This website was developed by undergraduate biology researchers working with Dr. Karen Bernd at Davidson College.

Effects of Estrogen (E2)

E2 and Lung Disease

E2 Exposure

E2 the molecule

Normal E2 function in the Body

Cellular Effects of E2

E2 and Oxidative Stress

E2 and Apoptosis

 

General Research Question

I am examining the combined effects of estrogen and ozone on lung cells to determine if estrogen alters lung cell susceptibility to ozone induced oxidative damage.

 

Indicators that Estrogen plays a role in lung disease pathogenesis

Estrogen and Lung Disease

  • Gender descrepancies in the morbidity / mortality of lung disease and response to oxidative stress in healthy patients
  • ARDS
    • Women have higher survivorship than do men of simillar health (Moss et al 2002).
  • Lung cancers
    • Adenocarcinomas 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).
    • Women may respond better to surgical removal of tumor (Lai et al. 2005).
    • Lung cancer causes more female deaths than breast, ovarian, and cervical cancer combined
  • Asthma
    • Boys under the age of 15 are more likely to go to the hospital for an asthmatic attack than are girls (Schatz et al. 2006).
  • Response to oxidative stress in healthy subjects
    • Some 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

  • Majority of estrogen exposure is the result of the ovarian cycle
  • Lifestyle changes have increased estrogen exposure
    • Hormone replacement therapy
      • Increases the time period women are exposured to high levels of estrogen
    • Obesity
      • Increases the amount of estrogen that both men and women are exposed to
      • Adipose cells produce estrogen

 

An Overview of Estrogen

Estrogen, the Molecule

  • Generated 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).
  • 2 main forms
    • 17-β estradiol (E2) = biologically active and reduced form of estrogen
    • Estrone (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
775_comp2.html

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

Estrogen in the Body

  • Both estrogen and its receptors are present in both males and females, although at gender specific concentrations
    • Post-menopausal women and men have similar levels of estrogen (Lai et al. 2005; Dougherty et al. 2006; Si et al. 2001).
  • Responsible for the development of female sexual characteristics
  • Role in the Ovarian cycle
    • Produced by ovaries during days 1-14 of the menstral cycle to stimulate ovulation (Sadava et al. 2008)

Estrogen in the Cell

  • Induce cellular changes by ….
    • Binding to its receptor in the cytoplasm, forming a transcription factor that can alter gene expression (a genomic response)
    • Binding to receptors on either the plasma and/or organelle membranes to increase second messengers, increasing the activity of other proteins (a non-genomic response)
  • Effect 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 Stress

  • Estrogen is an antioxidant
    • E2 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).
    • E2 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).
  • Estrogen and Glutathione  
    • Estrogen 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 Stress

  • E2 Metabolism
    • Some 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 al. 2004).
      • E2 meabolism can cause quinone recycling, increasing the number of free radicals in the cell (Zhu et al. 1998).
    • Cytochromes 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)
    • Bindingto 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).
      • Ligandsfor AhR
        • 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), found in cigarette smoke, has been shown to bind to AhR in lung cells (Lin et al. 2004)
        • Oxidized 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

Potential to Inhibit Apoptosis

  • Apoptsis = programmed cell death
    • Caspase proteins must be activated for apoptosis to occur
  • E2 can decrease mitochondrial membrane permeability via interactions with receptors on mitochonrdria
    • Prevents cytochrome c release and subsequent caspase activation (Felty et al. 2003; Miyaguchi et al. 2004).
  • E2 can activate Akt pathway via interactions with ERβ
  • Prostaglandin E2 (PGE2)
    • PGE2 is associated with increased inflammation and apoptosis inhibition in epitheliall cells (Hazra et al. 2007; Stenson 2007).
    • E2 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

  • In combination, E2 may act as a cytoprotectant, acting directly as an antioxidant or indirectly by increasing the expression of glutathione
  • The combination may increase oxidative damage via E2 metabolism
  • The combination may 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 hypotheses.