As exogenously administered RA suppressed the expression of the RA synthesizing enzymes, further investigation on whether this would lead to deficiency in endogenous RA concentrations was conducted. Results showed that exogenously administered RA significantly reduced the endogenous RA level in the head region with C57 embryos showing a greater reduction than ICR embryos. / In addition, detailed morphological and histological studies were conducted to determine if RA treatment caused early embryonic changes with strain difference. When compared with ICR embryos, C57 embryos exhibited more pronounced responses to RA, including developmental retardation, underdevelopment of the anterior neural plate and absence of or smaller optic pit/optic vesicle formation. However, RA treatment did not cause abnormal apoptosis in the early stages in both strains. / Since the teratogenic effect of RA is highly developmental stage-dependent, it is possible that there is a difference in the developmental stage between these 2 mouse strains at the time of RA injection. Indeed, it was found that the developmental stage of ICR embryos was approximately 6 hours ahead of C57 embryos. However, the role that this factor plays in the differential strain susceptibility to RA can be excluded since C57 fetuses were still 3 times more susceptible to developing anophthalmia/microphthalmia than ICR fetuses that were subject to RA treatment at equivalent developmental stages. Comparison of susceptibility to RA-induced anophthalmia/microphthalmia was also made among heterozygous fetuses obtained from reciprocal matings between C57 and ICR male and female mice, and those in homozygous ICR and C57 fetuses. Results showed that the C57 strain has conferred both genetic predisposition and maternal effects in increasing the embryo's susceptibility to RA-induced ocular defects. / Since the type of RA-induced ocular defects mimic those that developed in Raldh2 null mutant embryos, the effect of RA treatment on the expression of RA synthesizing enzymes, Raldh2 and Raldh3, and the RA-inducible gene Cyp26a1, as well as some early eye development genes were examined. Exogenously administered RA reduced the mRNA expression levels of Raldh2, Raldh3 and Cyp26a1 in the head region, with C57 embryos showing a greater reduction than ICR embryos. / Taken together, results of this thesis suggest that there is a strain difference in susceptibility to RA-induced ocular defects in which exogenously applied RA suppresses the expression of RA synthesizing enzymes and leads to endogenous RA deficiency. This finding may shed light on understanding why both excess and deficiency of RA can lead to similar types of ocular defects. / To determine if there are strain differences in the susceptibility to RA-induced ocular defects, two mouse strains were used. They are C57BL/6J (C57), mice that spontaneously develop ocular defects and ICR mice, which are not prone to developing ocular defects. Detailed time and dose response studies were conducted and eye defects were examined in near-term fetuses. C57 fetuses were found to be significantly more susceptible to RA-induced anophthalmia/microphthalmia than ICR fetuses. / Vitamin A (retinol) and its most active metabolite, all- trans retinoic acid (RA) is essential for vision in the adult and for eye development in the embryo. It is well documented that in humans, excess intake or deficiency of vitamin A or RA is associated with congenital ocular defects such as microphthalmia. However, the underlying mechanism remains unclear. The aim of this study is to examine the pathogenic mechanism of RA-induced developmental ocular defects. / Lau, Wing Sze Josephine. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0240. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 186-211). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344359 |
| Date | January 2009 |
| Contributors | Lau, Wing Sze Josephine., Chinese University of Hong Kong Graduate School. Division of Ophthalmology and Visual Sciences. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xxvii, 211 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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