**2.7 Environmental contaminant**

426 Endometriosis - Basic Concepts and Current Research Trends

Several MMP have been implicated in the development of endometriosis (Sillem et al., 2001). The levels of MMP and TIMP in patients with endometriosis are different depending on the method of measurement and collection of samples of different tissues at different stages of endometriosis. The values of TIMP-1 is determined by radioimmunoassay measurement in serum of patients with PF in endometriosis are lower than in controls. In contrast, the concentration of TIMP-1 was restored after treatment with gonadotropin releasing hormone. Another study reported that there was no significant difference in levels of cathepsin D, a proteolytic enzyme thought to promote digestion of ECM proteins in endometriosis, in

It is thought that the retrograde flow of the menstrual debris to the peritoneal cavity plays an important role in the origin of endometriosis but the mechanism of endometrial cells implantation remains unknown. Recently many studies have reported the importance of

Several adhesion molecules (CAM) are expressed in the human endometrium: i.e. integrins, cadherins and immunoglobulin superfamilies. These adhesion molecules show cyclical changes during the menstrual cycle. The major cell surface receptors of the ECM are the

β1-integrins are known to mediate the interaction between the cell-cell and cell-extracellular matrices and are represented by very late activation (VLA) antigen molecules. It is well known that endometriosis is frequently associated with immunological abnormalities. However, only a few studies have been conducted on the adhesion molecules, particularly on β 1-integrins, in endometriosis. It has reported that integrins are expressed in the endometrium in endometriosis. The ability of endometriotic tissues to express integrins may explain the high recurrence rates in patients with endometriosis, as these samples retain their adhesion potency after retrograde menstruation and are thus able to establish cell-cell

The soluble forms of the *intercellular-adhesion molecule-1 (sICAM-1)* are secreted from the endometrium and endometriotic implants. Moreover, endometrium from women with endometriosis secretes a higher amount of this molecule than tissue from women without the disease. Consequently, a strong correlation exists between levels of sICAM-1 and the number of endometriotic implants in the pelvis. Therefore, it has been hypothesized that sICAM-1 may be useful in the diagnosis of endometriosis (Leng et al., 2002). Many investigators have reported a significant increase in serum concentration of sICAM-1 in patients with endometriosis. The sICAM-1 concentrations were higher in patients with stage I−II endometriosis, suggesting that studies on these soluble adhesion molecules can help clarify the pathogenic mechanisms of endometriosis. Elevated ICAM-1 levels were found in patients with severe endometriosis, but its sensitivity is not high and the concomitant use of the CA125 marker increases the sensitivity and specificity of detection (Somigliana et al.,

The **E-cadherin** mediates cell-cell interaction and cells adhere preferentially to cells that express the same cadherin. Cadherins are distributed widely among animals and play a potentially significant role in morphogenetic events during embryogenesis. Cadherin is also

serum from women with and without endometriosis.

*integrins* that contain large (α) and small (β) subunits.

and cell-matrix interactions with the surrounding peritoneum.

**2.6 Soluble adhesion molecules** 

adhesion molecules in this process.

2002).

Environmental toxins, such as dioxins and polychlorinated biphenyls are some of the factors that have been suggested to play a significant role in the development of endometriosis. In fact, detection of environmental contaminant residues in serum and ovarian follicular fluid confirms this hypothesis. Dioxin-like chemicals, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polyhalogenated aromatic hydrocarbons (PHAHs), may exert effects on the pathophysiology of endometriosis through a number of pathways: (1) activation of procarcinogens; (2) altered synthesis and metabolism of estradiol; (3) altered production of proinflammatory growth factors or cytokines and (4) alterations in tissue remodelling processes.

Exposure to HAHs and TCDD seems to be associated with a dose-dependent increase in the incidence and severity of endometriosis. TCDD may target peripheral blood and peritoneal and endometrial leukocyte populations inducing chronic expression of TNF-α and other inflammatory mediators resulting in increased adhesion, vascularization and proliferation of endometriotic cells. It has been suggested that an elevated concentration of TNF-a might participate in TCDD-mediated toxicity and contribute to the pathogenesis of endometriosis.

Dioxins may affect the expression of TNF-α via the induction of an inflammatory cytokine network, since the region of DNA that recognize the ligand-activated AhR, the dioxinresponse element of DRE, is present in the genes of potent inducers of TNF-α including IL-1b, IL-6 and IFN-γ (Rier & Foster, 2003).
