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postgraduate thesis: Effect of the endocrine disruptor perfluorooctane sulfonate (PFOS) on human pregnancy establishment

TitleEffect of the endocrine disruptor perfluorooctane sulfonate (PFOS) on human pregnancy establishment
Authors
Issue Date2017
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Li , T. [李天天]. (2017). Effect of the endocrine disruptor perfluorooctane sulfonate (PFOS) on human pregnancy establishment. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractPerfluorooctane sulfonate (PFOS), a widely used man-made surface-active agent in a variety of industrial products, has been identified as an endocrine disruptor. PFOS is detectable in both wildlife and human bodies. The human serum PFOS level has been suggested to be associated with reproductive disorders including female infertility, preeclampsia and miscarriage. Yet, the molecular mechanisms leading to the reproductive problems remain largely unknown. The aims of the present study were to investigate the in-vitro effect of PFOS on early pregnancy events, including embryo attachment, trophoblasts invasion and decidual migration. It was hypothesized that PFOS might interfere with the above steps through perturbation of critical intracellular signaling pathways like WNT/β-Catenin signaling. In this study, the effect of PFOS on embryo attachment was investigated by the trophoblastic Jeg-3 spheroids/endometrial epithelium in-vitro co-culture model. The effect of PFOS on trophoblasts invasion was studied by the in-vitro spheroids collagen gel invasion model and transwell invasion model. Decidualization of endometrial stromal cells was induced in-vitro by cAMP, estradiol and progesterone supplemented medium. The effect of PFOS on decidual migration was analyzed in-vitro in the transwell migration model and on culture plate surface. Quantitative PCR and gelatin zymography were used to semi-quantitate the transcripts levels of trophoblastic intracellular MMP2/9 and the activities of secreted MMP2/9, respectively. The modulation of PFOS on WNT/β-Catenin signaling in both epithelial and trophoblastic cells was explored by Western blotting to understand the molecular mechanisms involved in the PFOS function. It was found that (1) PFOS suppressed Jeg-3 spheroids attachment on both endometrial epithelial cell line RL95-2 and primary epithelial cells. The effect was mediated mainly through epithelial PPAR-α and in turn the inactivation of the uterine WNT/β-Catenin signaling. (2) PFOS inhibited outgrowth and invasion of Jeg-3 spheroids on collagen gel as well as in Matrigel-coated inserts. This inhibition was mediated by the inactivation of trophoblastic WNT/β-Catenin signaling and down-regulation of MMP2 and MMP9. (3) Stromal decidualization, as confirmed by morphological changes and up-regulation of intracellular IGFBP-1 and prolactin proteins, was not affected by PFOS treatment. However, PFOS suppressed the trophoblasts-induced migration of decidual cells in transwell inserts and on culture plate surface, suggesting that PFOS may not affect decidualization, but interfere with the interaction between trophoblastic and decidual cells in early pregnancy. In summary, the in-vitro experiments demonstrated that PFOS exerted detrimental effects on embryo attachment, trophoblasts invasion and decidual migration. Abnormal embryo implantation and decidual function may contribute to infertility and pregnancy complications such as miscarriage and preeclampsia. Therefore the results from these in-vitro studies reveal several possible mechanisms underlying the epidemiologic associations between serum PFOS levels and above reproductive disorders.
DegreeDoctor of Philosophy
SubjectPregnancy
Organic compounds - Health aspects
Health aspects - Persistent pollutants
Dept/ProgramObstetrics and Gynaecology
Persistent Identifierhttp://hdl.handle.net/10722/253233

 

DC FieldValueLanguage
dc.contributor.authorLi ,Tiantian-
dc.contributor.author李天天-
dc.date.accessioned2018-05-14T02:02:22Z-
dc.date.available2018-05-14T02:02:22Z-
dc.date.issued2017-
dc.identifier.citationLi , T. [李天天]. (2017). Effect of the endocrine disruptor perfluorooctane sulfonate (PFOS) on human pregnancy establishment. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/253233-
dc.description.abstractPerfluorooctane sulfonate (PFOS), a widely used man-made surface-active agent in a variety of industrial products, has been identified as an endocrine disruptor. PFOS is detectable in both wildlife and human bodies. The human serum PFOS level has been suggested to be associated with reproductive disorders including female infertility, preeclampsia and miscarriage. Yet, the molecular mechanisms leading to the reproductive problems remain largely unknown. The aims of the present study were to investigate the in-vitro effect of PFOS on early pregnancy events, including embryo attachment, trophoblasts invasion and decidual migration. It was hypothesized that PFOS might interfere with the above steps through perturbation of critical intracellular signaling pathways like WNT/β-Catenin signaling. In this study, the effect of PFOS on embryo attachment was investigated by the trophoblastic Jeg-3 spheroids/endometrial epithelium in-vitro co-culture model. The effect of PFOS on trophoblasts invasion was studied by the in-vitro spheroids collagen gel invasion model and transwell invasion model. Decidualization of endometrial stromal cells was induced in-vitro by cAMP, estradiol and progesterone supplemented medium. The effect of PFOS on decidual migration was analyzed in-vitro in the transwell migration model and on culture plate surface. Quantitative PCR and gelatin zymography were used to semi-quantitate the transcripts levels of trophoblastic intracellular MMP2/9 and the activities of secreted MMP2/9, respectively. The modulation of PFOS on WNT/β-Catenin signaling in both epithelial and trophoblastic cells was explored by Western blotting to understand the molecular mechanisms involved in the PFOS function. It was found that (1) PFOS suppressed Jeg-3 spheroids attachment on both endometrial epithelial cell line RL95-2 and primary epithelial cells. The effect was mediated mainly through epithelial PPAR-α and in turn the inactivation of the uterine WNT/β-Catenin signaling. (2) PFOS inhibited outgrowth and invasion of Jeg-3 spheroids on collagen gel as well as in Matrigel-coated inserts. This inhibition was mediated by the inactivation of trophoblastic WNT/β-Catenin signaling and down-regulation of MMP2 and MMP9. (3) Stromal decidualization, as confirmed by morphological changes and up-regulation of intracellular IGFBP-1 and prolactin proteins, was not affected by PFOS treatment. However, PFOS suppressed the trophoblasts-induced migration of decidual cells in transwell inserts and on culture plate surface, suggesting that PFOS may not affect decidualization, but interfere with the interaction between trophoblastic and decidual cells in early pregnancy. In summary, the in-vitro experiments demonstrated that PFOS exerted detrimental effects on embryo attachment, trophoblasts invasion and decidual migration. Abnormal embryo implantation and decidual function may contribute to infertility and pregnancy complications such as miscarriage and preeclampsia. Therefore the results from these in-vitro studies reveal several possible mechanisms underlying the epidemiologic associations between serum PFOS levels and above reproductive disorders. -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshPregnancy-
dc.subject.lcshOrganic compounds - Health aspects-
dc.subject.lcshHealth aspects - Persistent pollutants-
dc.titleEffect of the endocrine disruptor perfluorooctane sulfonate (PFOS) on human pregnancy establishment-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineObstetrics and Gynaecology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2017-
dc.identifier.mmsid991043962780603414-

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