Cellular and biochemical mechanisms by which environmental oestrogens influence reproductive function

Human Reproduction Update 2000, Vol. 6, No. 4 pp. 332±350 Ó European Society of Human Reproduction and Embrology Cellular and biochemical mechanisms by which environmental oestrogens in¯uence reproductive function Marinella Rosselli1,*, Karin Reinhart1, Bruno Imthurn1, Paul J.Keller1 and Raghvendra K.Dubey1,2 1 University Hospital Zurich, Department of Obstetrics and Gynaecology, Clinic for Endocrinology, Zurich, Switzerland, and 2Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA The biology and physiology of the male as well as female reproductive system is hormonally regulated. Abnormalities in the dynamics of hormone production, metabolism and elimination, as well as their binding to certain target tissues, has been associated with pathophysiological conditions of the reproductive system. Although oestrogens are known to be one of the major hormone groups in regulating the reproductive function and the fertilization process, the cellular and biochemical mechanism or mechanism(s) via which oestrogens induce their effects are still not fully de®ned. Moreover, in a modern environment we are also exposed to a wide battery of environmental agents which are structurally similar to oestrogens, and termed `environmental oestrogens'. Because environmental oestrogens have been shown to mimic some of the effects of oestradiol, it has been postulated that these exogenous chemicals may in¯uence or interfere with the oestrogen-dependent reproductive processes, and may be associated with bene®cial as well as deleterious effects on the reproductive system. In this regard, two classes of environmental oestrogens have been widely studied, i.e. phyto-oestrogens (plant-derived dietary oestrogens) and xeno-oestrogens (industrial chemicals, including polychlorinated biphenyls, DDT, TCDD, dioxins, etc.). The main focus of this review is to provide an overview on the cellular and biochemical mechanism(s) by which xeno-oestrogens and phyto-oestrogens in¯uence the oestrogen-dependent reproductive functions and induce their deleterious or protective effects on the reproductive system. Key words: biochemical and cellular mechanisms/environmental oestrogens/exposure/reproductive function TABLE OF CONTENTS Introduction Role of oestrogen receptors Role of oestrogen metabolism Role of binding proteins Role of aryl hydrocarbon receptors (AhR) in regulating the biological effects of oestrogen Environmental oestrogens and reproductive disorders: potential mechanism(s) of action Conclusion Acknowledgements References Introduction Oestrogens in¯uence cell growth and cell differentiation of the male and female reproductive tissues, and in this regard are known to regulate the development of mammary glands, uterus, vagina, ovary, testes, epididymis and prostate (Korach, 1994). Oestrogens also play an important role in the biology as well as physiology of the vascular system which is strictly related to the reproductive processes. (Korach, 1994; Iafrati et al., 1997; Dubey et al., 1999a). Findings during the past decade have provided evidence that oestrogens induce their biological effects via genomic, as well as non-genomic, mechanisms that are triggered by oestrogen receptor (ER) -dependent as well as ER-independent mechanisms (Figure 1). Hence, we ®rst delineate the mechanisms by which endogenous oestrogens themselves induce their cellular and biochemical effects. Role of oestrogen receptors To mediate their receptor-dependent effects, oestrogens diffuse through the plasma membrane of cells and bind to the speci®c, high-af®nity ER within the target cell (Figure 1). The hormone± receptor complex is activated by undergoing surface-charge and conformational changes, triggered by changes in intracellular temperature and salt. The activated oestrogen±receptor complex * To whom correspondence should be addressed at: University Hospital Zurich, Department of Obstetrics and Gynaecology, Clinic for Endocrinology, 8091-Zurich, Switzerland. Tel: 41-1-255-5368; Fax: 41-1-255-4439; E-mail: Environmental oestrogens and reproductive function translocates to the nucleus and binds to chromatin at speci®c regions of the DNA, called hormone response element, and stimulates or inhibits speci®c genes resulting in the production of the respective messenger RNAs and subsequently synthesis of speci®c proteins. Changes in the generation of intracellular proteins result in activation of a cascade of events which ®nally in¯uences the metabolic processes and translates into cell growth and differentiation. In this regard, it is well documented that 17boestradiol induces uterine growth (hypertrophy and hyperplasia; Martin et al., 1973). Moreover, it has been shown that 17boestradiol rapidly induces the expression of proto-oncogenes which may play a role in oestrogen-induced cell growth and proliferation. In uterine tissue cells, treatment with 17b-oestradiol rapidly induces the steady-state expression of uterine N-myc and c-myc mRNAs (Murphy et al., 1987a; Travers and Knowler, 1987), c-ras- mRNA and c-fos mRNA (Travers and Knowler, 1987; Loose-Mitchell et al., 1988). The uterine epidermal growth factor (EGF) receptor, which is a homology of the erb-B oncogene, is also induced by 17b-oestradiol (Mukku and Stancel, 1985). Apart from up-regulating the expression of proto-oncogenes, 17b-oestradiol has been shown to up-regulate receptors of growth factors such as EGF, insulin-like growth factor (IGF) (Berthois et al., 1989; Stewart et al., 1990), and to stimulate the levels of growth-promoting peptides which can act in an autocrine fashion to induce cell growth (Rochefort et al., 1980; Dickson and Lippman, 1987; Murphy et al., 1987b; Murphy and Ghahary, 1990). Alternatively, oestrogens can synergize with growth factors by inducing their synthesis, activating their receptors as well as their effects on the protooncogenes. In MCF-7 cell lines, oestradiol has also been shown to increase EGF-induced activator protein-1 (AP-1) independent of its effect on c-fos and c-jun (Philips et al., 1993), which suggests that there may be cross-talk between the ER and AP-1 activity. In this regard, it has been shown that oestradiol can interfere with the growth factor pathway not only by inducing its own synthesis (Dickson and Lippman, 1987) or that of its receptors (Berthois et al., 1989; Stewart et al., 1990), but also by facilitating its action at the nuclear level. It has been shown (Van der Burg et al., 1990) that oestradiol, by inducing c-fos, could synergize with low concentrations of insulin, which is able to induce c-jun but not cfos. Subsequently, it was shown (Philips et al., 1993) that even when c-fos and c-jun synthesis and AP-1 activity are maximally induced by growth factors, oestradiol can still enhance AP-1dependent transcriptional activity. It has also been demonstrated (Gaub et al., 1990) that AP-1 DNA sequence in the chicken ovalbumin gene promoter can (...truncated)