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Environmental Estrogens: Assessing Human Gestational Exposure and Interactions with the Estrogen Receptor

Environmental xenoestrogens (EEs) are chemicals that when they enter the body, the body
responds to them as it would to endogenous estrogens. Humans are exposed to these
chemicals on a daily basis via natural components, additives and contaminants in food and
water, through the use of pharmaceuticals and personal care products such as sunscreens,
lotions and toothpaste. Exposure to EEs is thought to result in adverse effects on humans
such as decreased fertility, increased susceptibility to hormone-sensitive cancers, deformities
of the male genitalia and precocious puberty in females. The critical window of exposure is
thought to be early fetal development, when tissues are rapidly differentiating under the
control of endogenous estrogens. However, there is limited data in the literature on human
fetal exposure to EEs. The first objective of this study was to assess human fetal exposure to
a suite of 35 EEs by analysis of paired samples of amniotic fluid and maternal urine were
collected from 32 New Zealand women between 14 and 20 weeks gestation. The analytical
chemistry methods required for this study were developed and validated. The results
demonstrate that fetal exposure is highly correlated with maternal exposure. This study is the
first to report maternal urine levels of two UV filters and amniotic fluid levels of parabens,
UV filters and triclosan. A model based on simple additivity of effect was developed that
combined the measured concentrations with literature data on relative estrogenic potency to
assess the magnitude of the estrogen signal that may be attributed to the EEs. This model
suggests that the fetus may experience an estrogen signal due to the measured EEs that could
be as large as the endogenous estrogen signal. A second objective was to use computational
docking to study the interactions of the EEs with the human estrogen receptor (hER) protein.
The docking studies show that the rigid endogenous ligand, 17β-estradiol (E2) interacts with
the hER to produce a single, well-defined complex with the receptor and the flexible EEs
produce multiple, distinct energy-equivalent complexes. EEs are not able to interact with the
binding cavity to stabilise the rigid hER-E2-like topology of the complex. As a result, the
hER-EE complexes can be thought of as more pliable or ‘floppy’ and thus able to respond to
the cell context in multiple ways, leading to variations in gene expression in different target
tissues. These multiple pathways may explain the range of physiological responses attributed
to exposure that depend on the timing of exposure and the sex of the individual exposed.

Identiferoai:union.ndltd.org:canterbury.ac.nz/oai:ir.canterbury.ac.nz:10092/7173
Date January 2012
CreatorsGraham, Lisa Anne
PublisherUniversity of Canterbury. Chemistry
Source SetsUniversity of Canterbury
LanguageEnglish
Detected LanguageEnglish
TypeElectronic thesis or dissertation, Text
RightsCopyright Lisa Anne Graham, http://library.canterbury.ac.nz/thesis/etheses_copyright.shtml
RelationNZCU

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