Environmental determinants of chromosomal translocations and DNA methylation: towards identifying and understanding modifiable risk factors of childhood leukaemia

Saville, Jessica (2022) Environmental determinants of chromosomal translocations and DNA methylation: towards identifying and understanding modifiable risk factors of childhood leukaemia. Doctoral thesis, Northumbria University.

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Leukaemia is the most common type of cancer found in children, with incidence rates increasing. Chromosomal translocations are considered one of the leukaemia initiating events. Causes of many chromosomal translocations remain unknown. Further molecular events, such as epigenetic changes, are considered necessary for disease progression. Epidemiological studies have identified many environmental exposures associated with increased risk of childhood leukaemia. There is little understanding of the molecular role these exposures play in the induction of chromosomal translocations or epigenetic changes, such as DNA methylation.

The aim of this project was to use in vitro techniques to screen for the induction of chromosomal translocations in response to environmental exposures i.e. caffeine, benzene (smoking/air pollution), cotinine (smoking) and folate. To explore the potential role of DNA methylation in childhood leukaemia development, a bioinformatic analysis investigated the correlation between altered methylation in childhood leukaemia subtypes and environmental risk exposures.

The NALM6 cell line was used as an exposure model to detect TCF3-PBX1 and RUNX1-RUNX1T1 translocations via RT-PCR assays. Preliminary experiments investigating physiologically relevant concentrations of caffeine, benzene, cotinine, and folate, observed translocation events with each risk exposure. Further cell line models were optimised to investigate the impact of daily exposures and first exposure during exponential cell growth, which also observed translocation events for each risk exposure. However, in these further studies, translocation events were also observed in DMSO treated control cells suggesting DMSO could be a contributing factor to the translocation events observed.

Using a meet-in-the-middle approach, methylation patterns were found to be significantly overlapping between specific childhood leukaemia subtypes and radiation, alcohol, smoking, nursery attendance, reported colds and maternal plasma folate.

Understanding the environmental risk contributing to chromosomal translocations and epigenetic events that aid disease progression may be useful to influence public health policy to assist and tailor prevention strategies for childhood leukaemia.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: caffeine, smoking; benzene and cotinine, folate, environment, maternal exposure
Subjects: C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
University Services > Graduate School > Doctor of Philosophy
Depositing User: John Coen
Date Deposited: 12 Jul 2023 09:23
Last Modified: 12 Jul 2023 09:30
URI: https://nrl.northumbria.ac.uk/id/eprint/51612

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