Mechanisms of protection against genetic damage in utero

01 December 2011
Dr Ketan Patel, MRC Laboratory of Molecular Biology, Cambridge

The initiating genetic events that can lead to the development of childhood leukaemia can occur before birth, whilst the child is still in the womb. These events may be caused by harmful exposures during pregnancy and Dr Patel is investigating the processes that cause – and protect against – genetic damage before birth.

Amount of grant: £300,000  |  Date of award: December 2011 

Overview

We know that the initiating genetic events that can lead to the development of childhood leukaemia can occur before birth, whilst the child is still in the womb.

These predisposing genetic mutations may be caused by harmful exposures during pregnancy.
Dr Patel and his team have just completed work that indicates that naturally-produced substances called aldehydes can cause genetic damage in utero.

These aldehydes originate from dietary sources such as alcohol as well as from natural metabolic processes.

The team’s recent work demonstrates how the body has a double layer of protection against the harmful effects of aldehydes.

They now wish to understand how naturally produced aldehydes and those derived from alcohol intake interfere with fetal development, blood stem cell function and how they may lead to the generation of acute leukaemia.

Background

Dr Patel’s main research interest is a disease called Fanconi Anaemia (FA). Children with FA have a variety of problems, including developmental defects, bone marrow failure and an enormous lifetime risk of leukaemia and other cancers.

The basic biological defect in FA is that the body cannot repair a specific form of DNA damage caused by exposure to certain chemicals including a group of substances called aldehydes. Aldehydes originate from natural metabolic processes as well as from dietary sources such as alcohol.

Dr Patel and colleagues have shown that - in healthy children - the body has two layers of protection against genetic damage from aldehydes. The first layer consists of enzymes that break down aldehydes into harmless products. The second layer of protection is a mechanism that repairs damaged DNA.

In the current project, they will build on this previous work, further exploring the way in which aldehydes interfere with embryonic development and blood stem cell function.

They also aim to establish the role played by maternal alcohol consumption in these processes.

Mechanisms of protection against genetic damage

In this complex project, the team will study mice that lack one or both of the layers of protection against aldehydes to determine the effect that either or both defects have on their development.

They will also study the effects of exposure to alcohol – to establish its effects on blood stem cells and whether exposure promotes the development of blood cancers.

What difference will this project make?

This project will take forward our understanding of the mechanisms underlying the development of childhood leukaemia.

It will advance our knowledge of the extent to which the in utero environment may contribute to the development of ALL, in particular the impact of maternal alcohol consumption.

Read more: Acute lymphoblastic leukaemia (ALL)Acute myeloid leukaemia (AML) | Causes of childhood cancer
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