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Estrogen effects on fetal and neonatal testicular development

¹ Univ Paris 7–Denis Diderot, Fontenay-aux-Roses, F-92265 France, ² CEA, DSV/DRR/SEGG/LDRG, Fontenay-aux-Roses, F-92265 France and ³ INSERM, U566, Unit of Gametogenesis and Genotoxicity, Fontenay-aux-Roses, F-92265 France

Correspondence should be addressed to R Habert who is now at Unitè Gamètogenèse et Gènotoxicitè, Univ Paris 7, Denis Diderot, CEA, INSERM U566, CEA/DSV/DRR/SEGG/LDRG, Bat. 5A, RDC, Route du Panorama, 92265 Fontenay-aux-Roses, France; Email: rene.habert{at}cea.fr

	Abstract

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

 
In recent years, evidences have accumulated that exposure to environmental components with estrogenic activity causes reproductive disorders in human populations. Studies conducted over the past 50 years have clearly shown a continual decline in semen quality accompanied by an increase in male reproductive disorders during this period in industrial countries. As healthy gametes are a prerequisite for healthy children, such disorders are a significant problem not only for the current society, but also for future generations. These male reproductive disorders have been attributed to xenobiotics, and particularly to xenoestrogens, which have steadily increased in diversity and concentration in the environment and food. Epidemiological, clinical, and experimental studies have suggested that excessive exposure to estrogens and xenoestrogens during fetal and neonatal development may induce testicular developmental disorders, leading to alterations in the adult male fertility. Recently, we have clearly demonstrated that fetal and neonatal testes are very sensitive to estrogens, as the inactivation of estrogen receptor increases steroidogenesis and the inactivation of estrogen receptor ß enhances development of the germ cell lineage in the male.

	Alterations in male reproductive function

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

 
Changes in the environment and their consequences for male reproductive function have been of major concern for the past 20 years.

Alterations in male reproduction were first observed in wild animals, in studies reporting the effects of accidental exposure of estrogenic chemicals on wildlife in the natural environment. These changes in male reproductive function vary from very subtle changes to permanent alterations, such as feminization or changes in reproductive behavior (Vos et al. 2000). Guillette et al.(1994) studied the male reproductive functions of alligators in two lakes in Florida. These two lakes are located very close to each other geographically, excluding the possibility of climate-based bias in these studies. They found that adult male alligators in Apopka Lake, which was polluted with agricultural waste and experienced a major chemical spill in 1980, had lower testosterone levels and presented micropenis and disorganized testes (Guillette et al. 1994, Guillette & Guillette 1996). A key part of this story is that no chemicals could be detected in the water of the apparently contaminated lake and thus the alligators were being exposed simply by being at the top of the food chain. Other documented disruptions or alterations of reproductive activity and physiology have been correlated with exposure of contaminants in fish, amphibians, reptiles, birds, and mammals (examples in Table 1; for detailed review, see Vos et al. 2000, Edwards et al. 2006). Most of the reported effects on wildlife have been done on aquatic food chain organism making the causal link a direct or an indirect effect of pollutants hard to do.

	These abnormalities first arise during fetal development

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

 
The testes begin to carry out their two major functions (gametogenesis and steroidogenesis) during fetal development. Sertoli cells are the first to differentiate. From 12 days postconception (dpc) in the mouse, 13.5 dpc in the rat, and 42–45 dpc in human, they surround the germ cells to form the seminiferous cords. Sertoli cells divide actively until puberty, remaining quiescent thereafter. Primordial germ cells arise from the epiblast and migrate from the extra-embryonic mesoderm to colonize the genital ridge. The germ cells are named gonocytes once they reach the gonad, in which they proliferate until fetal day 15.5 in the mouse and fetal day 17.5 in the rat. The gonocytes (Fig. 1A) then enter a quiescent period during which their number does not change. This period extends to birth in the mouse and postnatal day 3 in the rat, when mitosis resumes and gonocytes differentiate into gonia (Olaso & Habert 2000). Fetal Leydig cells (Fig. 1B) differentiate soon after Sertoli cells and produce the testosterone and insulin-like factor 3 (Insl3) necessary for masculinization of the fetus (Habert et al. 2001, Kubota et al. 2002).

View larger version (74K): [in this window] [in a new window]   Figure 1 Histological aspect of the mouse neonatal testis observed 2 days after birth. (A) Seminiferous cord after coloration by Tushmann’s blue. Arrows indicate the gonocytes, arrowhead indicates the Sertoli cells from Delbes et al.(2004). (B) Leydig cells, located in interstitial compartment, after immunohistochemical labeling of 3ß-hydroxy-steroid dehydrogenase (3ßHSD); from Delbes et al.(2005).

The hypothesis of fetal origin of TDS is also supported by clinical and experimental reports.

The major clinical data concern the boys born of women treated during their pregnancy with diethylstilbestrol (DES), a very potent estrogen agonist, from 1950 to 1970. Some studies have reported alterations in sperm quality and a higher incidence of genital malformations, cryptorchidism, and testicular cancer than for the control population (Glaze 1984, Strohsnitter et al. 2001), whereas others found no such change (Wilcox et al. 1995). These discrepancies may be due to differences in the period of treatment during pregnancy, suggesting that there may be a specific period of sensitivity to xenoestrogens in the testis. A recent analysis of these epidemiological studies by Storgaard et al.(2006) pointed out that DES seems to have a negative effect on sperm count only if administered at high dose during the first semester of pregnancy.

Another clinical argument concerns the recent demonstration that phthalates (founds in cosmetics, paint, and PVC) have negative effects on human male reproductive tract development (Swan et al. 2005). Maternal urinary phthalate concentration during the pregnancy is inversely correlated with anogenital distance at birth. This finding is particularly important as it provides the first demonstration of negative effects of xenobiotics at environmental concentrations.

Experimentally, the following two approaches have been used in rodents to determine the effects of exposure to exogenous estrogens during fetal and neonatal development on male reproductive functions

In vitro studies in the rat are based on organ cultures and primary cell cultures (Table 2). These techniques are useful to detect short-term effects and have shown that estrogenic molecules (DES, 17ß-estradiol, etc.) may alter cord formation early in testis development (Cupp & Skinner 2001, Lassurguere et al. 2003) and disrupt the development of germ cells, Leydig cells, and Sertoli cells. Our recent unpublished results evidenced that rat testicular cells are more sensitive to estrogens during the early fetal period (Delbès G, Duquenne C, Habert R & Levacher C unpublished observation, Table 2).

	Estrogen receptors in the fetal testis

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

 
To date, two estrogen receptors have been described, ER (Green et al. 1986) and ERß (Kuiper et al. 1996). Both belong to the steroid nuclear receptor superfamily and regulate gene expression. ER and ERß are encoded by two different genes located on different chromosomes (10 and 12 respectively in mouse, 1 and 6 in rat, and 6 and 14 in humans). Numerous human isoforms are generated due to alternative splicing of the C-terminal region (Hirata et al. 2003). Similar isoforms have also been described in rodents (Chu & Fuller 1997, Lu et al. 1998). No biological function has yet been reported for the truncated ER protein, but many physiological implications of the ERß isoforms are currently being investigated.

The expression of these isoforms in the adult reproductive tract has recently been reviewed (Akingbemi 2005, Saunders 2005). ER and ERß are present in the fetal testis very early in development and their distribution in various types of testicular cell has been extensively studied in mammals. Immunohistochemical data have shown that ER protein is present in the undifferentiated gonad as early as 10.5 dpc in the mouse (Greco et al. 1992) and is localized in the fetal Leydig cells until birth in rodents review in O’Donnell et al.(2001). Only one study has shown some staining in the seminiferous cords (Greco et al. 1992). ERß mRNA is detected in the testis as early as 14 dpc in the mouse (Jefferson et al. 2000) and is present primarily in the gonocytes, and also in the Sertoli and Leydig cells, as early as 16 dpc in the rat (Van Pelt et al. 1999). ERß protein is present at 16 dpc in three main types of testicular cells in the rat but is found exclusively in the gonocytes in the mouse (Saunders et al. 1998, Jefferson et al. 2000). However, in a recent study, ERß was not detected in isolated Sertoli cells from 3-days-old rats (Wang et al. 2004). Immunohistochemical analysis has shown that in humans, ERß is not present in the testis but ERß is expressed in germ cells, Sertoli cells, and Leydig cells (Saunders et al. 2001).

Other rapid effects of estrogen have been described that cannot be accounted for by the ‘classical’ genomic action of estrogens. Some new ‘non-classical’ estrogen pathways involving a membrane receptor for estrogen capable of activating numerous intracellular pathways (G protein, kinases, etc.) have been proposed (Luconi et al. 2002). A G protein-coupled estrogen receptor was recently identified in a breast cancer cell line and shown to be present in the adult testis (Thomas et al. 2005). Studies of the effects of estrogen on the fetal and neonatal testis are still limited to the classical pathway, but further investigation of the involvement of other estrogen receptors is required.

	The role of endogenous estrogens in fetal and neonatal testicular development

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

 
It is now widely accepted that estrogens play vital role in the control of reproductive function in the adult male reviewed in Carreau et al.(2003) and Akingbemi (2005). Few human cases of spontaneous mutation in the estrogen pathway have been described: one homozygous mutation of the ER gene (Smith et al. 1994) and six cases of aromatase deficiency (Morishima et al. 1995, Carani et al. 1997, Deladoey et al. 1999, Herrmann et al. 2002, Maffei et al. 2004, Mittre Herve et al. 2004). These patients mostly display skeletal disorders, as they are very tall and continue to grow in adulthood. They display no masculinization disorders, but present high levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). These men also have low sperm viability (Smith et al. 1994), number, and motility (Herrmann et al. 2002) with bilateral cryptorchidism in one case (Maffei et al. 2004).

The development of transgenic mouse models has improved our understanding of the role of estrogens in male reproduction. Male mice with inactivated estrogen receptor (ERKO, ERßKO and ERßKO) or aromatase (ArKO) genes show reproductive disorders. ERKO and ArKO mice are sterile due to epididymal reabsorption fluid deficiency in ERKO mice and spermatogenesis disorders in ArKO mice reviewed in O’Donnell et al.(2001). Excess estrogens or xenoestrogens alter male reproductive function, but these data show that estrogen deficiency may also have negative effect, raising the possibility that endogenous estrogens are essential for the maintenance of male fertility.

We investigated the role of endogenous estrogens during fetal and neonatal testicular development by analyzing testis development in mice inactivated for ERKO and ERßKO (Delbes et al. 2004, 2005). Inactivation of the ERß gene induced a 50% increase in the number of gonocytes observed 2 and 6 days after birth (Fig. 2) due to an increase in the proliferation and a decrease in the apoptosis of these cells, with no change in Sertoli cell number or Leydig cell number ER gene did not modify the number of gonocytes; it increased testosterone production from the earliest stage studied (13.5 dpc, i.e. just 2 days after the first fetal Leydig cells start to differentiate; Fig. 3). We also found that the negative effect of estrogens on fetal and neonatal steroidogenesis did not depend on the hypothalomo–pituitary axis (Delbes et al. 2005), in contrast to reports of adults (Akingbemi et al. 2003). The activity of each fetal Leydig cell is increased by inactivation of the ER gene as shown by the hypertrophy of these cells and their higher levels of StAR, P450scc, and P450 c17 mRNA. These data clearly show that endogenous estrogens inhibit testicular development and function during fetal and neonatal life. ERß is involved in the control of gametogenesis, consistent with its location within the seminiferous cords, whereas ER is present in the fetal Leydig cells and regulates steroidogenesis.

View larger version (12K): [in this window] [in a new window]   Figure 2 Number of gonocytes per testis during fetal and neonatal life after ERß or ER gene inactivation. Proliferation and quiescent periods of the gonocytes throughout the considered developmental period are indicated. Gonocytes were counted on histological testis sections from 13.5, 15.5, 17.5 dpc, and 2 dpp animals. Values are mean ± S.E.M. of 4–13 animals. *P<0.001 versus wild-type in Student’s t-test. From Delbes et al.(2004).

View larger version (22K): [in this window] [in a new window]   Figure 3 Production of testosterone by the fetal and neonatal mouse testis after ERß or ER gene inactivation. Testes were collected on day 13.5 (13.5 dpc) of gestation and on postnatal day 2 (2 dpp) and cultured on floating Millipore filters for 3 h in the presence (+LH) or the absence (basal) of 100 ng/ml ovine LH. The testosterone secreted in the medium was measured by radioimmunoassay. Values are mean ± S.E.M. of 7–19 fetuses. *P<0.01 and **P<0.001 versus wild-type in Student’s t-test. From Delbes et al.(2005).

	Origin and levels of estrogens acting on the developing testis

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

Only one previous study reported the detection of aromatase mRNA in mouse fetal testis from 17.5 dpc onwards (Greco & Payne 1994). It had been suggested that expression of the aromatase gene in the fetal testis is repressed by the product of Sry gene (Haqq et al. 1993), from embryonic days 12 to 16. We recently demonstrated the importance of aromatase activity by using organotypic culture. Addition of ICI 182.780, an antagonist of ER, to the culture medium increased the testosterone production by 20.5 dpc fetal rat testis, suggesting that estrogens produced by the cultured testis is sufficient to partially inhibit steroidogenesis (Delbès et al. unpublished data). On the contrary, ICI 182.780 did not change the testosterone production of 14.5 dpc testis when aromatase is probably not yet expressed (Lassurguere et al. 2003).

During late fetal life, aromatase is probably expressed by Sertoli cells at this stage in the rat as estrogens production is stimulated by FSH (Weniger & Zeis 1988, Rouiller-Fabre et al. 1998). Aromatase activity is weaker in the fetal Leydig cells than in adult Leydig cells (Saez 1994). Thus, the main source of estrogens is the Sertoli cells during fetal and neonatal life, whereas it is the Leydig cells in the adult. Furthermore, aromatase has been found in adult germ cells (Lambard et al. 2005), but no study has investigated whether aromatase is expressed in the gonocytes. This issue is of importance for the determination of the local concentration of estrogens in the target cell.

	Remaining debates

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

 
Experimental data have shown that estrogens may have irreversible negative effects on testicular development and masculinization during fetal and neonatal life, consistent with the current hypothesis concerning the origin of TDS. However, controversy persists concerning the possible causal link between estrogen exposure during fetal and neonatal development and TDS (Storgaard et al. 2006). Recently, new data showed that polymorphism and lifestyle changes may also be responsible for male infertility (Aschim et al. 2005, Safe 2005).

We provided the first demonstration that endogenous estrogens physiologically regulate testicular development in a negative manner during fetal and neonatal life by controlling the two main functions of the testis, gametogenesis and steroidogenesis. As explained previously, changes in the establishment of the germ cell lineage may induce testicular cancer and abnormal sperm production. Furthermore, if testosterone secretion is regulated by estrogens, then estrogens control masculinization of the genital tract and testicular descent. This model is consistent with Sharpe & Skakkebaeck’s (1993) hypothesis. Nevertheless, the link between abnormalities at birth and their real consequences for adult fertility is very weak, as the regulation of spermatogenesis changes considerably during puberty. Estrogen deficiency has positive effects during fetal development (increasing number of germ cells and steroidogenic activity) and negative effects in adulthood, with affected mice becoming infertile. Determination of the real impact of estrogen deficiency during gestation on adult fertility would require studies of transiently transgenic mice, in which the expression of estrogen receptor genes was repressed only during this period of life.

Each estrogen receptor is involved in regulating one particular function, ERß being involved in gametogenesis and ER in steroidogenesis processes. These precise mechanisms of action of estrogens in the fetal testis could help us to anticipate the effects of different estrogenic compounds depending on their affinity for each receptor. For example, genistein, which has a stronger affinity for ERß than ER (Kuiper et al. 1997), would be expected to have a stronger effect on germ cells than that on steroidogenesis.

The existence of periods of development during which the testis is particularly sensitive to estrogens is strongly suggested by epidemiologic study of men exposed in utero to DES. These sensitive periods may vary depending on the susceptibility of the individual, as reported for the different strains of experimental animals (Spearow & Barkley 2001). We have shown in organ culture that exogenous estrogens inhibit gametogenesis only during fetal life (14.5 dpc) in the rat, whereas studies in ERßKO mice showed inhibition to occur later. It is unclear whether this difference is due to the difference in species (rat versus mice) or dose (addition of estrogens versus deficiency). Studies of the sensitivity of the human fetal testis would provide important new information, particularly as human testes differ from rodent testes in not expressing ER and in containing numerous ERß mRNA variants (Moore et al. 1998).

Despite the accumulation of experimental data, the question of a possible direct effect of the increase in xenoestrogen levels in the environment on male fertility remains unanswered. With the exception of the report by Swan et al.(2005), studies using phytoestrogens or DES (Atanassova et al. 2000, Fielden et al. 2003) at low doses or at doses equivalent to human dietary exposure levels have reported no deleterious effect (Table 3). This has led some authors to conclude that endocrine disruptors do not reach sufficiently high concentrations in the body to have a deleterious effect on human health. However, individual can be exposed to a combination of chemicals with different activities (estrogenic, anti-androogenic, etc.). Moreover, the lipophilic characteristics of these molecules may result in their accumulation in fat tissues and these molecules may exert their effects by acting in combination. The developing fetus may be subjected to higher levels of xenoestrogens as maternal lipid stores are metabolized during pregnancy. Therefore, this raises the question of what is a physiologically relevant concentration of xenoestrogens.

Finally, a recent study highlighted the importance of this problem by demonstrating that rats descended from a great-grandfather exposed to high levels of endocrine disruptors during fetal development have low levels of sperm production (Anway et al. 2005, 2006). Thus, changes in fetal testis development are observed not only in the contaminated individual during adulthood, but are also transmitted to subsequent generations by an undetermined epigenetic mechanism. This would have potentially major implications in terms of evolutionary biology and disease etiology and provides support for health care and environmental preventive action with respect to endocrine disruptors.

	Acknowledgements

Top Abstract Alterations in male reproductive... These abnormalities first arise... Estrogen receptors in the... The role of endogenous... Origin and levels of... Remaining debates Acknowledgements References

 
We thank C Duquenne for useful technical assistance, Prof P Chambon and A Krust (IGBMC, Illkirch, France) for providing transgenic mice, A Gouret for expert secretarial assistance and C Joubert, C Chauveau, S Leblay, and V Neuville (CEA, Fontenay-aux-Roses, France) for caring the animals. This work was partly supported by a grant from INSERM project ‘Environnement et Santé’ (2004–2006) and a grant from Ministère de l’Ecologie et du Développement Durable, Programme National de Recherche sur les Perturbateurs Endocriniens (2005–2007). G Delbès held a fellowship from the Ministère de l’Education Nationale de la Recherche et de la Technologie and from the Association pour la Recherche contre le Cancer (ARC). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

	Footnotes

 
Received 23 March 2006
First decision 14 July 2006
Accepted 14 August 2006

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