland. He has over 15 years’ experience as a toxicologist focussed to developing and improving on models and methods for assessment of toxicological hazard, including in vivo approaches, high content omics technology and iPSC in vitro models of the airway. He is a European registered toxicologist and currently holds a position as principal toxicologist at UK Health Security Agency directing research into the mechanisms of chemical, particulate and allergen hazard associated with asthma and allergic airway disease. Martin has published extensively in the fields of toxicology, cell biology and Immunology.
EEH Themes:
Theme 3 Project 3: The role of the AhR in Asthma
Publications:
Theme III Projects
Project outline: There is an incomplete understanding of the initial biochemical and physiological disturbances related to pollutant exposure that drive the causal pathways to disease and disease exacerbation. These pathway data are necessary to strengthen the causal basis for the epidemiological findings of an association between air pollution and disease outcomes and disease interventions. We will use multivariate metabolic phenotyping to discover novel blood-based markers of air pollution exposures and discern causal pathways (asbestos, diesel exhaust, wood smoke).
Project outline: Changes in the traffic fleet are leading to alterations in the types of airborne particles. To date, the major public health focus has been on exhaust particles. As these exhaust particles decrease, focus is changing to particles from tyre, brake, and road wear. These particles are generated from both electric and combustion vehicles and they have a different composition from combustion particles and thus may have different health effects. This project will use in vitro models to examine the effects of non-exhaust particles on pulmonary immunity, with focus on macrophage and dendritic cell function.
Project outline: To build on work from the previous HPRU, and link with other projects to test a range of PM samples for their effects in humans to understand components that drive inappropriate inflammatory responses. This will be associated with PM compositional data in order to identify relevant signalling pathways and explore potential mediators that may mitigate detrimental PM effects.
Project outline: Knowledge gaps exist around the toxicity of e-cigarette components, especially around flavour chemicals that are considered as safe based only on oral toxicology data. Toxicity to human airway cells will be investigated by combining air-liquid interface exposure and high-throughput toxicity screening assays. This work will be undertaken by a NIHP-funded PhD student. Additional studies will evaluate the contributions of e-cigarette device characteristics (coil age, temperature settings, coil resistance etc.) and ageing to aerosol characteristics. Characterisation will include analysis of aerosol (number concentration and size distribution) and determining the concentrations of nicotine, VOCs, metals and flavour compounds in air and deposited on surfaces. Using these analyses estimate theoretical quantities and location of aerosol deposited within the lung.
Project outline: Build on previous HPRU networks, capitalising on the novel systems developed in the toxicological assessment of particulates and in vitro cell systems to investigate the mechanistic basis of the adverse health effects of combustion derived particulates and NO2, that are currently ill-understood and difficult to separate in epidemiological studies. These novel systems have many advantages in terms of achieving more realistic exposure modalities (e.g. ALI aerosol exposure) and biological relevance (e.g. co-culture models). Comparative toxicology using these approaches will allow measured/considered judgement on the plausibility and likely size of possible mechanistic effects, to include lung inflammation, oxidative stress, aging, carcinogenicity potential and innate immunity governing adaptive immune responses to allergens. The initial part of this project will focus on establishing, characterising and validating the laboratory conditions for such combinatorial experiments to take place.
Project outline: Uncertainties remain about the potential health impact of nanomaterials and other advanced materials, especially at environmentally relevant levels. This work commenced in the previous HPRU and the intention is to extend this. Using established cellular models and exposure systems further advanced under Project 5, the size of possible mechanistic effects, to include lung inflammation, oxidative stress, aging, carcinogenicity potential and innate immunity governing adaptive immune responses to allergens, in response to a number of relevant materials will be evaluated. Attempts to classify materials into response type groups will be made to assist in supporting future read-across approaches for regulatory control. With its focus on mechanistic toxicity and inhaled materials the project has many synergies with projects in Theme III and will have useful input on materials and exposure levels from Theme I project 4.
Theme III Investigators
Dr Adam Boies
Investigator
MRC Toxicology Unit, Cambridge
Dr. Adam Boies is Reader of Nanomaterials and Aerosol Engineering and is Head of the Energy Group at the Cambridge University Engineering Department. His research focuses on characterizing the evolution, dynamics and impacts of gas-phase nanoparticles with an emphasis on energy applications, aerosol instrumentation and emissions. He is director of the Advanced Carbon Application and Manufacturing network and is Partnership Director of the Aerosol Doctoral Training Centre. He is a Fellow of Trinity College and has over 70 publications and 11 patents. He has been granted >£40m worth of total project funding from EPSRC, IUK, EU Horizon2020 and NERC. His group has produced three spin-outs, where he serves as Research Director for Catalytic Instruments, advisor to Atmose Ltd and as a co-founder of Echion Technologies.
EEH Themes:
Theme III Project 2: Health effects on non-combustion particles
Publications:
Dr Alison Buckley
Investigator
UK Health Security Agency
EEH Themes:
Theme III Project 6: Use of improved in vitro systems to evaluate mechanisms of toxicity
Publications:
Professor Paul Elliott
Investigator
School of Public Health, Imperial College London
EEH Themes:
Theme III Project 1: Understanding key molecular events following pollutant exposures
theme IV Project 6: Air pollution and infertility
Publications:
Dr Chang Guo
Investigator
UK Health Security Agency
Dr. Guo serves as a Senior Scientist in the Experimental Toxicology Programme, part of the Toxicology Department at the UK Health Security Agency. With over fifteen years of experience in nanotoxicology, she has been actively engaged in researching the impact of air pollution on public health, with a specific focus on understanding cellular and molecular mechanisms. Her investigations go beyond the respiratory system, extending to explore neurological effects associated with inhaled particulate matter, including through accessing advanced facilities at STFC. Before joining the UK Health Security Agency, Dr. Guo earned her PhD in Pharmacology from Cambridge University and subsequently worked in the field of nanotechnology, where she contributed to the development of engineered nanomaterials for drug delivery systems.
EEH Themes:
Dr Yiqun Han
Investigator
Environmental Research Group, School of Public Health, Imperial College London
EEH Themes:
Theme III Project 1: Understanding key molecular events following pollutant exposure
Publications:
Dr Ayokulehin (Ayo) KOSOKO
Investigator
UK Health Security Agency
I am a Cellular and Molecular Pharmacologist by training [understanding the mechanism(s) involved in the onset, progression, and possible management strategies of neurodegenerative diseases like Alzheimer’s disease] with industrial experience in primary and mammalian cell culture as well as iPSCs in-vitro models of the kidneys, airway, neuronal and microglia cells; downstream assays, viral (adeno-associated virus, lentivirus) and lipid nanoparticle (LNPs) gene delivery strategies.
I am a member of the Royal Society of Biology and currently holds a position as a Higher Research Scientist within the Experimental Toxicology Group at the UK Health Security Agency.
My research will involve assay development/validation/optimization and providing mechanistic insights into chemical, particulate and allergen hazard associated asthma exacerbation and allergic airway disease.
EEH Themes:
Dr Rachel Smith
Investigator
UK Health Security Agency
Dr Rachel Smith had led the multidisciplinary Nanoparticle Inhalation Research Group at the UK Health Security Agency’s Centre for Radiation, Chemical and Environmental Hazards for the past decade. Key research interests are lung deposition, clearance, translocation and toxicity of inhaled nanoparticles and other air pollution components, including their impact on pre-existing health conditions. She provides advice to UK Government on Nano safety and is a member of the OECD Working Party on Manufactured Nanomaterials.
EEH Themes:
Theme III Project 3: The role of AhR in Asthma
Theme IV Project 2: Microplastics and health
Publications:
Professor Anne Willis
Investigator
University of Cambridge
EEH Themes:
Theme III Project 1: Understanding key molecular events following pollutant exposure
Publications:
Dr Matthew Wright
Investigator
UK Health Security Agency
Dr Matthew Wright is a Senior Aerosol Scientist within the Nanoparticle Inhalation Research Group, Toxicology Department, UK Health Security Agency. His main area of research involves studies on the aerosol characteristics, composition, lung deposition and toxicological effects associated with exposure to a range of agents including aerosolised carbon nanotubes, e-cigarette aerosol, nanoparticle-enabled consumer products and 3D printing emissions. He is partly responsible for the design, maintenance, operation and data analysis associated with aerosol generation, measurement instrumentation, and in vitro and in vivo exposure systems.Matthew previously worked as Senior Research Associate in the Atmospheric Chemistry Research Group, University of Bristol, having obtained Ph.D. (2011) and M.Sci. (2004) degrees in Physics, also at Bristol, where research focused on a range of topics including submicron and ultrafine aerosol size distributions in urban, rural, indoor and transport environments, development of gas and aerosol tracer technologies to study dispersion (including infiltration into buildings) and chemical reactivity in the urban atmosphere. Whilst at Bristol he was also involved in studies involving air pollution measurements in a SE Asian megacity (Bangkok, Thailand), ambient aerosol electric charge state and the potential influence on lung deposition in human volunteers, and the relationship between air ions, aerosols and atmospheric electricity in urban and other environments.
Matthew has been involved with a number of outreach activities to share the group’s research with the public, including New Scientist Live and Oxford Ideas Festival, and is active within the UK Health Security Agency on the Environmental Sustainability Champions Group. He has also been an active member of the Aerosol Society throughout his postgraduate and postdoctoral career, and has served on the Committee for several years, most recently taking up the role of Treasurer in November 2020, and as a member of the Institute of Physics.
EEH Themes:
Theme III Project 4: E-cigerettes toxicity and health effects from second-hand exposures
Theme IV Project 2: Microplastics and health