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osteosclerosis, carly depigmentation of hair, sebaceous gland hyperplasia, reduced female fertility and starvation. TTD mice are a valuable experimental model to study a possible link between compromised genome functioning (transcription) induced by DNA damage and the process of aging. RESULTS Tluough regular observation of a large group of aging TTD mice and wild-type littelTI13tes, we noticed that TTD mice develop an overall aged appearance (see Figure 1) at a young age. This, together with the reduced lifespan and characteristic stagnation of development tTiggered us to conduct a more systematic analysis of specific parameters indicative of premature aging. For proper comparison all mice were in a 50% C57BLl6 and 50% 129 background. Cutaneous features of premature aging As reported previously, both skin and hair keratinocytes display abnormalities at late stages of the telTI1inal differentiation process [20]. A more prominent granular and cornified layer in the skin is associated with reduced expression of the SPRR2 gene which is considered a marker for late stages of terminal differentiation of skin keratinocytes [21]. Similarly, TID hairs are brittle due to a deficiency in the group of cystein-rich matrix proteins. These proteins crosslink hair keratin filaments and are expressed at the end of the differentiation program [22]. Another hair abnormality we observed frequently in aging TTD mice was depigmentation, for which the onset and manifestation was heterogeneous but which was significantly earlier and more frequent than the sporadic cases of graying we noticed in wild-type littem13tes. A clear example is shown in Figure 2a with a large patch of gray hairs, which are completely devoid of melanin granules (not shown). Other TTD mice exhibited more subtle depigmentation (e.g. brown instead of black). Besides brittle and depigmented, TrD hairs also had a greasy appearance. Histologic analysis showed that hyperkeratosis in the outer and inner root sheet resulted in follicular plugging and dilatation. Moreover, hyperplasia of the sebaceous gland was observed frequently (Figure 2b). Sebaceous gland cells are indistinguishable between wild-type and TTD mice indicative of their benign nature. Moreover, no malignant conversions were detected, neither in aging mice nor in skin of mice subjected to an UV- or a chemical-induced skin cancer protocol (de Boer et aI., submitted). Both graying and sebaceous gland hyperplasia are features of human aging. 108 Chapter 6
Ovarian dysfunction Although sexual behaviour of most female TTD mice appeared to be unimpaired, as evidenced by the presence of copulatory plugs, full telTIl pregnancy was observed only sporadically. For instance, a group of six female TTD and six wild-type mice were test bred for a period of 6 months to wild-type stud males (starting age 2 months). Only one litter of three pups was observed in the TTD group while all six wild-type females yielded several litters in the same period. To study ovarian function in TTD females in more detail, eight TTD and eight wild-type control females (both age 16 months) were placed with stud males, checked for copulatmy plugs and ovaria were analysed. On histological basis, two groups of TTD animals could be discerned. In the first group (three animals) no signs of an active estrous cycle were found. Ovaries were very small and contained inlmature preanh'al and small antral follicles, but no preovulatOlY follicles, little interstitium and absent corpora lutea, implying complete anovulation (Figure 3A). In these animals a A. B. wi TTO Figlll'e 2. Cutaneous symptoms of aging A) Typical examp\c of early depigmentation in fur of a 13 months old TTD mouse. No depigmentation was found in a group of 10 aged-matched wild-type micc. B) Follicular dilation and scbaceous gland hyperplasia (asterix) in 'fTD compared to wild-type (wt) skin. Mark the hyperkeratoLic TTD epidermis (indicated with an alTow). copulatmy plug was never found, probably resulting from the absence of an estrous cycle. In the other group (five TTD females) a more heterogeneous picture was found. In two animals antral folIicles were present together with new corpora lutea indicating that ovulation had occurred. In addition, ova were present in the oviduct. However, ovulation ill these females probably occurred infrequently, corpora lutea velY Since from prevIOUs cycles were absent (Figure 3B). In another female, an ovulatOlY LH peak probably had taken place, SInce large preovulatory follicles were present with an Premature aging in TTD mice 109
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A MOUSE MODEL FOR TRICHOTHIODYSTROP
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CONTENTS Aim of the thesis 5 Chapte
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AIM OF THE THESIS Nucleotide excisi
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NUCLEOTIDE EXCISION REPAIR AND HUMA
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capacity to generate bulky base add
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strong interaction between XPG and
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XP is characterized by genetic hete
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are diagnosed as a collodion baby (
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23. Gerard, M., Fischer, L., Moncol
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associatcd with mutations in the DN
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CHAPTER 2 MOUSE MODELS TO STUDY THE
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NER DEFICIENCY AND GENOTOXIC SENSIT
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XPC-I-p53+1- mice were more aggress
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tumor development was absent in a g
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[8, 9] reported substantial embryon
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in male sterility. As suggested by
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A point of concern in the extrapola
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CHAPTER 3 DISRUPTION OF THE MOUSE X
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INTRODUCTION To counteract the dele
Page 57: RAD3 and RAD25 protein (the latter
Page 63: CHAPTER 4 A MOUSE MODEL FOR THE BAS
Page 72 and 73: Death occurs after a short period o
Page 77: Table 3. Comparison of the TTDIBEL
Page 81 and 82: model (UDS, UV survival, pathology,
Page 84 and 85: 33. Stefanini, M., Giliani, S., Nar
Page 88 and 89: INTRODUCTION Genomic instability is
Page 91: correlates very well with literatur
Page 96 and 97: mice, which are histologically noml
Page 98 and 99: proneness in mice cOlTesponds with
Page 101 and 102: 18, Lehmann, A. R., C. F, Arlclt, B
Page 103: CHAPTER 6 SYMPTOMS OF PREMATURE AGI
Page 106 and 107: INTRODUCTION The genome is under co
Page 110: oocyte that showed gemlinal vesicle
Page 114 and 115: DISCUSSION Human aging syndromes Ag
Page 116 and 117: lower levels of the anti-oxidants s
Page 118: 6. Nance, M.A and Ben·y, S.A. (199
Page 121 and 122: SUMMARY AND CONCLUSIONS DNA damage
Page 123 and 124: features are due to an impairment o
Page 125: symptoms in normal aging. Oxidative
Page 130 and 131: In Hoofdstuk 5 worden experimenten
Page 132 and 133: LIST OF PUBLICATIONS Bitter, W., va
Page 134 and 135: DANKWOORD Het schrijven van een dan
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