The Modification of the Endocrine System of Domestic Animals

Manipulation of the endocrine status of domestic animals was an obvious early target for transgenesis following the pioneering research of Palmiter et al. (6,7) in laboratory mice and, as a consequence, has received considerable attention over the past few years. The results have been reviewed in detail several times in recent years (13-18), so in this section, only the overall conclusions from the work will be summarized, together with some evaluation of the commercial potential of the approach.

When the genes used in the initial mouse experiments were transferred to pigs, sheep, and rabbits (8), using the mouse metallothionein-I (MT-I) promoter and the human or the bovine growth hormone coding sequences, constitutive expression of the transgenes was obtained (13,14,16). This gave rise to a large rise in the level of circulating growth hormone but, in contrast to the mice, did not result in larger animals. Moreover, the animals were physiologically abnormal (13,14), and it became clear that the larger domestic animals did not respond to elevated growth hormone concentrations in the same way as laboratory mice (19,20).

The initial results in pigs and sheep were obtained with transgenes encoding heterologous growth hormone proteins (bovine or human), and therefore, it was suggested that the poor growth response may have been owing to poor recognition of the hormone, particularly in view of a report that a faster-growing transgenic pig had been produced that contained a transgene-encoding porcine growth hormone (15). However, such an explanation now appears unlikely, because transgenic sheep with elevated levels of the natural ovine growth hormone and transgenic pigs with elevated porcine growth hormone all exhibit the same poor growth and abnormal physiology, as do those animals with excess heterologous hormone (9,21). Rexroad et al. (19) showed that transgenic sheep with excess bovine growth hormone were diabetic, which suggests that the animals become acromegalic, diabetes being a typical symptom of this disease state. Nancarrow et al. (18,21) looked in detail at the physiology of transgenic sheep containing extremely high levels of the natural sheep growth hormone, and arrived at similar conclusions to those of Rexroad and his col leagues. The animals had an elevated basal metabolic rate and an associated high cardiac output, IGF-1 was elevated, and renal function was impaired. Bone growth was abnormal, particularly in the front limbs, and the internal organs of the transgenic sheep were significantly larger than controls. The animals showed obvious symptoms of diabetes, and all died within one year of birth.

For the commercial application of this line of research, the chronic high production of growth hormone must be avoided. Although a number of attempts at achieving this goal have been made, as yet none have been successful. One approach has been to control the actual release of the growth hormone by the action of other genes. Thus, the gene encoding the growth-hormone-releasing factor has been placed under metallothionein promoter control by Pursel et al. (13,14), and the resulting transgenic animals produced elevated levels of the releasing factor, but the concentration of growth hormone itself was not altered. As a result, the transgenic animals remained healthy and of normal appearance, and did not grow at any faster rate than controls. In a similar experiment (22), growth-hormone-releasing factor coding sequences were placed under the control of the human transferrin gene promoter, but similar results were obtained.

A different approach has been to use promoters other than that of the metallothionein gene. Wagner (12) placed the growth-hormone-coding sequence under the control of a promoter sequence isolated from the gene encoding the enzyme phosphoenolpyruvate carboxykinase, the expression of which can be regulated by the ratio of carbohydrate:protein in the diet, but again, no growth of the transgenic animals beyond that of controls was obtained. Rexroad et al. (22) have used the albumin promoter to direct growth-hormone synthesis to the liver in transgenic sheep, but this also failed to provide the appropriate regulation for enhanced growth in these animals.

It is apparent that animals with enhanced growth and improved feed efficiency are possible using the approach of modifying growth-hormone levels, but only if the production of the hormone is very tightly regulated so that its concentration remains within physiological limits and if the transgene can be rendered transcriptionally silent at will. With current technology, this is a formidable challenge, but achieving it is essential for commercial application of the results.

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