Development of mechanistic understanding of the integrative effects of chemicals
Projects within this theme are combining transgenic and epigenomic technologies, in vitro, in vivo testing and the adverse outcome pathway (AOP) approach to develop an understanding of the effects of chemicals at molecular, cellular and tissue levels and how these effects translate to impacts on individual organisms. This includes seeking translation (read-across) from in vitro to in vivo for reducing and avoiding the use of animal models in chemicals testing.
Projects that align with this theme are;
Angel Ceballos Ramirez - University of York
Project: From water fleas to elephants: Multispecies Extrapolation of Pesticide Toxicity using high-throughput testing methods and Dynamic Energy Budgeting
Partner: Bayer
Modern mechanistic modelling can create extrapolations of chemical toxicity across multiple organisms; however, it tends to require large amounts of measurements. New technology and equipment have introduced the opportunity of using high-throughput testing techniques to facilitate the collection and automated processing of high volumes of experimental data assisted by Artificial Intelligence or specialized image analysis software.
This project aims to adapt the Daphnia magna chronic OECD standard procedures to a High Throughput setting using a Cell imager and well plates. The method will then be extended to other invertebrates used in similar ecotoxicological tests, such as Moina macrocopa, Thamnocephalus platyurus and Heterocypris incongruens. We aim to standardize high throughput methods, expose the organisms to different chemicals with varying modes of action and octanol-water partition coefficients, measure chronic toxicity responses and derive Dynamic Energy Budget Theory (DEB) Toxicokinetic – Toxicodynamic (TKTD) parameters.
Contact: adcr501@york.ac.uk
Eleanor Phillips - University of Sheffield
Project: A geometric framework approach to understand multi-metal toxicity on individual organisms to evaluate relative risks and benefits of pollution and mitigation
Partner: Natural Resources Wales
Metals are key cofactors in many cellular processes. Altered metal exposure disrupts these processes, affecting organismal fitness, and potentially having impacts at higher ecological scales. Predictive models of mixture toxicity lack mechanistic insight, and AOPs often lack a quantitative element. While metal toxicity response pathways are characterised, the regulation of multi-metal exposure and the role of other nutrients, and how they may heighten or lower toxicity thresholds, are less understood.
My project aims to use a trait-based approach, with Drosophila melanogastor, to study the physiological effects of metal interactions and apply a geometric framework, developed in nutritional research, to interpret these dynamics. I am focusing initially on the developmental and reproductive impacts of exposure to combinations of essential metals such as copper, zinc and iron, and how this is potentially modulated by important macronutrients such as phosphorus. I plan to utilise Drosophila's genetic tractability to uncover mechanisms of multi-metal toxicity regulation through functional genetics, and targeted gene expression analysis. If metal combinations have an interactive effect on physiology (especially in physiological aspects ubiquitous across species), then I could extrapolate these estimates of how multiple essential metals interact to shape fitness to environmentally relevant species. This project is in partnership with UKCEH and National Resources Wales.
Contact: ephillips3@sheffield.ac.uk
Chung Laam Tsui (Tiffany) - University of Exeter
Project: Leveraging genomics and artificial intelligence to develop predictive pesticide risk assessment frameworks for wild bees
Partner: Bayer
Bees are among the world’s most environmentally and economically important group of insects, pollinating a remarkable diversity of flowering plants and playing a key role in the production of a wide range of food and commodity crops. However, while carrying out this ecosystem service, bees can be exposed to a variety of potentially harmful toxins such as pesticides used in agriculture. Current bee pollinator pesticide risk assessment relies on testing a handful of model managed bee species such as the western honeybee and the buff-tailed bumblebees. However, bees are a highly diverse group of insects comprising more than 20,000 known species.
Cytochrome P450s are a group of enzymes that exists in virtually all organisms. CYP9Q-type P450s are a subfamily of P450s known to detoxify insecticides such as thiacloprid(bee-safe insecticide) in honeybees and bumblebees. However, the leafcutting bee(Megachile rotundata) lacks such enzyme and is significantly more sensitive to thiacloprid.
My PhD project will be based at the University of Exeter (Penryn Campus), working in partnership with Bayer CropScience. This project aims to create a framework that uses bioinformatics to locate the candidate detoxification gene(cytochrome P450s) in wild bees in order to develop new tools and predictive pipelines for bee pesticide risk assessment.
Contact: clt216@exeter.ac.uk
Skye Stephenson - University of York
Project: Optimising high throughput mechanistic ecotoxicology for assessing comparative toxicity across species and chemicals?
Partner: Syngenta
With an abundance of chemicals accumulating in our environment and most studies focusing on lethal endpoints of toxicity, it is becoming increasingly difficult to accurately predict the overall impact on our ecosystem. The focus needs shifting to sub-lethal endpoints such as effects on growth and reproduction as these often go unnoticed, to create a more accurate overview of the impacts of chemical toxicity. The research on life history traits (sub-lethal) and its link to molecular level interactions could be the key to predicting species sensitivity and will aid the development of more accurate models to predict chemical toxicity. To aid efficiency and scalability of this research, high throughput testing methods are required.
I will be working under the supervision of Dr John Wilkinson at York, Prof Dave Spurgeon at UKCEH and Roman Ashauer from my project partner Syngenta to achieve a number of objectives. These are to; (i) Develop a high-throughput method to measure the growth and reproduction of the model species throughout its life cycle when exposed to different chemical stressors, (ii) Develop a method to observe what is happening to the organism at a molecular level, (iii) Use the collated data to find a link between molecular interactions and life history traits.
Contact: skye.stephenson@york.ac.uk
Owen Trimming - Cardiff University
Project: Advancing in vitro fish models for assessing environmental pharmaceutical risk: Integrating spatial-temporal kinetics of pharmaceutical uptake, biotransformation, metabolism and effect.
Partner: AstraZeneca
My current research seeks to utilise cell culture methods to assess the ecotoxicology of drugs in fish. Pharmaceuticals have been an emerging class of pollutant over the last 30 years and their adverse effects in aquatic environments are often missed by traditional acute toxicity testing.
In my work I will investigate the chronic toxicity of drugs that is associated with their mode of action. The in vitro model will be made up of both primary gill and liver cells so that uptake, metabolism and biotransformation of the drugs can be assessed. A multi-omic approach will be taken, investigating changes in both the transcriptome and metabolome. I also want to explore how individual gill and liver cell types respond to the drugs by utilizing advances in single cell sequencing technology.
I have the privilege of working with Astra Zeneca as my industry partner. My project is also in collaboration with Exeter University and King’s College London.
Contact: TrimmingO1@cardiff.ac.uk
ECORISC CDT
Department of Environment and Geography
University of York
York
United Kingdom
Tel: +44 (0)1903 322999
ecorisc-cdt@york.ac.uk