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Title: The role of xenoestrogens in the initiation of primary biliary cirrhosis
Author: Axon, Andrew
ISNI:       0000 0004 2730 475X
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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Introduction Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease common in postmenopausal women, characterised by the presence of serum antimitochondrial antibodies. Exposure to environmental xenobiotics and estrogenic drugs has been linked to an increased incidence of PBC and cholestasis respectively. We hypothesized that exposure to environmental xenoestrogens may be a risk factor for PBC. Methods A screening system by which compounds could be tested for transcriptional estrogenic activity was developed and validated. Compounds were screened for human estrogenic activity by dual luciferase reporter assay and by measurement of the induction of a known estrogen responsive gene, TFF1. The effects of exposure to xenoestrogens on mitochondrial function was assessed by MTS assay and by measurement of TMRM localization. In vivo effects of exposure to xenoestrogens was examined in a range of mouse models. Results A number of xenoestrogens were identified, notably the azo dyes sunset yellow and tartrazine, however, neither of these tested positive in the classical mouse uterotrophic assay. Further investigations suggested that these compounds might have a higher affinity and/or specificity for ERβ, which may not be critical for sexual development and therefore potentially explains the findings of the in vivo assay. Both sunset yellow and tartrazine caused a significant decrease in hepatocyte TMRM localization and sunset yellow caused a reduction in MTS reduction in primary rat hepatocytes, suggesting these compounds have a detrimental effect on mitochondrial function. In a mouse model of chronic exposure, tartrazine was found to significantly increase portal tract inflammation (PTI), collagen deposition and increase serum ALP activity, all of which are biomarkers of cholestatic liver injury. SYBR-Green qRT-PCR analysis revealed that both estrogen and tartrazine cause significant changes in the expression MRP 1-6 and other drug/bile salt transport proteins in the mouse liver, indicating a potential mechanism for the observed cholestasis. The expression of hepatic 3a11 was inhibited in this model implying antagonism of the pregnane X receptor. Conclusions These findings suggest that exposure to tartrazine, or other xenoestrogens may cause ERβ activation and PXR antagonism in the liver, resulting in altered transporter expression and a cholestatic injury. If this liver insult was coupled with damage/alteration to mitochondrial reductase enzyme function, and/or other genetic/environmental factors, it may be an initiating factor in PBC.
Supervisor: Not available Sponsor: British Toxicology Society ; Health Protection Agency
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available