Prenatal programming of the reproductive axis: the role of somatostatin

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During life in the womb animal and human foetuses are largely protected from substances that might adversely affect their development. However, there are certain situations in which substances that may be present in the mothernal environment in unusually high concentrations or reach the developing foetus because of some physiological disfunction in the mother, that may cause abnormalities in foetal development. These abnormalities are not always obvious at birth and may not cause a problem or lead to a disease state until maturity is reached. Because there is a long lag time between the appearance of the abnormal state and the causal agent we refer to the disease as having been 'programmed' by early life experience. Hormones like those made in our gonads can, are required to programme certain aspects of normal development, the most obvious being the secondary sexual characteristics of males and females. However, in some situations, exposure to abnormal amounts or patterns of such hormones can result in abnormal or disease states. For example, if female foetuses are exposed to abnormally high concentrations of the male hormone testosterone during development this can lead to malfunctions in the reproductive system of the offspring in adulthood that, in extreme cases, may result in infertility. These abnormal hormone concentrations might be produced by some malfunction in the mother (for example a hormone releasing tumour) and cross that cross to the unborn young. Alternatively they may originate in the environment, pass into the mother and from her to the foetus. Examples of environmental agents include the so-called 'endocrine disruptors' that bear little chemical resemblance to the hormones themselves but are able to mimic their actions in the body. Several reports in the scientific and popular press have suggested that infertility in the human population is increasing and that substances in our environment, including those we are exposed to before birth, may contribute to this. Studies, that have already been completed, have have shown that certain hormones act in the developing brain (including the parts that control the reproductive system) to organise it in such a manner that it eventually begins to behave abnormally in later life. The major aim of this project is to understand how the specialised nerve cells (neurones) that control female reproduction become disrupted by exposure to testosterone before birth. These specialised cells synthesise Gonadotrophin releasing hormone (GnRH). As we cannot use the human brain to make these determination we use a good animal model of the situation, which is the case of this proposal is the female sheep that has been exposed, as a foetus, to an abnormally high concentration of testosterone. Our studies focus of a group of neurones that play a key role in controlling the GnRH neurones and release a peptide known as somatostatin. The project will identify somatostatin cells in the brain, the factors that make them active to release somatostatin and the location of receptors on which the somatostatin might act. Importantly, we will determine if there are differences between normal ewe brains and those that have been exposed to testosterone in the uterus.