Effects of Estrogen (E2)
I am examining the combined effects of estrogen and ozone on lung cells to
determine if estrogen alters lung cell susceptibility to ozone induced
Indicators that Estrogen plays a
role in lung disease pathogenesis
Estrogen and Lung Disease
descrepancies in the morbidity / mortality of lung disease and
response to oxidative stress in healthy patients
have higher survivorship than do men of simillar health (Moss et al
account for 3/4 of all types of lung cancers in women but only 1/3 of
all lung cancers in men (Omoto et al. 2001; Dougherty et al 2006).
may respond better to surgical removal of tumor (Lai et al. 2005).
cancer causes more female deaths than breast, ovarian, and cervical
under the age of 15 are more likely to go to the hospital for an
asthmatic attack than are girls (Schatz et al. 2006).
to oxidative stress in healthy
studies suggest that men have significantly greater antioxidant
capactiy, or ability to protect against oxidative damage, than women;
however, other studies have shown that women have increased levels of
8-iso-PGF – a molecule that mitigates oxidative damage – when exposed
to ozone (Chen et al. 2007)
Increased Exposure to Estrogen
of estrogen exposure is the result of the ovarian cycle
changes have increased estrogen exposure
the time period women are exposured to high levels of estrogen
the amount of estrogen that both men and women are exposed to
cells produce estrogen
An Overview of
Estrogen, the Molecule
by the aromatization of androgens in several different tissues (Zhu et
al. 2005; Chang et al. 2007; Lin et al. 2003; Hayes et al. 1996).
estradiol (E2) = biologically active and reduced form of estrogen
(E1) = biologically inactive and oxidized form of estrogen (Zhu et al.
1998; Abplanalp et al. 1999).
Image from http://www.nature.com/nchembio/journal/v2/n4/compound/nchembio
Figure 1. Chemical
structure of 17-β estradiol (E2)
Image from http://www.womentowomen.com/menopause/estrogendominance.aspx
Diagram of E2 levels throughout the ovarian cycle
in the Body
estrogen and its receptors are present in both males and females,
although at gender specific concentrations
women and men have similar levels of estrogen (Lai et al. 2005;
Dougherty et al. 2006; Si et al. 2001).
for the development of female sexual characteristics
in the Ovarian cycle
by ovaries during days 1-14 of the menstral cycle to stimulate
ovulation (Sadava et al. 2008)
in the Cell
cellular changes by ….
to its receptor in the cytoplasm, forming a transcription factor that
can alter gene expression (a genomic response)
to receptors on either the plasma and/or organelle membranes to
increase second messengers, increasing the activity of other proteins
(a non-genomic response)
may differ based on cell type or concentration
Image from http://arthritis-research.com/content/11/5/241/figure/F3?highres=y
Estrogen and Oxidative Stress
Potential to Reduce Oxidative
is an antioxidant
can donate H+ early in the propagation of free radical chain reaction,
thus protecting cells from oxidative damage (Ayres et al. 1996;
Angoa-Perez et al. 2006; Si et al. 2001).
has greater antioxidant capabilities than E1 and cells
decrease the conversion of E2 to E1 in
response to oxidative stress (Zhu et al. 1998;
Abplanalp et al. 1999).
increases both the expression of Glutathione and γ-glutamylcysteine in
response to oxidative stress via Estrogen Receptor β (Erβ) (Russo et
al. 2005; Urata et al. 2006).
Potential to Exacerbate Oxidative
E2 metabolites (E2-OH2 and E2-OH4) = potentially carcinogenic (Ho et
al. 2008; Hayes et al. 1996; Chang et al. 2007; Zhu et al. 1998; Lin et
meabolism can cause quinone recycling, increasing the number of free
radicals in the cell (Zhu et al. 1998).
P450 1A1 / 1A2 / 1B1 are all involved in E2 metabolism, specifically
conversion to E2-OH2 and E2-OH4 (Ho et al. 2008; Hayes et al. 1996; Lin
et al. 2004)
the Aryl hydrocarbon Receptor (AhR) upregulates the expression of
cytochromes p450 1A1 and 1A2 (Zhu et al. 1998; Sindhu et al. 1999;
Hayes et al. 1996; Chang et al. 2007; Lin et al. 2004).
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), found in
cigarette smoke, has been shown to bind to AhR in lung cells (Lin et
tryptophan has also been shown to bind to AhR in liver cells (Singhal
et al. 2009).
Image from http://emedicine.medscape.com/article/126919-overview
to Inhibit Apoptosis
= programmed cell death
proteins must be activated for apoptosis to occur
can decrease mitochondrial membrane permeability via interactions with
receptors on mitochonrdria
cytochrome c release and subsequent caspase activation (Felty et al.
2003; Miyaguchi et al. 2004).
can activate Akt pathway via interactions with ERβ
is associated with increased inflammation and apoptosis inhibition in
epitheliall cells (Hazra et al. 2007; Stenson 2007).
may increase PGE2 expression via activation of the COX-2 pathway (Lu et
al. 2004; Kim et al. 2007; Chang et al. 2007; Bloomberg 2000)
Net Effect of E2 and Ozone induced-oxidative
stress is unknown
combination, E2 may
act as a cytoprotectant, acting directly as an antioxidant or indirectly
by increasing the expression of glutathione
combination may increase oxidative damage via E2 metabolism
inhibit apoptosis via interactions with mitochondria, increasing the
expression of inflammatory molecules like PGE2.
We are working to characterize the alveolar cells system and test these