Mechanisms underlying establishment and maintenance of pregnancy

Implantation is initiated when an embryo attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2α), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2α expression. Further studies revealed that HIF2α regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2α-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during maternal adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy. Endocrine-disrupting chemicals like di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are ubiquitous in nature and human exposure to these chemicals is inevitable. The impact of exposure to these phthalates in the establishment and maintenance of pregnancy remains largely unknown. The current study focuses on understanding the effect of exposure to an environmentally relevant dose (20 µg/kg/day) of DEHP or DiNP on pregnancy. The study shows that phthalate exposure during early pregnancy results in loss of fetuses at latter stages of gestation, causing a reduction in the litter size. Interestingly, between the two phthalates, the extent of fetal loss was significantly greater in the DiNP group. While both DEHP and DiNP affect stromal cell differentiation and decidual angiogenesis, significant disorganization of the placental layers was only observed in the DiNP-treated mice. Interestingly, the fetuses from the DiNP group that do manage to survive in the sub-optimum uterine environment, though weigh less at birth, eventually gain weight and develop normally. Further studies are needed to gain a comprehensive understanding of how phthalates affect different cell types during placentation.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

VMS - Comparative Biosciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Bhurke, Arpita Shridhar

Contributors dc:contributor

• Bagchi, Indrani C
• Bagchi, Milan
• Yang, Jing
• Nowak, Romana

• pregnancy
• embryo implantation
• HIF2α
• RAB27B
• DEHP
• DiNP

Statement dc:rights

• copyright 2021 Arpita Bhurke

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/113330

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/113330