THE HUMAN FETAL LIVER: DEVELOPMENTAL GENETICS AND RESPONSE TO MATERNAL DRUG USE

"It is well known that if a woman smokes while pregnant there are bad consequences for the resulting offspring, especially slowed growth in the womb. However, other serious problems are also likely to occur in children exposed to their mothers' cigarette smoke chemicals during pregnancy. These include an impaired immune system (e.g. increased asthma), poorer educational performance and a raised chance of developing obesity, diabetes and heart disease (called metabolic syndrome). Many of these effects also happen if the mother regularly drinks alcohol while pregnant, even if not to the extent of addiction. We do not know exactly how much the chance of somebody developing metabolic syndrome is altered if their mother smoked and/or drank while pregnant. However, a recent study of 74,000 women found that if their mothers smoked while pregnant, the women had a 53% higher chance of becoming obese. This would be a major added drain on the NHS and would mean that many more people would be likely to suffer these debilitating conditions since smoking and/or alcohol use during pregnancy continues in 20-40% of women. In 2006-07 costs to the English NHS of lifestyle and related conditions were: smoking £3.3 billion, alcohol £3.3 billion, overweight/obesity £5.1 billion and diabetes £3.5 billion annually.

Adult health is partly programmed by events during fetal life when the individual is still in the womb and an individual may be badly adjusted for life if the mother uses recreational drugs. Growth restriction is important in this process and the liver is one of the organs most affected by disturbed growth before birth. The fetal liver is a key organ, protecting the fetus from harmful chemicals and controlling fetal growth. Progress in understanding the effects of maternal drug use on fetal development suffers from two problems: firstly, our ignorance of the levels of drugs to which the fetus is exposed and, secondly, the mechanisms by which these drugs affect development. Two factors contribute to our ignorance. Firstly, very little research uses normal human fetuses. Secondly, there is a lack of low-cost means with which to measure how much/which chemicals (nicotine, alcohol, cannabis etc.) are getting into the human fetus during pregnancy. This project aims to resolve these issues using our uniquely large collection of normal, second trimester human fetal livers and by collecting both the liver and the placenta from further terminations of normal pregnancies.

We will use highly sophisticated methods at the National Institute on Drug Abuse (USA) to measure chemicals from tobacco, cannabis, cocaine and alcohol in the fetal liver and in matched pairs of fetal livers and placentas. This will tell us how much the fetus has been exposed to drugs taken by the mother and whether the placenta can be used to measure the fetal burden of drugs and chemicals from the mother. This would allow us to carry out much larger studies of newborn babies to measure exposure levels in the placenta and their contribution to adult ill-health.

At the same time as measuring drug levels in the fetal liver we will work out how those drugs have affected liver function. Then, by using cell culture, it will be possible to re-create the effects of drug exposure in the culture dish with a view to understanding the long-term consequences. We will also be able to find out more about how liver function develops and how it differs between male and female babies Overall, our aim is to relate changes in the control of fetal liver development to the effects of chemicals in cigarette smoke. This will allow us to understand liver mal-development turns to metabolic syndrome. The information from this study will allow us to measure, and to understand, the effects of exposing the developing fetus to its mother's recreational drug use. This will enable treatments to be designed to reverse these effects and to lower the incidence of the modern scourge of metabolic syndrome."