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Osteoporosis   p 11
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5 Current research on programming Link to the Medical Research Council web site
5.3 Programming
Programming is the term used to describe permanent changes in structure and function caused by environmental stimuli during critical periods of early development. During embryonic life, the basic form of the human baby is laid down in miniature. The embryo does not contain a description of the final person. Rather, it contains in its genes a programme for making a person. The genes have to be expressed to make the proteins which determine the structure and physiology of the body's tissues and systems. They are then transcribed into mRNA and translated into the proteins (see The human genome project to find out more). An adverse environment during sensitive periods of early life can permanently alter gene expression. The effect has been shown very clearly in animals (see below).

An animal model of programming
A remarkable example of programming can be seen in the effect of temperature on the sex of reptiles. If the eggs of an American alligator are incubated at 30°C, all the offspring are female. If incubated at 33°C, all the offspring are male. At temperatures between 30 and 33°C, there are varying proportions of females and males. It is believed that the fundamental sex is female, and a transcription factor is required to divert growth along a male pathway. Instead of the transcription factor being controlled genetically by a sex chromosome, it depends on an environmental factor - in this case, temperature.
Programming and the risk of osteoporosis
Organ systems in the body are most susceptible to programming during periods when they are growing rapidly. In the fetal period (from 9 weeks after conception onwards) the highest skeletal growth rates are observed. Growth slows in late gestation and continues to slow in childhood. The main feature of fetal growth is cell division. Slowing of the rate of cell division is a major adaptation to under-nutrition. A reduction in cell numbers is a possible mechanism for programming in humans. However recent research suggests that the risk of osteoporotic fractures may depend on the programming of the endocrine systems which control bone growth.

It has been found that birth weight and weight in infancy are predictors of basal levels of growth hormone (GH) and cortisol during late adult life. The levels of these hormones are also determinants of bone loss rate. The secretion of these hormones is controlled by the hypothalamic–pituitary gland–adrenal (HPA) axes. It is thought that an inbalance in maternal body composition, nutritional demands and fetal demands may permanently change the HPA axes (Figure 17).

Build up diagram of programming
Figure 17. This is a schematic representation of the programming of osteoporosis. Roll over the arrows to build up the diagram.
Look at figure 17. It shows a theory for how the programming might work.
Roll over the arrows to build up the diagram.

If there is an inbalance between maternal body composition, nutritional and fetal demands, there may be a change in the setting of the hypothalamic-pituitary growth hormone and adrenal glucocorticoid axes, which affects peak skeletal size and mineral density as well as subsequent rate of bone loss. Poor fetal nutrition also modifies muscle function and connective tissue ageing, increasing the risk of falls in later life.

The programming mechanism

The mechanism may involve receptor proteins. The hypothalamus is connected to and regulates the pituitary gland. The hypothalamus - pituitary gland axis is the main link between the nervous system and the endocrine system and its hormones; cell receptors in the nervous system monitor the blood and the hypothalamus passes the information to the pituitary gland which, by its secretion of hormones, regulates the activity of other endocrine glands. For example, in the case of glucocorticoids, the pituitary gland regulates secretion from the adrenal cortex. The principal role of the system is to maintain homeostasis, or constant conditions. Programming permanently modifies the feedback systems that control growth. It is thought that it may involve changes in the sensitivity of the receptor proteins to hormone levels. If the sensitivity is permanently set to a different level this could lead to a corresponding change in the basal level of the circulating hormones.

The underlying cause is thought to be the interaction of the nutrient environment with the genome. Although the mechanism is not yet understood, gene expression would be permanently altered so that changes persist. Evidence for an interaction between genes and the environment comes from studies on the effect of polymorphisms within the Vitamin D receptor gene (VDR). It has been demonstrated that the effect of different VDR polymorphisms on an individual's BMD depends on their birth weight.

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Question 10
In the alligator model of programming, it is thought that a ‘transcription factor’ is affected by the temperature.

A transcription factor is a protein which regulates the process of transcription.

What is this process?