Role of estrogen in regulation of cellular differentiation: A study using human placental and rat Leydig cells
Introduction
Traditionally, estrogen is considered to be a mitogenic hormone, and several cancers in human females are estrogen dependent. Thus, anti-estrogens have found a place in therapy for cancer. It is known that exposure to estrogens can influence the risk of cancer in the main target organs, breast, endometrium and ovary, during different phases of a woman's life (Persson, 2000). In men, estrogen is considered as one of the hormonal risk factors in the development of benign prostatic hyperplasia and prostate cancer although the evidence for the possible role of estrogen in prostate cancer has come largely from epidemiological and experimental studies (Harkonen and Makela, 2004). Recent evidence suggests that, in addition to the traditional role of estrogen in tumorogenesis, estrogens are also involved in a wide variety of cellular and physiological functions, involving the central nervous system (Korol, 2004, Li and Shen, 2005), immune system (Lang, 2004), cardiovascular system (Zhu et al., 2004) and bone homeostasis (Gennari et al., 2005).
Recently, we proposed that E2, classically recognized as a growth-promoting hormone, has a distinct, novel role in human trophoblastic differentiation (Rama et al., 2004). Similarly, we hypothesized a role for 17β-estradiol-mediated down-regulation of Col IV α4 expression could be one of the possible mechanisms for inhibition of progenitor Leydig cell proliferation (Anbalagan and Rao, 2004). In this review, we summarize the results from both model systems, the placental cytotrophoblast and Leydig cells, which permit us to conclude that 17β-estradiol has a very unique role in differentiation, in a stage-specific fashion.
Section snippets
Estrogens and female reproduction
Placentation is the pinnacle of reproductive evolution and a great evolutionary pressure favors hemochorial placenta (Carter and Enders, 2004), where the trophoblasts are in direct contact with maternal blood, as in humans. Two distinct pathways of differentiation lead to the formation of two distinct trophoblastic cells: the extravillous trophoblast which is engaged in remodeling the endometrium during pregnancy, its vasculature and the villous syncytiotrophoblast which is involved in
E2-induced terminal differentiation in placental trophoblast and BeWo cell lines
With a view to elucidate the mechanism of action of 17β-estradiol during placentation, we employed two in vitro model systems. In the first model, cytotrophoblasts isolated from human term placentae were allowed to spontaneously differentiate in DMEM-HG containing 20% FCS. In the second model system, BeWo human choriocarcinoma cells were induced to differentiate following addition of either 10 μM Forskolin (Rama and Rao, 2001) or 10 ng/ml recombinant human TGFβ1 (Rama et al., 2003) or 10 μM E2 (
E2 governs TGFβ1 expression in differentiating trophoblastic cells
A significant increase in TGFβ1 at the transcriptional level, with a parallel increase in TGFβ1 protein level, was observed in BeWo cells treated with 10 μM E2. This suggests that E2-induced trophoblastic differentiation is coupled with increased production of TGFβ1. At this juncture, it is interesting to recall our earlier observations that TGFβ1, on its own, can bring about terminal differentiation in these cells (Rama et al., 2001, Rama et al., 2003). Therefore, it was important to determine
Effects of TGFβ1 on telomerase activity and telomerase associated components
In TGFβ1-treated (10 ng/ml) BeWo choriocarcinoma cells a decrease in telomerase (TR) activity and a decrease in expression of only hTERT along with cellular differentiation were noted. These results confirm the observations that correlate down-regulation of TR with cell differentiation (Koyanagi et al., 2000, Yu et al., 2004). Further, TGFβ1 down-regulates expression of hTERT at the mRNA level (Rama et al., 2001). TGFβ1-induced suppression of hTERT gene expression could represent an important
E2 regulates cell cycle proteins during placental differentiation
Human trophoblastic BeWo cells cultured in the presence of 10 μM 17β-estradiol for 72–96 h had a significant loss in transcript levels of Cyclin A2 in addition to an appreciable down-regulation in the level of protein expression of Cyclin E. There are two known isoforms of Cyclin E, 52 kDa and 50 kDa in size (McKenzie et al., 1998). Though human trophoblastic cells were found to predominantly express the larger isoform (i.e. the 52 kDa protein), we could find that both isoforms are down-regulated by
Estrogens and male reproduction
The role of estrogen and ER in male reproduction has been of interest since the production of estrogen was first reported in the male reproductive system by Staffieri et al. (1965). Estrogens are produced by male gonads and accessory reproductive tissues, and the presence of ERα and ERβ has been described in testis, prostate, efferent ducts and penis (Bodker et al., 1999, Makela et al., 2000, Salmi et al., 2001, Dietrich et al., 2004). Male mice lacking estrogen receptor-α, i.e. ERKO mice, are
Leydig cells and estrogen
Synthesis of steroid hormones and production of spermatozoa are two essential functions of the mammalian testis. Normal testicular development and maintenance of spermatogenesis are controlled by gonadotrophins and testosterone whose effects are modulated by locally produced factors, including estrogens (Carreau et al., 2003). While testis is a target organ for the actions of estrogens, they have a dramatic influence, usually inhibitory, on Leydig cell function (Abney, 1999). However, the
Acknowledgements
The authors wish to thank Council of Scientific and Industrial Research, Department of Science and Technology, Department of Biotechnology, Indian Council of Medical Research, Govt. of India, and Mellon and CONRAD Foundation, USA, for financial assistance. One of the authors (A. Jagannadha Rao) is thankful to Council of Scientific and Industrial Research, Govt. of India, for award of Council of Scientific and Industrial Research Emeritus Scientist Fellowship.
References (86)
- et al.
The regulatory effect of estrogens on fetal growth. I. Placental and fetal body weights
Am. J. Obstet. Gynecol.
(1971) The potential roles of estrogens in regulating Leydig cell development and function: a review
Steroids
(1999)- et al.
Gonadotropin regulation of Leydig cell DNA synthesis
Mol. Cell. Endocrinol.
(1986) - et al.
Collagen IV-mediated signalling is involved in progenitor Leydig cell proliferation
Reprod. Biomed. Online
(2004) - et al.
Immunocytochemical identification of the oestrogen receptor in the nuclei of cultured human placental syncytiotrophoblasts
Placenta
(1997) - et al.
Oestradiol stimulates morphological and functional differentiation of human villous cytotrophoblast
Placenta
(1999) - et al.
Differential distribution of type IV collagen chains in the developing rat testis and ovary
Differentiation
(1998) - et al.
Role of estrogens in development of prostate cancer
J. Steroid Biochem. Mol. Biol.
(2004) - et al.
Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis
J. Biol. Chem.
(1993) - et al.
Ovariectomy decreases the mRNA levels of transforming growth factor-[beta]1 and increases the mRNA levels of osteocalcin in rat bone in vivo
Biochem. Biophys. Res. Commun.
(1993)
Role of estrogen in balancing contributions from multiple memory systems
Neurobiol. Learn. Mem.
Estrogen as an immunomodulator
Clin. Immunol.
Direct inhibition of rat Leydig cell function by tamoxifen
Metabolism
Erratum to “differential expression of estrogen receptors [alpha] and [beta] in adult rat accessory sex glands and lower urinary tract”: [Mol. Cell. Endocrinol. 164 (2000) 109–116]
Mol. Cell. Endocrinol.
Reproductive functions illustrating direct and indirect effects of genes on behavior
Horm. Behav.
Effects of in-utero exposure to zeranol or diethylstilboestrol on morphological development of the fetal testis in mice
J. Comp. Pathol.
Estrogens in the causation of breast, endometrial and ovarian cancers—evidence and hypotheses from epidemiological findings
J. Steroid Biochem. Mol. Biol.
Paracrine regulation of human placenta: control of hormonogenesis
J. Reprod. Immunol.
Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion
Crit. Rev. Oncol. Hematol.
Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture
Bone
Regulation of telomerase during human placental differentiation: a role for TGF[beta]1
Mol. Cell. Endocrinol.
TGF [beta]1 induces multiple independent signals to regulate human trophoblastic differentiation: mechanistic insights
Mol. Cell. Endocrinol.
Hormonal regulation of human trophoblast differentiation: a possible role for 17[beta]-estradiol and GnRH
Mol. Cell. Endocrinol.
Co-localization of androgen receptor with estrogen receptor beta in the lower urinary tract of the male rat
J. Urol.
Forskolin and methotrexate induce an intermediate trophoblast phenotype in cultured human choriocarcinoma cells
Am. J. Obstet. Gynecol.
Estrogen receptor-{alpha} gene deficiency enhances androgen biosynthesis in the mouse Leydig cell
Endocrinology
Estrogen regulation of placental P-450 cholesterol side-chain cleavage enzyme messenger ribonucleic acid levels and activity during baboon pregnancy
Endocrinology
Estrogen receptors in the human male prostatic urethra and prostate in prostatic cancer and benign prostatic hyperplasia
Scand. J. Urol. Nephrol.
Induction of transforming growth factor [beta]1 in human breast cancer in vivo following tamoxifen treatment
Cancer Res.
The promoter(s) of the aromatase gene in male testicular cells
Reprod. Biol.
Aromatase expression and role of estrogens in male gonad: a review
Reprod. Biol. Endocrinol.
Comparative aspects of trophoblast development and placentation
Reprod. Biol. Endocrinol.
Estrogen stimulates oxytocin gene expression in human chorio-decidua
J. Clin. Endocrinol. Metab.
Male genitourinary abnormalities and maternal diethylstilbestrol
J. Urol.
The regulation of the secretion of transforming growth factor-beta 1 by estrogen on ovarian cancer AO, 3AO cell lines and its relationship with cell proliferation
Zhonghua Fu Chan Ke Za Zhi
Immunodetection of cell adhesion molecules and extracellular matrix proteins in rat Leydig cell cultures
Int. J. Androl.
Effect of extracellular matrix proteins on in vitro testosterone production by rat Leydig cells
Mol. Reprod. Dev.
Expression of estrogen receptors in human corpus cavernosum and male urethra
J. Histochem. Cytochem.
Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility
Endocrinology
Effect of transforming growth factor [beta]2 on oestrogen metabolism in the MCF-7 breast cancer cell line
J. Clin. Pathol.
Ovariectomy selectively reduces the concentration of transforming growth factor [beta] in rat bone: implications for estrogen deficiency-associated bone loss
Proc. Natl. Acad. Sci. U.S.A.
Decreased cyclin A2 and increased cyclin G1 levels coincide with loss of proliferative capacity in rat Leydig cells during pubertal development
Endocrinology
Cited by (22)
Serotonin-estrogen interactions: What can we learn from pregnancy?
2019, BiochimieCitation Excerpt :Indeed, CYP19 is highly active in the human placenta [292–295] and estrogen production requires perfect cooperation between mother, placenta and fetus. Estrogens produced by the placenta can be transferred to the maternal and fetal circulation where they have endocrine actions [295] or act as autocrine/paracrine factors on placenta cells [296–298]. For example, estrogen activation of ERs are involved in villous cytotrophoblast syncytialization [299], growth [300] and endocrine regulation [301,302].
Profile of CYP19A1 mRNA expression and aromatase activity during syncytialization of primary human villous trophoblast cells at term
2018, BiochimieCitation Excerpt :Villous trophoblast syncytialization in the human placenta is regulated by a positive feedback mechanism where the hormones secreted by the syncytiotrophoblast cells (STs) stimulate the fusion of villous cytotrophoblast cells (vCTs) into the adjacent syncytium [1].
The use of a unique co-culture model of fetoplacental steroidogenesis as a screening tool for endocrine disruptors: The effects of neonicotinoids on aromatase activity and hormone production
2017, Toxicology and Applied PharmacologyCitation Excerpt :The control of placental estrogen production by this positive feedback mechanism would also explain why neonicotinoid-induced CYP3A7 expression is reversed by a co-treatment with estriol (Fig. 6). During pregnancy, estrogens regulate uteroplacental blood flow, trophoblast invasion and cellular differentiation (Yashwanth et al., 2006). Disruption of estrogen biosynthesis during this critical period may impact the development of the fetus and placenta, as well as affect the mother's health (Kaijser et al., 2000).
The xenoestrogens, bisphenol A and para-nonylphenol, decrease the expression of the ABCG2 transporter protein in human term placental explant cultures
2016, Molecular and Cellular EndocrinologyCitation Excerpt :This is the first study showing downregulation of ABCG2 transporter protein by environmental xenoestrogens, bisphenol A and para-nonylphenol, in human placenta. It was already known that physiological changes, such as syncytialization/differentiation and the amount of endogenous hormones like estradiol and progesterone, affect the expression of the ABC transporters in human placenta (Evseenko et al., 2007; Yashwanth et al., 2006). However, data in the literature are controversial and further studies are needed to determine the most important factors behind the differences.
Reduction of progesterone, estradiol and hCG secretion by perfluorooctane sulfonate via induction of apoptosis in human placental syncytiotrophoblasts
2015, PlacentaCitation Excerpt :The placenta produces several essential hormones which are required for nearly all aspects of pregnancy [24] including the establishment and maintenance of pregnancy, maternal adaption to pregnancy, fetal growth and well-being, and parturition [25]. In humans, estrogens produced by the placental syncytiotrophoblasts regulate various functions critical for pregnancy and fetal development [26,27]. Since human placenta lacks p450c17 hydroxylase which is responsible for the conversion of progesterone to estrogen [28], it relies on the aromatization of androgen for estrogen synthesis.