Epigenetic biomarkers for predicting transgenerational consequences of pollution exposure.

Supervisors:

• Dr Hollie Marshall Hjm32@leicester.ac.uk
• Dr Ricky Joshi
• Dr Mathew Van de Pette (Toxicology Department UKHSA)
• Professor Anna Hansell (Centre for Environmental Health and Sustainability)

Project Description: 

We are beginning to understand how everyday environmental exposure to things like pollution can cause disease. Of particular concern are “forever chemicals”, such as Per- or poly-fluorinated alkyl substances (PFAS), with some compounds taking >1000 years to degrade. Whilst we are starting to understand the adverse health outcomes linked to “forever chemicals” in individuals, the transgenerational consequences of exposure to these compounds remain largely unknown. This means that even if these substances are cleaned up from the environment, future generations may still be affected.

Epigenetic mechanisms, such as DNA methylation, provide a means of transmitting environmental information from one generation to the next. Not only are they sometimes the causative agent of disease, as is the case with certain cancers, but they can also act as biomarkers, predicting future disease states. Transgenerational epigenetic inheritance of pollution exposure is particularly difficult to predict in human populations due to a lack of historical data. With the mandated decrease in the use of animal testing, New Approach Methodologies (NAMs) and New Approach Technologies (NATs) are now heavily relied on to model potential transgenerational outcomes. However, the lack of biological similarity (with NAMs) and complexity (with NATs) means that results are often not representative of real-world epigenetic changes. 

This project will assess the applicability of an OECD approved NAM (Daphnia magna – a water flea) and NAT (iPSC-derived cells) for predicting PFAS-induced DNA methylation changes in humans. 

Brief expected timeline:

• Year 1: Link parental DNA methylation changes in PFAS-exposed Daphnia to transgenerational fitness outcomes (are there epigenetic biomarkers for future offspring health?). 
• Year 2: Identify DNA methylation changes in PFAS-exposed iPSC-derived cells and determine the similarity to the identified biomarkers from year 1 (do Daphnia and human cells show similar epigenetic changes?)
• Year 3: Compare publicly-available DNA methylation data (Generation Scotland) from families with assumed higher/lower PFAS exposure, to the DNA methylation changes observed in years 2 and 3 (how appropriate are the tested NAMs and NATs to real-world human epigenetic responses?)

Research environment:

This is a multi-disciplinary project where you will learn skills in; experimental lab work, multiple toxicological approaches, generation of genetic sequencing data and bioinformatic analysis – opening doors for a career in a wide variety of sectors. You will be supervised by a team of epigenetic and disease specialists spanning the core components of the project: Dr Marshall - UoL (Daphnia and non-model organism bioinformatics), Dr Joshi - UoL (human bioinformatics), Dr Van de Pette – UK Health Security Agency (mammalian toxicology) and Prof Hansell - UoL (human environmental epidemiology).

References:

• Takahashi, et al. (2023) Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice. Cell. 186, 1-17.
• Thorson, et al. (2020) Epigenome-wide association study for pesticide (Permethrin and DEET) induced DNA methylation epimutation biomarkers for specific transgenerational disease. Environmental Health. 19(109).
• Jeremias, et al. (2022) Multigenerational DNA methylation responses to copper exposure in Daphnia: Potential targets for epigenetic biomarkers? Chemosphere. 308(1).
• Chaturvedi, et al. (2023) The hologenome of Daphnia magna reveals possible DNA methylation and microbiome-mediated evolution of the host genome. Nucleic Acids Research. 51(18).