This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonIntroduction: Endocrine disrupting chemicals are environmental toxicants that
humans are exposed to. Bisphenol A is classified as an endocrine disrupting chemical
with xenoestrogenic capacity. The placenta is one of the least researched human
organs, although it is crucial for the development of the embryo and fetus, and
abnormal placental physiology can cause gestational complications that can lead to
pregnancy determination. As such, we have elucidated the effects of bisphenol A in
physiologically relevant doses on placental cell lines as well as human placental cells
Methods: qPCR, Western blot, immunofluorescence, image stream, ELISA,
microarray, 3D cell culture. Results: In placental cell lines BeWo and JEG-3, estrogen
receptor a was the predominant receptor (p>0.001) in both non-syncytialised BeWo
cells and in JEG-3 cells. 3 nM BPA treatment significantly increased cell proliferation
in BeWo cells compared to controls (p<0.05), and this increase in cell proliferation was
most likely due upregulation of estrogen receptor a (p<0.001) via a pathway involving
p-p38 or p-AKT. Using microarray, pathways involving development of metabolic
diseases such as type II diabetes, obesity and hypertension were significantly
enriched in both the BeWo cell line and human placental cells after bisphenol A
treatment. Finally, 3D models for placental culture were tested, showing that the 3D
environment produces more physiologically relevant models of the human placenta,
and methods prolonging the life of placental explants to up to 16 days were
successfully developed. Conclusion: Bisphenol A in physiologically relevant doses
changes the physiology of the human placenta via an upregulation of estrogen
receptor a, causing an increase of cell proliferation and upregulating pathways that
may result in the development of metabolic diseases, possibly exerting effects as early
as fetal development. 3D models of human placenta should be used as a more
physiologically relevant model of the human placenta when investigating these issues
further