<p> The uterus is essential for mammalian reproduction as it provides environment for conceptus implantation and subsequent development. Endometrial glands synthesize and secrete or transport substances critical for conceptus survival and implantation, demonstrated by the fact that female sheep and mice containing no uterine glands are infertile mainly due to impaired implantation and early pregnancy loss. FOXA2, a transcription factor, has been showed indispensable for not only the development of uterine glands in the neonate but also its differentiated function in the adult. The goal of the current study is to (1) generate a mouse model for the conditional overexpression of FOXA2, and to (2) determine the effects of FOXA2 overexpression on uterine morphogenesis and female fertility.</p><p> In this thesis, Chapter 1 will review the early pregnancy of mice and discuss in detail how the early pregnancy events including blastocyst activation, uterine receptivity, apposition, attachment, penetration, stromal cell decidualization are regulated by different factors and signaling pathways. Chapter 1 will also introduce FOXA2 including its finding, structure, functions in organ development and differentiated function, functions in carcinogenesis and the regulation of its expression. Chapter 2, the research chapter, shows that we developed a mouse model which could express FOXA2 continuously only in the cells with expression of Cre recombinase. By applying two different mouse strains with special Cre expression, we found that misexpression of FOXA2 in the neonatal mouse uterus alters or inhibits normal differentiation and genesis of endometrial glands and function of the adult uterus, leading to female infertility. It also suggests that regulatory elements may localize inside the <i>Foxa2</i> coding sequence and can be targeted by some unknown epigenetic mechanism. This chapter has been recently published in a journal: Endocrinology.</p><p>

Nearly 20% of U.S. children are reported to have neurobehavioral deficits in part linked to environmental exposure to industrial chemicals like polychlorinated biphenyls (PCBs). PCB exposure is associated with neurotoxicity including both reduced IQ and response inhibition. PCBs may affect normal brain development by acting on the thyroid hormone (TH) system, either by reducing serum TH levels and/or by interfering with TH receptors (TRs). A critical endpoint, dependent upon sufficient TH, is maturation of oligodendrocytes during development and therefore subject to disruption by PCBs. Due to the complexity of the brain we used both in vitro and in vivo approaches to understand the mechanism of PCBs interfering with TH action. Previous work in our lab has demonstrated that metabolism of PCB congeners is necessary for them to act on the TR in vitro. In neonatal rat livers, we evaluated the TR-agonistic properties of PCBs on TR-dependent gene expression in the presence and absence of metabolism. We found that expression of TH target genes in PCB-exposed livers varied between different congener combinations and was independent of the PCB-induced reduction in circulating T4 levels. Further evaluation of global changes in gene expression between a commercial PCB mixture A1254 and hypothyroidism revealed that only 25% of TH-responsive genes also respond to PCB exposure. Individual congeners accounted for only half of the A1254 effects on TH-regulated genes, suggesting that unidentified congeners or metabolites are affecting TH action. In the neonatal brain, we evaluated the congener-specific effects on a TH- sensitive endpoint during development, the white matter cell numbers in the corpus callosum (CC). In the CC, hypothyroidism decreased oligodendrocytes by about 80%. A1254 achieved a 35% reduction in oligodendrocytes; an effect mediated by a mixture of individual congeners. Hypothyroidism and A1254 exposure increased astrocyte numbers by 30%, but the effect of A1254 seems to be mediated by yet another subset of PCB congeners independent of the TH serum levels. PCB exposure has a differential effect on glial cell differentiation in the CC compared to hypothyroidism that is congener-specific as well as region-specific. Both changes in glia cells during development are not observed in adulthood. The disruption of glia cell ratio in the CC by PCBs could lead to diminished CNS functionality during a critical window of neonatal development.

Please read the abstract in the section 00front of this document / Dissertation (MSc (Agric))--University of Pretoria, 2007. / Animal and Wildlife Sciences / unrestricted

Typescript. / "April 1987." / Includes bibliograpical references (leaves 160-194). / xii, 194 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Presents direct comparative information on growth and endocrinological aspects of reproductive development in intact and gonadectomized male and female Merino lambs born in autumn and treated prepubertally with either a non-aromatizable androgen (trenbolone acetate) with higher androgenic potency than testosterone, oestradiol -17beta(oestradiol), or a combination of these two steroid hormones. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Sciences, 1988