Testicular dysgenesis syndrome

In the Western world fertility rates are low and infertility is a major health problem. Unofficial statistics from Denmark reveal that about 6% of all Danish children are now born after assisted reproduction techniques, including in vitro fertilization, intracytoplasmic sperm injection, donor insemination or homologous insemination. However, there are no retrospective data on trends in fecundity (ability to conceive). We, and others, have focused on some aspects of adverse trends in male reproductive health such as the rising incidence of testicular cancer, low and probably declining semen quality, high and possibly increasing frequencies of undescended testes and hypospadias. Due to medical specialization and the different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, for instance paediatric endocrinologists, urologists, andrologists or oncologists. There is evidence that poor semen quality, testicular cancer, undescended testes and hypospadias are symptoms of one underlying entity, testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is the result of disruption of embryonal programming and gonadal development during fetal life. An endocrine disrupter hypothesis to explain the adverse trends has been proposed. It is recommended that future epidemiological studies on trends in male reproductive health should not focus on one symptom alone, but be more comprehensive and take all aspects of TDS into account.     

Le cancer à cellules germinales du testicule, élément constitutif du Syndrome de Dysgénésie Testiculaire: rôle des facteurs environnementaux et de la susceptibilité génétique

The incidence of testicular germ cell cancer has been increasing over recent decades in many countries of the world. Many studies over recent years have reported adverse trends in other aspects of male reproductive health, such as high and possibly increasing frequencies of undescended testis and hypospadias, declining semen quality, and an apparently growing demand for assisted reproduction due to male infertility. This article summarises the available evidence supporting a new concept that these male reproductive abnormalities may be signs of a single underlying entity: testicular dysgenesis syndrome (TDS). This syndrome, caused by nonspecific delays and aberrations of early testicular development, may be increasingly common because of deteriorating environmental and life-style factors that impair gonadal development. Geographical and ethnic differences in the incidence of various forms of TDS could be explained either by differences in exposure to adverse factors or by differences in genetic susceptibility to these factors.     

Le cancer du testicule : facteurs de risque génétiques et environnementaux

The incidence of testicular cancer (TC) has a distinct geographic distribution but is increasing in most countries, including France. The most likely origin of TC is a lack of normal germ cell differentiation in the foetal testis. The maintained immature germ cells could proliferate after puberty to induce testicular tumor. Because of its frequent association with cryptorchidism and infertility, TC could be part of the testicular dysgenesis syndrome. The role of genetic factors is suggested by the frequency of familial TC cases, but no responsible gene has been clearly identified until now. Among the various studied genes, those regulating the KITLG/KIT pathway involved in primordial germ cell proliferation seem to play an important role. Studies made in immigrants and twins suggest the influence of environmental factors on the origin of TC. Hormonal deregulation occurring during prenatal life or puberty could facilitate the development of TC. However, the role of exogenous substances acting as endocrine disruptors has not been demonstrated yet.     

Altérations environnementales du développement du testicule foetal: zoom sur les phtalates

There are great concerns about the increasing incidence of abnormalities in male reproductive function. Human sperm counts have markedly dropped, and the rate of testicular cancer has clearly increased over the past four decades. Moreover, the prevalence rates of cryptorchidism and hypospadias are also probably increasing. It has been hypothesized that all these adverse trends in male reproduction result from abnormalities in the development of the testis during foetal and neonatal life. Furthermore, many recent epidemiological, clinical and experimental data suggest that these male reproductive disorders could be due to xenobiotics termed endocrine disruptors, which are becoming more and more concentrated and prevalent in our environment. Among these endocrine disruptors, we chose to focus this review on phthalates for different reasons: 1) they are widespread in the environment; 2) their concentrations in many human biological fluids have been measured; 3) the experimental data using rodent models suggesting a reprotoxicity are numerous and are the most convincing; 4) their deleterious effects on the development and function of the rat foetal testis have been largely studied; 5) some epidemiological data in humans suggest a reprotoxic effect at environmental concentrations at least during neonatal life. However, the direct effects of phthalates on human foetal testis have never been explored. Thus, as we did for the rat in the 1990s, we recently developed and validated an organotypic culture system, which allows maintenance of the development of the different cell types of human foetal testis. In this system, the addition of 10^?4 M MEHP (mono-2-ethylhexyl phthalate), the most produced phthalate, had no effect on basal or LH-stimulated production of testosterone, but it reduced the number of germ cells by increasing their apoptosis, without modifying their proliferation. This is the first experimental demonstration that phthalates alter the development of the foetal testis in humans. Using our organotypic culture system, it is interesting to compare these results obtained in humans with the response to MEHP in the mouse and the rat testes to analyse the relevance of toxicological tests based on rodent models.     

Environmental oestrogens disrupt testicular descent and damage male reproductive health: Mechanistic insight

Environmental oestrogens (EEs) as environmental pollutants have been paid much attention due to their impact on congenital malformation of male genitourinary system. Exposure to EEs for prolonged time could hinder testicular descent and cause testicular dysgenesis syndrome. Therefore, it is urgent to understand the mechanisms by which EEs exposure disrupt testicular descent. In this review, we summarize recent advances in our understanding of the process of testicular descent, which is regulated by intricate cellular and molecular networks. Increasing numbers of the components of these networks such as CSL and INSL3 are being identified, highlighting that testicular descent is a highly orchestrated process that is essential to human reproduction and survival. The exposure to EEs would lead to the imbalanced regulation of the networks and cause testicular dysgenesis syndrome such as cryptorchidism, hypospadias, hypogonadism, poor semen quality and testicular cancer. Fortunately, the identification of the components of these networks provides us the opportunity to prevent and treat EEs induced male reproductive dysfunction. The pathways that play an important role in the regulation of testicular descent are promising targets for the treatment of testicular dysgenesis syndrome.     

Biophysical Evaluation of Radiofrequency Electromagnetic Field Effects on Male Reproductive Pattern

There are possible hazardous health effects of exposure to radiofrequency electromagnetic radiations emitted from mobile phone on the human reproductive pattern. It is more effective while keeping mobile phones in pocket or near testicular organs. Present review examines the possible concern on radio frequency radiation interaction and biological effects such as enzyme induction, and toxicological effects, including genotoxicity and carcinogenicity, testicular cancer, and reproductive outcomes. Testicular infertility or testicular cancer due to mobile phone or microwave radiations suggests an increased level of reactive oxygen species (ROS). Though generation of ROS in testis has been responsible for possible toxic effects on physiology of reproduction, the reviews of last few decades have well established that these radiations are very harmful and cause mutagenic changes in reproductive pattern and leads to infertility. The debate will be focused on bio-interaction mechanism between mobile phone and testicular cancer due to ROS formation. This causes the biological damage and leads to several changes like decreased sperm count, enzymatic and hormonal changes, DNA damage, and apoptosis formation. In the present review, physics of mobile phone including future research on various aspects has been discussed.     

Les différentes anomalies de la reproduction masculine sont-elles en augmentation ? Faits et controverses, possibles facteurs en cause: une analyse actualisée des données de la littérature et des registres

In recent decades, numerous observations in wildlife of various anomalies of the male reproductive functions-some being reminiscent of experimental toxicology data-have raised questions about the possible role of environmental pollutants. A number of studies suggest an increased prevalence of reproductive disorders in adult humans in recent decades in many (but not all) Western countries. The best documented data concern testicular cancer, its increasing rate suggesting that environmental factors and/or changes in lifestyle may come into play. However, considerable regional and ethnic differences exist in absolute incidence rates, suggesting in turn the concomitant role of the genetic background. Finally, several studies suggest that semen quality has declined in many countries. In the early 2000’s, Skakkebæk’s group in Copenhagen postulated a common origin to these different abnormalities — the so-called testicular dysgenesis syndrome (TDS) — all possibly related to abnormal testis development during gestation. Is there a causal link between these different conditions and deleterious environmental and/or lifestyle factors? The answer is far from being unequivocal, and the subject, a potential major public health problem, remains a source of hot debate both within the scientific community and in the media. The present review aims to provide an updated synthesis of these complex issues.     

Augmentation de l’incidence du cancer du testicule: état de la question

Although germ cell cancer is rare (about 1% of cancers in male), it is the commonest cancer in young man. Many studies in Europe, Northern America and Australia show that incidence rates of testis cancer are climbing. In Northern Europe and America, where cancer registration exist since the fifties, it is showed that overall age-adjusted incidence rate of testis cancer has increased more than 3 fold during the past 50 years. This increase affect particularly teenagers and young men. The increase of incidence rates is less documented in under developed countries but recent studies seem to confirm an increase of incidence rates in many parts of the world, even if testis cancer remain rarer in non Caucasian populations. Etiologies of a such increase are still unknown, but arguments point in view a possible relation between environmental hormone disrupters and many hormonodependent cancers, such as testicular neoplasm, the cancer of the breast or even prostate cancer. Epidemiological studies with large sample size are needed to identify risk factors responsible for the increase of incidence rates of testis cancer.     

Components of plastic: experimental studies in animals and relevance for human health

Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A (TBBPA), are detected in humans. In addition to their utility in plastics, an inadvertent characteristic of these chemicals is the ability to alter the endocrine system. Phthalates function as anti-androgens while the main action attributed to BPA is oestrogen-like activity. PBDE and TBBPA have been shown to disrupt thyroid hormone homeostasis while PBDEs also exhibit anti-androgen action. Experimental investigations in animals indicate a wide variety of effects associated with exposure to these compounds, causing concern regarding potential risk to human health. For example, the spectrum of effects following perinatal exposure of male rats to phthalates has remarkable similarities to the testicular dysgenesis syndrome in humans. Concentrations of BPA in the foetal mouse within the range of unconjugated BPA levels observed in human foetal blood have produced effects in animal experiments. Finally, thyroid hormones are essential for normal neurological development and reproductive function. Human body burdens of these chemicals are detected with high prevalence, and concentrations in young children, a group particularly sensitive to exogenous insults, are typically higher, indicating the need to decrease exposure to these compounds.     

Cryptorchidism: an indicator of testicular dysgenesis?

Cryptorchidism is a common ailment of new-born boys, affecting 1–9% of full term boys at birth. Cryptorchidism has been associated with an increased risk of testicular cancer and reduced fertility. Aetiology of cryptorchidism remains obscure in most cases. Familial occurrence suggests a heritable susceptibility to cryptorchidism; however, seasonal variation in the incidence of cryptorchidism suggests that environmental factors also contribute. Testicular descent is characterised by androgen-dependent regression of cranial suspensory ligament and androgen + insulin-like hormone 3 (Insl3)-dependent gubernacular outgrowth. Even though hormonal defects are rarely detected in patients, both hypo-and hypergonadotropic hormonal patterns have been associated with cryptorchidism. Moreover, cryptorchid boys have significantly reduced serum androgen bioactivity at 3 months of age when normal boys have a strong surge of reproductive hormones. Defects in Insl3 action cause cryptorchidism in male mice, and over-expression in female mice causes ovarian descent. Defects in leucine-rich repeat-containing G-protein-coupled receptor 8/G-protein-coupled receptor affecting testis descent (LGR8/GREAT), the receptor for Insl3, manifest the same phenotype as Insl3 knockout mutants. Even though mutations found in Insl3 and LGR8/GREAT genes are not a common cause of cryptorchidism in patients, it remains to be resolved whether low Insl3 levels during development are associated with cryptorchidism. Cryptorchidism may reflect foetal testicular dysgenesis that may later manifest as subfertility or testicular cancer.This work was supported by the Turku University Central Hospital, the Academy of Finland and the European Commission (contracts BMH4-CT96-0314, QLK4-CT1999-01422, QLK4-CT2001-00269 and QLK4-CT2002-00603).     

Développementin vitro de la lignée germinale foetale mâle chez le rat, la souris et l’homme

The key role of the foetal germ cell line in the reproductive capacity of the adult has been known for a long time. More recently, the observed increase in male reproductive disorders such as the decline of sperm count and quality and the increased incidence of testicular cancer has been postulated to be due to alterations of foetal and neonatal testicular development in response to increasing environmental pollution. However, few tools are available to study foetal and neonatal germ cell line development and the effects of physiological or toxic substances on this process. The authors have developed an organ culture system in which foetal or neonatal testis is grown on a filter floating on a synthetic medium free of serum, hormones or biological factors. This study, using rats and mice, first compared the long-term morphological and functional development of Sertoli and germ cells in thisin vivo system. In rats, these cells developed normally over a period of two weeksin vitro. Fewer cells were produced thanin vivo, but a similar level of differentiated function was observed. Germ cells, which are difficult to maintainin vitro, resumed mitosis after a quiescent period, at the same time asin vivo. Similar results were obtained with mouse fetuses, but this model was less efficient. This culture model can be used to study post-natal development of the germ cell lineage in testes derived from foetuses on the last day of foetal life and invalidated for P63, that do not survive after birth. This gene was found to be involved in the regulation of germ apoptosis which resumes after birth in the mouse. Lastly, this model applied to the human species (from 6 to 12 weeks of gestation) showed that testicular architecture and germ cells can be maintained for 4 days with better efficiency at younger stages than at older stages. p]In conclusion, testicular architecture and intercellular communications are sufficiently preserved to sustain gametogenesisin vitro with no added factors. This method is potentially useful to study the effects of various factors, particularly xenobiotics.     

Fetal Cyclophosphamide Exposure Induces Testicular Cancer and Reduced Spermatogenesis and Ovarian Follicle Numbers in Mice

Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼70% of control and induced atrophic seminiferous tubules in ∼30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.     

A treatise on hazards of endocrine disruptors and tool to evaluate them

Hormones mediate a major part of our essential physiological functions. Both endogenous and exogenous compounds and their metabolites are known to act through hormone receptors leading to regulation of endocrine function. The endogenous ligands that control reproductive functions are generally steroids such as 17beta-estradiol, androgens, progesterone, pregnenolone and glucocorticoids. However, exogenous compounds that are structurally and functionally similar gain entry into animals including humans through the diet or by occupational exposures, causing endocrine disruption. In the recent decade, there is a lot of apprehension about the so-called "endocrine disruptors" which are wide spread in the environment, mainly due to unrestricted human activity. These compounds of anthropogenic or natural origin mimic the action of sex hormones and can interfere with the endocrine system. It has been hypothesized that environmental exposure to synthetic estrogenic chemicals and related endocrine active compounds may be responsible for malformations in the male reproductive tract, crytorchidism, hypospadias, decrease in sperm counts, decreased male reproductive capacity and even testicular cancers. The increasing concern in both public and scientific communities about these abnormalities have prompted the initiation of epidemiological studies to not only identify, but to also analyze the short and long term effects of endocrine disruptors. As a result, a number of assays have been developed and are undergoing validation aimed at high throughput screening of chemical agents that disrupt endocrine activity. This review consolidates the findings of epidemiological studies, particularly in relation to male reproductive disorders and brings to light the various types of in vitro and in vivo models that are available for tiered testing of suspected compounds.     

Fetal radiation exposure induces testicular cancer in genetically susceptible mice

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis.     

Evidence of testicular dysgenesis syndrome in the dog

Human male reproductive disorders comprising testicular dysgenesis syndrome (TDS) have become more prevalent during the last 50 years. These disorders include cryptorchidism, hypospadias, decreased semen quality, and the development of seminomas. Based on experimental evidence, it has been suggested that environmental pollutants with oestrogen-like or anti-androgenic activities play a role in the pathogenesis of TDS. In humans, histological lesions associated with TDS have been well characterized; this includes seminomas as well as their precursors, carcinoma in situ (CIS) lesions. CIS are seminiferous tubules lined by gonocytes and are a sign of testicular maldevelopment. Such CIS have recently been described in canine species, and an increased frequency of testicular tumours in dogs has also been reported. In this study, we investigated the presence of TDS lesions in canine testes submitted to routine histological examination. Histological features considered typical of human TDS were observed in 8/38 dogs examined; as in humans, individual dogs presented with various TDS features with a range of severity. In all eight dogs, CIS and at least one of the histological feature of TDS was observed in combination with seminoma. These findings suggest that as in humans, TDS may predispose canines to develop testicular cancer. A larger study is needed to better evaluate the actual incidence of TDS in canines, its clinical consequences, and the possible underlying pathogenic factors.     

Impact of environmental pollutants on the male: effects on germ cell differentiation

A variety of so-called innocuous chemicals can have insidious and long lasting effects on the developing male reproductive system. Developmental exposures of male rabbits to common industrial contaminants in drinking water (a mixture of arsenic, chromium, lead, benzene, chloroform, phenol, and trichloroethylene); alkyl phenols (e.g. octylphenol); water disinfection by-products (e.g. dibromoacetic acid); anti-androgenic pesticides (e.g. p,p'-DDT and vinclozolin); and plasticizers (e.g. dibutyl phthalate) produce testicular dysgenesis. The lesions include testicular carcinoma in situ, also called intratubular germ cell neoplasia--the precursor lesion of germ cell tumors in men, and acrosomal dysgenesis--characterized by sharing of a dysplastic acrosome by two or more spermatids resulting in characteristic sperm acrosomal-nuclear malformations. Certain manifestations of testicular dysgenesis arch across environmental agents, and sequelae of intentional developmental exposures of rabbits duplicate what has been encountered in deer, horses, and humans for which the etiology is uncertain.     

Perspectives in Endocrine Toxicity of Heavy Metals—A Review

An attempt has been made to review the endocrine/hormonal implications of a few environmentally significant metals, viz, lead, mercury, cadmium, copper, arsenic and nickel, in man and animals. Special emphasis has been given to the adrenals, thyroid, testis, ovary and pancreas. Toxic metals can cause structural and functional changes in the adrenal glands. Their effects on steroidogenesis have been reviewed. It has been reported that thyroid hormone kinetics are affected by a number of metallic compounds. Occupational exposure to a few of these metals can cause testicular injury and sex hormone disturbances. Protective effects of a few antioxidants on their reproductive toxicity have also been discussed. Information gathered on female reproductive toxicity of heavy metals shows that exposure to these metals can lead to disturbances in reproductive performance in exposed subjects. Certain metals can cause injury to the endocrine pancreas. Exposure to them can cause diabetes mellitus and disturb insulin homeostasis. The need to develop molecular markers of endocrine toxicity of heavy metals has been suggested. Overall information described in this review is expected to be helpful in planning future studies on endocrine toxicity of heavy metals.     

Estrogen regulation of testicular function

Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i) localization of aromatase and the target protein for estrogen (ER-alpha and ER-beta) in tissues of the reproductive tract; ii) analysis of testicular phenotypes in transgenic mice deficient in aromatase, ER-alpha and/or ER-beta gene; and, iii) investigation of the effects of environmental chemicals on male reproduction. Estrogen is thought to have a regulatory role in the testis because estrogen biosynthesis occurs in testicular cells and the absence of ERs caused adverse effects on spermatogenesis and steroidogenesis. Moreover, several chemicals that are present in the environment, designated xenoestrogens because they have the ability to bind and activate ERs, are known to affect testicular gene expression. However, studies of estrogen action are confounded by a number of factors, including the inability to dissociate estrogen-induced activity in the hypothalamus and pituitary from action occurring directly in the testis and expression of more than one ER subtype in estrogen-sensitive tissues. Use of tissue-specific knockout animals and administration of antiestrogens and/or aromatase inhibitors in vivo may generate additional data to advance our understanding of estrogen and estrogen receptor biology in the developing and mature testis.     

Is fetal testis in danger?

Estrogens are classically known to play a major role in female reproduction, but there is now compelling evidence that they may also be involved in the regulation of male reproductive function. In humans, a decrease in sperm count and an increase in the incidences of testicular cancer, cryptorchidism and hypospadia have been observed in many countries over the last 50 years. Male reproductive alterations were also observed in wildlife. Such male reproductive disorders have been attributed to the increase in concentration of xenobiotics, and of xenoestrogens in particular, in the environment and in food. Epidemiological, clinical and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders in adulthood. Using an in vitro model, we showed that estrogens directly affected the development of the fetal testis. Lastly, we clearly demonstrated that the fetal and neonatal testis is very sensitive to estrogens since the invalidation of estrogen receptor alpha leads to an increase of steroidogenesis and the invalidation of estrogen receptor beta enhances the development of the germ cell lineage in the male.     

Environmental endocrine disrupters dysregulate estrogen metabolism and Ca2+ homeostasis in fish and mammals via receptor-independent mechanisms

Xenoestrogen endocrine disrupters (EDs) in the environment are thought to be responsible for a number of examples of sexual dysfunction that have recently been reported in several species. There is growing concern that these compounds may also cause abnormalities of the male reproductive tract and reduced spermatogenesis in man. Whilst some effects of EDs may be receptor-mediated, there is growing evidence that these compounds can exert potent effects in vivo by directly interacting with cellular enzyme targets. Here we report on, and review, the effects of alkylphenols and other EDs on two such enzymes: (1) sulfotransferases, which convert active estrogenic steroids to inactive steroid sulfates; and (2) Ca(2+)-ATPases, which are responsible for maintaining low, physiological, intracellular Ca(2+) concentrations. These enzymes are potently inhibited by EDs in both fish and mammalian species. The increased concentrations of active estrogens and the likely cytotoxic effects of elevated concentrations of intracellular Ca(2+) arising from these effects may underlie some of the endocrine disrupting potential of these widespread industrial pollutants.