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    Mechanisms of estrogenic endocrine disruption of female puberty and reproduction and functions of LHFPL2 on distal reproductive tract development

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    Date
    2014-08
    Author
    Zhao, Fei
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    Abstract
    Reproduction is essential for the continued existence of species. Both environmental and genetic factors can affect reproduction. This dissertation has two main focuses: I) effects and mechanisms of estrogenic endocrine disruptors, zearalenone (ZEA) and diethylstilbestrol (DES), on puberty and female reproduction; II) effects of a point mutation in lipoma HMGIC fusion partner like-2 (Lhfpl2) gene on distal reproductive tract development in mice. Results from the 1st part of the research can be summarized as follows: A. Postweaning exposure to dietary ZEA advanced the timing of pubertal onset indicated by vaginal opening and disrupted embryo implantation in a dose-dependent way. Pre-mating or post-mating exposure to 40 ppm ZEA in diet affected fertilization or delayed embryo transport and embryo development, respectively, to impair embryo implantation (Chapter 2). B. Multigenerational exposure to 20 ppm dietary ZEA cumulatively impaired fertility, which could be partially alleviated upon exposure cessation (Chapter 3). C. Exposure timing is critical for endocrine disruption of puberty and early pregnancy. Peripubertal exposure to 50 ppb DES significantly advanced the timing of vaginal opening. Peripubertal exposure to 50 ppb DES reduced the numbers of corpora lutea whereas post-mating exposure to 50 ppb DES affected postovulation events, both led to impaired embryo implantation (Chapter 4). The initial goal in part II of the dissertation was to investigate the mechanisms of vaginal opening using a Lhfpl2 mutant mouse model that had vaginal imperforation (Chapter 5). However, extensive studies showed that the vaginal imperforation was due to defective embryonic development of the distal vagina, resulting in female infertility. Interestingly, similar pathology was observed in Lhfpl2 mutant males that had abnormal structure of the distal reproductive tract, causing infertility in ~70% of males. In situ hybridization and immunohistochemistry localized Lhfpl2/LHFPL2 in the epithelium of female and male reproductive tracts. In vitro overexpression studies showed that wild-type and mutant LHFPL2 were both localized in the endoplasmic reticulum but only the wild-type LHFPL2 was expressed in the filopodia. This dissertation provides novel knowledge about mechanisms of estrogenic endocrine disruption of female puberty and reproduction, as well as a genetic basis of distal reproductive tract development.
    URI
    http://purl.galileo.usg.edu/uga_etd/zhao_fei_201408_phd
    http://hdl.handle.net/10724/31357
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