| Ornithine decarboxylase: Expression and regulation in rat brain and in transgenic mice | ||
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A transgenic mouse line expressing ODC cDNA under the control of an MMTV-LTR promotor was generated and used to study the pathological and physiological effects of deregulated ODC expression during the life of transgenic animals. After the transgenic founder animal was generated, the transgenic mice were followed in seven generations. The average litter size, including both live and dead pups, was not significantly different from that of non-transgenic. However, the breeding of homozygous transgenic mice proved to be difficult due to the high number of infertile mice. In later generations, the ratio of males to females decreased, resulting in low availability of transgenic males for reproduction. At birth, the offspring appeared normal. At about 4 weeks of age, some of transgenic pups were smaller than non-transgenic controls, but that did not prevent them from reaching normal size at adult stage.
When ODC activities were systematically assayed in tissues of transgenic and control animals, the most significant difference was detected in some of the reproductive organs of male mice. The ODC activity was two times higher in testis, about 20 times higher in seminal vesicle and fat pads and about 400 times higher in preputial gland of transgenic males when compared to age-matched non-transgenic animals. A moderate increase in ODC activity was assayed also in the heart and lung of transgenic males. In contrast, the ODC activity was significantly lower in the prostate and kidney tissues. The lower ODC activity in kidneys was observed also in the female transgenic mice, but there were no significant changes in the enzyme activity in the reproductive organs of females. In addition to kidneys, the transgenic females had lower ODC activity in the heart, but increased activity in the brain and liver. Changes were statisticly significant but moderate.
The low fertility rate of transgenic mice can be explained by abnormalities found in the histological examination of sexual organs. The testes of the transgenic mice were smaller than those of control animals. Although the testicular epithelium of most fertile transgenic males was normal and produced normal-appearing spermatozoa, the testicular tissues of several infertile transgenic mice showed a reduced number of mature spermatozoa and immature spermatogenic cells were seen in the testicular lumen. The number of preputial glands in the infertile transgenic mice was reduced and the epithelium in the lumen was occasionally stratified and keratinized. The seminal vesicles and prostates of the transgenic males appeared to be normal. The ovaries of infertile female transgenic mice were smaller than those control females. In addition, the number of follicles was low and chronic inflammatory infiltrates were frequently seen.
The physiological and pathological state of heterozygous transgenic mice was followed for a two-year period. No abnormalities were observed before the age of six months. However, as the mice aged, the number of diseased animals increased and by the age of two years pathological changes were found in 25% of the transgenic mice. Histological examination of tissues from necropsies revealed that most common pathological alterations were inflammatory processes including pancreatis, hepatitis, sialoadenitis and pyelonephritis. Spontaneous tumours were found in eight transgenic mice, including a benign fibroid skin tumour and vascular tumour in the liver, three mammary carcinomas with one lung metastasis, one intestinal adenocarcinoma and a lymphoma. Age-matched non-transgenic mice had no overt histological abnormalities.