Endocrine Disrupting Compounds Exposure and Testis Development in Mammals

EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

Mini review:

ENDOCRINE DISRUPTING COMPOUNDS EXPOSURE AND TESTIS DEVELOPMENT IN MAMMALS

Biola F. Egbowona and Olajide A Mustapha a School of Science and Technology, Erasmus Darwin Building ERD 200, Nottingham Trent University, Clifton Lane, NG11 8NS, UK * corresponding author: [email protected]

ABSTRACT In the last few decades, there is substantial evidence that male reproductive function is dete- riorating in humans and wildlife and this is associated with unintentional exposure to widely used synthetic chemicals. Subsequently, much has been done to show that certain chemicals in the environment adversely interfere with the developing fetal gonads of the laboratory animals. Some in vitro studies have demonstrated treatment-induced reproductive problems in offspring exposed to endocrine disrupting compounds (EDC) which are similar to those observed in wildlife and human population. Few EDC studies have demonstrated that there are certain periods of gestation when the developing fetus is highly sensitive and at risk of small endocrine changes. Similar observations have been made in the sewage sludge model, however, while animal studies have been insightful in providing valuable information about the range of effects that can be attributed to in utero exposure to EDCs, varying levels of maternal doses administered in different studies exaggerated extrapolation of these results to human. Thus the EDC concentration representative of fetal exposure levels is uncertain because of the complexities of its nature. So far, the level of fetal exposure can only be roughly esti- mated. There is substantial evidence from animal data to prove that EDCs can adversely affect reproductive development and function in male and more has accumulated on the mechanisms by which they exert their effects. This paper therefore, reviews previous studies to highlight the extent to which testis development can be disrupted during fetal life.

Keywords: endocrine disrupting compound, human direct exposure, humans, wildlife and male reproductive

INTRODUCTION evidence have shown declines in human semen quality during the last 5-6 decades The adverse effects of environmental (Leto and Frensilli, 1981; Bostofte et al., disrupting compound (EDC) exposure on 1983). Several studies have reported diverse various aspects of human health and, espe- trends in male reproductive health, includ- cially, reproductive development during ing increasing incidence of testicular cancer fetal and early post-natal life, have been a (Forman and Moller, 1994), declining se- growing concern in most parts of the world. men quality (Andersen et al., 2000). Re- This is particularly evident from the emerg- ports have shown significant decreases in ing trends in human reproductive health sperm concentration (113 million/ml vs. 66 such as testicular cancer, decreasing sperm million/ml) and semen volume (3.40 ml vs. counts and or hypospadias/cryptorchidism, 2.75 ml) over the period between 1938 and which are collectively ‘termed testicular 1990 (Carlsen et al., 1992). A number of dysgenesis syndrome’ (TDS), over the last reports on the available data from cancer few decades. Clinical and epidemiological registries have been reviewed (Toppari et

173 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

al., 1996) with evidence of an increase in effects, which include growth inhibition, testicular cancer in many countries includ- reproductive dysfunction and immune sys- ing England and Wales (Pike et al., 1987), tem impairment (Rhind, 2002) on many Scotland (Hakulinen et al., 1986), the Nor- animal species including ruminants and dic and Baltic countries (Adami et al., humans. They are often referred to as endo- 1994; Stone et al., 1991), Australia (Pearce crine disruptors; indicating their potential et al., 1987), New Zealand (Wilkinson et ability as either hormone agonists, or an- al., 1992; Spitz et al., 1986), and the United tagonists of the endogenous compounds. States (Harris and Steinberg, 1954). Their adverse effects may include im- Studies on wildlife species have re- paired testosterone secretion, (certain vealed various effects of environmental phthalates), altered metabolism (PCBs, compounds (Toppari et al., 1996). These polychlorinated bisphenyls hydrocarbons), include some key observations in gastro- blockage of hormone action (pesticides) or pods, fish, reptiles, and mammals (Ta- direct activation of androgen or estrogen ble 2A, B). Generally, some of the repro- receptors (several EDCs) (Rhind, 2002). ductive failures reported in wildlife include Animals may be exposed to relatively high decreased fertility, decreased hatching suc- concentrations of EDCs mostly through cess, birth deformities, metabolic abnor- feeding and water; they could be stored and malities, behavioural abnormalities, demas- concentrated mainly in the fat tissues (Eke- culinisation/feminisation of males, and de- lund et al., 1990; Ahel et al., 1993; Pojana feminisation/masculinisation of females et al., 2007). The accumulated fats may be (Hollander, 1997). A number of reproduc- utilised in periods of pregnancy and lacta- tive dysfunctions which were reported in tion when the animals’ energy requirements male offspring from animal studies have are particularly very high. This could exert been associated with maternal EDC expo- endocrine disrupting effects on the animals sure (Sweeney and Brooks 1996; Imajima (Bigsby et al., 1997) thus exposing their et al., 1997). Experimental evidence from embryos and neonates to relatively high many animal studies has also explained concentrations of EDCs. Detectable con- some of the anatomical and physiological centrations of EDCs were reported in body changes which may occur as a result of tissues from adults, young children and fe- EDC exposed in humans. These includes tuses (Fowler et al., 2008, 2009; Choi et al., oviductal malformations (Newbold et al., 2008), following absorption of the EDCs 1983) and a high incidence of uterine fi- from the environment. broids (Baird and Newbold, 2005; Cook et al., 2005).

Environmental disrupting compounds (EDCs) Environmental disrupting compounds (EDCs) constitute a diverse range of anthropogenic compounds, including organochlorine pesticides, polychlorinated bisphenyls (PCB), alkylphenol polyethoxylates, phytoestrogens, bisphenol-A, phthalates, dioxins, polybrominated diphenyl ethers and heavy metals (Rhind et al., 2002) (Ta- ble 1). They are ubiquitous, persist in the environment at low concentrations, however, they appear to exert a range of adverse

174 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

Table 1: Common environmental contaminants, sources and health effects from developmental and adult exposures (animal and human data) Contaminant Sources Selected health Selected health effects with effects with postnatal exposure prenatal exposure Bisphenol A (BPA) Industrial chemical and Oocyte chromosome ab- Altered puberty onset, al- building block for polycar- normalities, recurrent mis- tered prostate development, bonate plastic and epoxy carriage, ↓ semen quality ↓ semen quality, hormonal resins, lining of metal food (Hunt et al., 2003) changes (Herath et al., and drink cans, plastic 2004) bottles, baby toys, dental sealant, cell phones etc.

Pesticides in general Many classes of insecti- Menstrual irregularities, ↓ Altered sex ratio, altered cides, fungicides, herbi- fertility, ↓ semen, quality, puberty onset, malformation cides, rodenticides and premature birth, sperm of reproductive tract, ↓ fertil- fumigants. Exposure can chromosome abnormali- ity, impaired fetal growth, occur through food, drink- ties, hormonal changes (IUGR) (Gray et al., 2001) ing water or simply from (Farr et al., 2004) domestic applications

Phthalates Plasticizers (added to Altered (earlier) menarche Shortened anogenital dis- soften plastics like PVC), onset, altered oestrus tance, malformations of cosmetics, perfumes, toys, cycle, ovulatory irregulari- reproductive tract, hormonal pharmaceuticals, medical ties, ↓ semen quality, re- changes, ↓ semen quality devices, lubricants and duced fertility, fetal loss, (Couse and Korach, 2004) wood finishers endometriosis (Cobellis et al., 2003) Chlorinated hydrocarbons PCBs, DDT, dioxins/furans Menstrual irregularities, Malformations of the repro- endometriosis, reduced ductive tract, altered oestrus fertility, fetal loss, ↓ semen cycle, reduced fertility al- quality, altered puberty tered sex ratio, altered pu- onset, altered menarche berty onset, ↓ semen quality, onset delayed time to pregnancy (Venners et al., 2005) (Miller et al., 2004; Denham et al., 2005)

Pharmaceuticals DES, ethynylestradiol Malformations of reproductive tract, altered hormone response, menstrual irregularities, reduced fertility, uterine fibroids, miscarriage, - hormonal changes, reduced birth weight, fetal loss (Lau et al., 2004)

Wildlife, laboratory and human studies occurrence. For instance, reduced testoster- Reproductive and developmental ab- one synthesis, plasma steroid concentra- normalities associated with EDC exposures tions and male phallus size were reported in have been well documented in wildlife. juvenile alligators from seven Florida lakes These include birds, frogs, seals, polar following EDC exposure (Guillette et al., bears, marine mollusks, and many other 1999). The mechanism by which Di(n- wildlife species. For example, alligators butyl)phthalate (DBP) caused reduced tes- from Lake Apopka in Florida, which was tosterone levels was through decreased pro- highly polluted due to extensive farming duction of androgen and the associates sex activities around the lake, the presence of a steroids by the fetal Leydig cells (Lam- sewage treatment plant, and the past spills bright et al., 2003). Exposure of rat testes of organochlorine pesticides, were reported on gestation days 12-21 caused downregu- to have been feminized (Hood, 2005; Mil- lation of mRNA expression for SRB1, nes et al., 2008). Over time, many of the StAR, P450scc, 3β-HSD, P450C17 and c- adverse effects observed in wildlife popula- kit and upregulation of mRNA expression tions have been induced in laboratory ani- for TRPM-2 (Barlow et al., 2003). mals, supporting the role of EDCs in their

175 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

Many studies in a variety of species exposure (Duty et al., 2005). In addition, have shown that there is a tendency for re- some phthalates such as DEHP can inhibit productive success to be jeopardized not aromatase activities (Davis et al., 1994) and only by direct effects of pollutants on re- may thus interfere with estrogen production productive pathways but also by adversely in fetal testis. During gestation, exposed affecting the general health status of the human maternal-fetal unit and maternal tis- individual. EDCs are known to have the sues contain levels of EDCs that are associ- potential to disrupt processes as diverse as ated with many in utero effects (Ikezuki et immune function (Markman et al., 2008), al., 2002; Younglai et al., 2002; Tsutsumi, thyroid function (Langer et al., 1998; New- 2005; Barr et al., 2007; Chao et al., 2007; bold et al., 2007), bone structure (Fox et al., Huang et al., 2007; Thundiyil et al., 2007). 2008), mammary structure and function Testes exposed to dieldrin caused a reduc- (Moral et al., 2008), cardiovascular function tion in LH-induced testosterone secretion, (Ha et al., 2007) and social behaviours tissue protein concentrations of LH recep- (Markman et al., 2008). Perturbation of any tor, steroid acute regulatory protein and in- one of these systems has the potential to duced proteins associated with cancer and adversely affect an animal’s reproductive apoptosis (Fowler et al., 2007). In addition, success (Rhind, 2009). The complexity of protein expression of WNT-2B in the Ser- EDCs mechanism could be implicated in toli and Leydig cells was significantly re- processes ranging from the increased inci- duced. The ‘anti-androgenicity’ of DBP dence of breast cancer (Kortenkap 2006) was shown in the suppression of fetal Ley- and a variety of male reproductive effects dig cell androgen production and conse- (Sharpe and Skakkebaek, 2003) to meta- quently the occurrence of cryptorchidism bolic disturbances. A number of develop- and hypospadias (Johnston et al., 2004). mental abnormalities from laboratory stud- Studies have shown that Polychlorinated ies have been associated with EDC expo- bisphenyls (PCBs) can alter estrogen levels sures. Many chemicals have been associ- in the body and contribute to reproduction ated with the aetiology of various reproduc- problems such as feminisation of males and tive disorders which are thought to originate intersex (Venners et al., 2005). in fetal life (Sharpe and Skakkebaek 2003; Skakkebaek et al., 2001) and can be in- EDC exposure and testis development duced in animal models by fetal exposure to Testis development is accompanied by environmental chemicals (Fisher et al., the expression and activation of a large 2003; Mylchreest et al., 1999; Parks et al., number of genes. Perturbation of some of 2000). Prolonged exposure of rats to Di-2- these genes has been reported following in ethylexyl phthalate (DEHP) caused reduced utero exposure of developing fetuses to testosterone production (Akingbemi et al., EDCs. The chief of these is sex- 2004). There is also evidence of obstruct determining gene located on the Y chromo- gonocyte development in rats exposed to some (Sry gene), which dictates the extent DBP or DEHP leading to significant reduc- of sex determination and favours testis de- tion in the number of germ cells per Sertoli velopment. Sheep Sry transcripts persist cell at age 25 days compare with controls, after the full differentiation of the testis as as well as some evidence of altered Sertoli opposed to what happens in mice, (disap- cell function and proliferation after such pears after differentiation), indicating that exposures (Hutchison et al., 2008). DBP its role is not limited to initiating sex de- exposed rats at days 4-6 postnatally showed termination and Sertoli cell differentiation reduced numbers of spermatogonia and (Payen et al., 1996). In addition, some other their resumption of proliferation was de- genes are involved in mammalian sex delayed. Another study reported increased termination including Wilms’ tumour gene damage to the DNA in the rats spermatozoa (WT-1), Steroidogenic factor gene (SF-1), as a result of monoethylphthalate (MEP) and some growth factors such as anti-

176 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

Mullerian hormone (AMH). Interference studies have provided more evidence for with the expression of these genes might testosterone and/or dihydrotestosterone result in impaired testis development (Yao (DHT) playing a role in testis descent, this et al., 2002). include extensive expression of AR in the In humans, disrupted DHH gene is also gubernaculum (Staub et al., 2005), the ex- correlated with gonadal dysgenesis (Canto pression of 5α reductase (George, 1989), et al., 2004). Insulin-like factor 3 (INSL3) and interaction of Insl3 and androgens in acts through the receptor LGR8 to mediate vitro to regulate gubernaculum growth testicular descent, enhancing the growth (Emmen et al., 2000). Exposure of rats to gubernaculum’s primodia and caudal geni- flutamide a synthetic antiandrogen between toringuinal ligament. Mutation of the two ER 15.5 and 18.5 caused incomplete in- genes is associated with failure of testicular guino-scrotal descent (Mylchreest et al., descent in developing males (Ferlin et al., 1999; Amann and Veeramachaneni, 2007). 2008; Adham and Agoulnik, 2004). Several

Table 2A: Examples of reproductive and developmental abnormalities attributed to endocrine disruption in mammals

Species Location Observation Contaminant References

Mammals

Humans Finland, Denmark Oligospermia, impo- DDT, kepone, oral contracep- Degen and Bolt (2000) tence, hypogonadism, tive, stilbene derivatives decrease libido, reduced Coumestrol Hughes (1988) sperm dysfunction, men- Isoflavonoids Tyler et al. (1998) strual cycle irregularities PCBs Infertility Cattle Detroit, Michigan, Infertility, dystocia PCBs, dioxins Sheep USA Impaired reproductive Isoflavonoids Safe et al. (2000) functions DDE Puga et al. (2009) Kung et al. (2009) Seals Population decline, de- Isoflavonoids, counmestans Mink Wadden sea velopmental toxicity, U.S Columbia hormonal alterations Panthers River System & Infertility, ovulation fail- Clarke et al. (2000) Canadian Fraser ure, implantation failure Hughes (1988) River Infertility System Rabbits Low ejaculates volume, Guniea pigs low sperm concentra- Mice Florida tions, poor sperm motil- ity, a very high proportion DES, isoflavonoids Hughes (1988) of sperm with morpho- Newbold et al. (2000) logical abnormalities

177 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

Table 2B: Examples of reproductive and developmental abnormalities attributed to endocrine disruption in birds, reptiles and fish Species Location Observation Contaminant References

Birds Pacific coast of the Proliferative lesions, reproduc- DDT Newbold et al. (2000) Japanese quail USA tive tract tumours, infertility, DDT Bryan et al. (1989) Gulls inhibition of oestrus, inhibition of DDE, PCBs Safe et al. (2000) Waterbirds ovulation Reptiles Lake Apopka, Abnormal reproductive behav- DDT, DDE, dicofol Guillette et al. (1994), Alligators Florida, USA iour Guillette et al. (1999) Red-eared Feminisation of male embryos slider turtle Egg shell thinning, developmen- Willingham and Crews tal abnormalities, growth retar- (1999) dation

Abnormal gonads, decreased phallus size, altered sex hormone levels Fish St. Lawrence Abnormal reproductive devel- trans-Nonachlor, cis- Howell et al. (1980) Mosquito fish River opment Nonachlor, arochlor, Abnormal expression of secon- DDE, chlordane dary sex characteristics, masculinisation failure Hermaphroditism, vitellogenin in males, altered testes development Early mortality, organs deformities Reduced sex steroid levels, delayed sexual maturity, reduced gonad size

Decreased hormone levels, Androstenedione Safe et al. (2000) reduced ovarian development, reduced egg/larvae viability

EDC health risk from animal perspective numbers in fetal tissues was evident in the There are numerous studies on trends of sewage sludge model, suggesting that ef- changes in human reproductive health, evi- fects are present and that animal perform- dent in declining male fertility and associ- ance may be influenced by small, but po- ated developmental disorders (Skakkebaek tentially economically-significant reduction et al., 2001). However, there appears to be in immune capacity. The subtle nature of less concern about the risks associated with the effects of EDC exposure in farm ani- exposure of farm animals to EDCs as there mals may take a long time to establish is little evidence of a defined risk to farm whether there are measurable consequences animal fertility as a result of exposure to associated with it. There is a need for more EDC, however, emerging preliminary ob- evidence of subtle differences in perform- servations are suggesting that risks may yet ance due to EDC exposure. become apparent (Rhind, 2005). Rhind (2009) reported that subtle perturbation of Impacts and limitations of epidemiology underlying processes associated with EDC and laboratory studies exposure is not significantly apparent under Substantial evidence accumulated from field observations however, it may be dev- epidemiological studies to support the hu- astating to animal health or reproductive man health risk related with exposure to performance. The possibility that the in- endocrine disruptors. Most studies on the creases in the incidence of poor perform- effects of EDCs were based on rodent mod- ance and ill health may become significant els, and the impacts of such studies have led in future is not negligible, particularly if to the understanding of potential effects and exposure to EDCs is increased (Rhind, the mechanisms of actions of individual 2005). For instance, reduced immune cell EDCs from such studies. However, such

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studies are of limited empirical value in the DAX1, FGF9, DHH and DMRT1. Many assessment of health risks in human devel- other genes are being expressed by the Ser- opment because the patterns of experimen- toli cells including WNT-4, LHX-1, EMX-1, tal exposure are not representative of nor- LHX-9 and SF1 (Wilhelm et al., 2007). mal human exposure. The majority of the Sertoli cell proliferation forms essential laboratory studies have used a number of part of testis development as there is finite selected chemicals, which were adminis- number of germ cells which each of the tered at doses higher than environmental Sertoli cells can support through spermato- levels (Parks et al., 2000; Gray et al., 2001; genesis in adulthood and consequently, the Hayes et al., 2002). Nevertheless, the im- number of Sertoli cells per testis determines portance of environmental relevance of both the testis size and maximum number these compounds to exert reproductive ab- of sperm that it can produce (Sharpe and normalities in mammals remains. This will Skakkebaek, 2003). These cells are no certainly involve the study of the effects of longer mitotic after puberty, so the popula- multi-component mixtures of compounds to tion at that time is definitive. determine the effects on mammalian repro- Proliferation of Sertoli cells occurs dur- duction. ing two periods of life: fetal or neonatal and peripubertal, which is morphologically in- • Origin of testicular cells target for EDC different in most species. In sheep, sexual effects differentiation and postnatal testicular In mammals, gonad formation is initi- growth are separated by a period of at least ated by the migration of primordial germ five months giving a more precise analysis cells from the proximal epiblast of the ex- (Hochereau-de Reviers et al., 1995). In traembryonic mesoderm, via the hindgut sheep there are two periods of mitotic activ- into the gonad (Adams and McLaren, ity of Sertoli cells, first after sexual differ- 2002). The somatic cells which constitute entiation and second after birth. By con- about 80 % of the testicular cells originate trast, in the fetal rat testis, mitotic activity from either the coelomic epithelium or of Sertoli cells is maximal just before birth, mesonephros adjacent to the gonad. How- while gonocytes divide earlier (Hilscher et ever, the origin of both fetal and adult Ley- al., 1972), making the two periods overlap dig cells remains controversial and recent (Sharpe and Skakkebaek, 2003). Only one studies have suggested that these cells do peak of DNA synthesis in rat Sertoli cells not have a common source. However, it is has been observed at the end of gestation not unlikely that both the coelomic epithe- (Orth, 1982). lium and mesonephros have contributed to Mitotic divisions of Sertoli cells are the fetal Leydig cell population. more numerous before birth but functional maturation of Sertoli cells occurs around • Sertoli cells (SC) the onset of puberty (Sharpe and Skakke- Sertoli cells main functions during testis baek, 2003), coinciding with the time they development include cord formation and exit the cell cycle (Gondos and Berndston, secretion of anti-Mullerian hormone 1993). They undergo morphological (AMH) during fetal life (Mackay, 2000), changes which include enlargement of nu- and provide the germ cells with the physical cleus to become tripartite and nucleolus to and metabolic support needed for sper- become more distinct (Sharpe and Skakke- matogenesis during postnatal life (Sharpe, baek, 2003) and between each Sertoli cell 1994). The pre-Sertoli cells populations are the formation of specialized tight junctions derived from the coelomic epithelium and to create the blood-testis barrier (Gondos are stimulated by Sry to differentiate into and Berndston, 1993). Sertoli cells. Sertoli cells express a number FSH has been shown to stimulate Ser- of genes that play important role in testis toli cell proliferation in both around and development which include SOX9, WT1, after birth in rat testis (Orth and Boehm,

179 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

1990). However, very few FSH binding ing the clusters of Sertoli cells enclosing sites per Sertoli cell were present in the germ cells, and cooperating with the Sertoli postnatal testis (Barenton et al., 1983). Fur- cells to form the base lamina membrane thermore, Sertoli cell number has been ex- (Martineau et al., 1997). They proliferate amined in fetal and postnatal hypophysec- during fetal life but decline rapidly after tomy sheep and hypogonadal (hpg) mice, birth (Palombi et al., 1992). The age at lacking GnRH and therefore no circulating which peritubular myoid cells differentiate gonadotrophins (FSH and LH). Fetal Sertoli is not clear but it was reported that these cell proliferation is independent of gonad- cells do not differentiate until around pu- otrophins, whereas postnatal Sertoli cell berty when they become flatter and longer proliferation requires gonadotrophins (Ho- (Skinner, 1991). Peritubular myoid cells chereau-de Reviers et al., 1995; Baker and express all known markers of differentia- O’Shaughnessy, 2001). tion including desmin, α-smooth muscle Androgens also play an important role actin (SMA) and alkaline phosphatase, in Sertoli cell proliferation in the fetal testis shortly after birth (Palombi et al., 1992). which may be direct or indirect (Johnston et SMA expression has long been reported in al., 2004). In addition to the endocrine the peritubular myoid cells of ER19 fetal rat functions, some growth factors have been testes (Fisher et al., 2003). Expression of found to support Sertoli cell proliferation. dhh and Protein patched homolog 1 (ptch1) This includes epidermal growth factor is important in peritubular myoid cells dif- (EGF) and transforming growth factor-α ferentiation and consequently cord forma- (TGF-α) which stimulate postnatal Sertoli tion as inhibition of the dhh/ptch1 signaling cell proliferation, at least in culture (Peter- pathway results in disrupted cord formation sen et al., 2001) and testis organ cultures (Yao et al., 2002) and mice with a null mu- (Cupp and Skinner, 2001). Furthermore, tation for dhh have impaired differentiation TGF and EGFR expression can be regu- of the peritubular myoid cells (Clarke et al., lated through growth stimulatory hormones 2000). This is suggesting that DHH/PTCH1 such as FSH and testosterone (Cupp and transduction between SC and PTM cells Skinner, 2001). While FSH and androgens may play a role in peritubular myoid cell were reported to have stimulatory effects on migration and differentiation. Similarly, Sertoli cell proliferation, thyroid hormone PTM cells have also been shown to express has been reported to have inhibitory effect the androgen receptor during fetal and on the Sertoli cell proliferation in rodents as postnatal life (You and Sar, 1998); hence, hypothyroidism prolonged Sertoli cell pro- they may likely be involved in testicular liferation (Van Haaster et al., 1992), and development (Anderson et al., 2002). conversely, shortens the period of Sertoli cell proliferation in rodents (van Haaster et • Primordial germ cells (PGC) al., 1993). In addition, thyroid hormone was Primordial germ cells are the embryonic found to inhibit Sertoli cell proliferation by precursors of the gametes which are re- increasing the expression of the cycling- sponsible for the transfer of genetic infor- dependent kinase inhibitors (CDKIs), mation between generations. Unlike in so- P27kip and P21cip, which disrupt the ad- matic cells of the testis, PGC neither arise vancement of the Sertoli cell through the from the coelomic epithelium nor meso- cell cycle and consequently result into pre- nephros, but emerge from a small popula- mature maturation (Holsberger et al., 2003). tion of epiblast cells, which are derived from the embryonic endoderm lining the • Peritubular myoid (PTM) cells yolk sac. The yolk sac situated on the ven- The peritubular myoid cells are flat, tral surface of the embryo forms the devel- smooth-muscle-like cells that migrate into opmental circulatory system during early the gonad from the mesonephros and con- embryo development. It provides nourish- tribute to testis cord formation by surround-

180 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

ment and protection for the developing em- male embryo but the male germ cells have bryo (Ginsburg et al., 1990). been said to be protected from retinoic acid PGCs migrate along the hindgut, before effect by the Sertoli cells, which express colonizing the genital ridge. These cells P45026, an enzyme that catabolises retinoic were first thought to migrate to the genital acid and consequently acts as a male- ridge independently (De Felici and Dolci, specific meiosis-inhibiting factor (Bowles 1987), however, studies have shown that et al., 2006). Li et al. 2009 also reported they relate with one another through cyto- that P45026 in Sertoli cells acts as a mascu- plasmic processes called filopodia, which linising factor to arrest male germ cells in form extensive networks interlinking the the G0 phase of the cell cycle and prevents cells (Bendel-Stenzel et al., 2000). Cadher- them from entering meiosis. The gonocytes ins, a family of cell adhesion molecules remain mitotically arrested until after birth were shown to be involved in the associa- when they resume proliferation (McLaren, tion of the primordial germ cells during the 1984). They then migrate from the centre of migration since the absence of E-cadherin the cord to the basement membrane and has caused an increase in the number of ec- start to differentiate into spermatogonia topic primordial germ cells (Bendel-Stenzel (Boulogne et al., 2003). et al., 2000). The PGCs proliferate rapidly during their migration to the genital ridge • Leydig cells (LC) (Tam and Snow, 1981). After colonizing The primary function of Leydig cell in the genital ridge, they undergo the process the testis includes steroid synthesis. Two of maturation which involves sequence of types of Leydig cells have been identified, transition into fetal germ cells and express both of which are responsible for steroido- germ cell nuclear antigen-1 protein genesis; the fetal Leydig cells and adult (GCNA1 protein), a marker of post-migra- Leydig cells, arising from different cell tory germ cells (Enders and May, 1994). lines (Habert et al., 2001; Kerr and Knell, The germ cells at this stage are bipotential, 1988). Both the coelomic epithelium (Yao capable of developing as primary meiotic et al., 2002; Luo et al., 1994) and meso- oocytes or mitotic spermatocytes. Whether nephros (Buehr and McLaren, 1993; Ni- they become oocytes or spermatocytes, is shino et al., 2001) were suggested to con- dependent upon the sex of the gonad (Ford tribute to the precursors of Leydig cells as et al., 1975) that is their surrounding envi- the coelomic epithelium is known to give ronment rather than the chromosomal sex rise partly to the Sertoli cells and a signifi- of the germ cells themselves. For instance, cant number of interstitial cells (Karl and XY germ cells can develop as oocytes in a Capel, 1998). These two cell lines are struc- phenotypically female chimaeric embryo turally similar, but their functional proper- and XX germ cells can develop as sperma- ties differ considerably (Huhtaniemi, 1989). tocytes in a phenotypically male chimaeric The main origin of fetal Leydig cells re- embryo (Palmer and Burgoyne, 1991; Ko- mains controversial as many studies have cer et al., 2009). In other word entry into been involved in this subject and no defini- meiosis is inherently based on a cell- tive evidence was shown. They were autonomous programme (McLaren and thought to differentiate from mesenchyme- Southee, 1997). The embryonic testis was like stem cells (Byskov, 1986). In addition, thought to produce an unknown factor that neural crest has been suggested to contrib- inhibits entry into meiosis and rather initi- ute to the fetal Leydig cell population, as ates mitotic arrest, therefore establishing a these cells express the neural cell adhesion spermatogenic fate (McLaren and Southee, molecule (NCAM) (Mayerhofer et al., 1997). Retinoic acid is usually produced by 1996). The primary role of the fetal Leydig the mesonephros of the bipotential gonad cells is to produce androgens for masculini- (Bowles et al., 2006) inducing germ cells to sation of the embryo and to secrete insulin- enter meiosis and establish the fate of fe- like growth factor 3 (Insl3), which, com-

181 EXCLI Journal 2011;10:173-191 – ISSN 1611-2156 Received: August 16, 2011, accepted: October 03, 2011, published: October 10, 2011

bine with androgen action to induce testicu- phins dependent steroidogenesis (O'Shaugh- lar descent (Klonisch et al., 2004). The nessy et al., 1998). adult Leydig cells differentiate after birth, and are thought to evolve from undifferen- CONCLUSIONS tiated precursor cells from the mesenchy- mal cells of the interstitial compartment This review has shown various repro- (Hardy et al., 1993). However, Brennan et ductive health risks associated with EDC al. (2003) reported that coelomic epithelium exposure. Testicular cells can be a target for is not the main origin of Leydig cells al- EDC adverse effects and EDC exposure though; some of them may differentiate responses maybe different among testicular from the coelomic epithelium. cells. The EDC effects can be directly on Fetal Leydig cell differentiation and de- the cells number or shape through several velopment requires activation of sf1 and other mechanisms which can influence cell dhh (Park et al., 2007). Fetal DHH gene function. There is need to investigate what could be a target for EDCs’ action during other mechanism plays a role in disrupting testis development. Maternal smoking dur- the development and functions of the two ing pregnancy specifically reduced human primary cells in the testis with respect to fetal DHH expression during testis devel- EDC exposure. opment (Fowler et al., 2008). Sertoli cells, peritubular myoid cells, endothelial cells REFERENCES and interstitial fibroblasts are also involved Adami HO, Bergström R, Möhner M, Za- in Leydig cell differentiation. Sertoli cells toński W, Storm H, Ekbom A et al. Testicu- activate dhh and pdgf-α that promote Ley- lar cancer in nine northern European coun- dig cell differentiation while others express tries. Int J Cancer 1994;59:33–8. the X-linked aristaless related homebox gene (arx), which has been shown to con- Adams IR, McLaren A. Sexually dimorphic tribute to Leydig cell development (Kita- development of mouse primordial germ mura et al., 2002). The fetal Leydig cells cells: switching from oogenesis to sper- are more active and steroid production per matogenesis. Development 2002;129:1155- cell is much greater than in the adult Leydig 64. cells (Huhtaniemi et al., 1982). This may be because of the non-regulatory nature of the Adham IM, Agoulnik AI. Insulin-like 3 testosterone synthesis from the fetal Leydig signaling in testicular descent. Int J Androl cells. In sheep, mitotic activity of Leydig 2004;27:257-65. cells is similar to that of Sertoli cells; at least, seven and six mitotic divisions were Ahel M, McEvoy J, Giger W. Bioaccumu- reported before birth and before day 110 of lation of the lipophilic metabolites of non- gestation respectively (Hochereau-de Revi- ionic surfactants in freshwater organisms. ers et al. 1995). However, Leydig cells de- Environ Pollut 1993;79:243–8. crease in size with increasing fetal age, indicating likely decrease in their secretion Akingbemi BT, Sottas CM, Koulova AI, during the last month of gestation. Adult Klinefelter GR, Hardy MP. Inhibition of Leydig cell steroidogenesis is regulated by testicular steroidogenesis by the xenoestro- luteinizing hormone (LH), component of gen bisphenol A is associated with reduced the hypothalamus pituitary gonadal axis pituitary luteinizing hormone secretion and (HPG-axis). Perinatal regulation of steroi- decreased steroidogenic enzyme gene ex- dogenesis requires LH (O’Shaughnessy et pression in rat Leydig cells. Endocrinology al., 1998) indicating, there must be a 2004;145:592–603. switch, around the time of birth, from gonadotrophins independent to gonadotro-

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