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PubMed2004

Developmental effects of embryonic exposure to toxaphene in the American alligator (Alligator mississippiensis).

A variety of organochlorine pesticides have been shown to adversely affect embryonic development. A number of abnormalities have been documented in alligators (Alligator mississippiensis) from highly-contaminated Lake Apopka, FL, USA that are similar to the results of experimental studies exposing embryos to pesticides. In the current study, we exposed developing alligator embryos to varying concentrations of toxaphene, a broad-spectrum pesticide found in relatively high concentration in Lake Apopka alligator egg yolk. The toxaphene, dissolved in 50 microl of ethanol, was applied topically to the eggshell just prior to the sex-determining period of development. Shortly after hatching, we examined a number of morphological and physiological endpoints to determine the consequences of sub-lethal embryonic exposure to toxaphene. Our results indicate that toxaphene had little or no effect on the morphological endpoints examined including body mass (BM) and size, liver, thyroid, and gonad development. In addition, toxaphene failed to affect sexual differentiation, or in vitro thyroxin, testosterone (T), and estradiol production. However, male plasma T concentration was higher in animals treated with 10 and 0.01 microg toxaphene/kg (based on mean egg mass) than control males. Because in vitro T production was not different among control groups, we suggest the difference in plasma T could be due to differences in hypothalamic-pituitary stimulation of the gonad or hepatic steroid degradation. This study indicates that technical grade toxaphene, at the applied doses, does not induce the same developmental abnormalities associated with alligators living in Lake Apopka. Future studies should consider the effects of embryonic exposure to a mixture of chemicals, including toxaphene metabolites, on development in alligators to better evaluate the consequences of environmental contamination.

Alligators and Crocodiles↗
PubMed2003

Sexually dimorphic roles of steroid hormone receptor signaling in gonadal tumorigenesis.

Sex steroids control cellular phenotypes by binding to receptor proteins that in turn regulate downstream gene expression. They are important tropic factors in hormonally responsive tissues and have been implicated in the pathogenesis of both benign proliferations and malignancies at some of these sites. Knockout mice lacking inhibins, alpha:beta heterodimeric peptide hormones of the TGFbeta superfamily, develop gonadal tumors that produce sex steroids and depend on pituitary gonadotropin hormones. To better appreciate how sex steroid receptor signaling pathways contribute to the loss of granulosa/Sertoli cell proliferation in the ovary and testis of inhibin alpha (Inhalpha) knockout mice, we are using both pharmacologic and genetic approaches. Roles of androgens in testicular tumor development have been investigated in our previous studies using double-mutant mice lacking inhibins and carrying the null testicular feminization (tfm) mutation of the androgen receptor. Herein, we report that androgens also participate in the development of ovarian tumors, as tumor development is forestalled in mice treated with flutamide, a nonsteroidal inhibitor of androgen actions. Additionally, we generated double-mutant mice lacking estrogen receptor alpha (ERalpha) and Inhalpha or ERbeta and Inhalpha, as well as triple-mutant mice lacking ERalpha, ERbeta, and Inhalpha to determine the effects of individual and combined ER signaling pathways on tumor development. Although estrogens may have proliferative effects during follicle development and are important in specifying the granulosa cell phenotype, ERalpha and ERbeta signaling are not essential for timely granulosa cell tumor development or granulosa cell-like morphological features in ovarian tumors. However, redundant ER signaling through ERalpha and ERbeta in males is critical for testicular tumor formation, as triple-knockout, but not double-knockout, males are protected from early Sertoli cell tumorigenesis and death. Together, these studies indicate important and sexually dimorphic functions of estrogens and androgens in tumor development in this mouse model and indicate, for the first time, overlapping functions of ERalpha and ERbeta in Sertoli cell pathophysiology.

Androgens↗
PubMed1977

Isochromosome Yq in a woman with atypical Turner's syndrome.

A female with 46,X,i(Yq) in all cells and a survey of previous cases of isochromosome Yq is presented. She was first admitted to hospital 15 years old due to nanismus and retarded sexual development. Gonadal dysgenesia was observed, and the diagnosis 'atypical Turner's syndrome' was applied. The patient, who presents only a few Turner stigmata, has been given cyclic estrogen treatment since the age of 16. She has developed normal secondary sex characteristics, cyclic bleedings and has attained normal height (161 cm). Since the age of 18 the patient has suffered various periods of anemia caused by gastrointestinal hemorrhage. This hemorrhage is probably due to intestinal teleangiectasiae which are found with increased frequency in patients with Turner's syndrome.

Adult↗
PubMed2026

Mismatch repair protein MLH1 controls testis development by regulating the Hippo-YAP signaling pathway.

DNA mismatch repair (MMR) maintains genomic stability, and defects in MMR genes such as MLH1 and MSH2 predispose to cancer. Unlike other MMR components, MLH1 has unexplained roles in development, as Mlh1-deficient male mice exhibit severe testicular hypoplasia and sterility. Here, we uncover that MLH1 regulates testis development through the Hippo-Yes-associated protein (YAP) pathway. MLH1 directly binds YAP via its C-terminal domain and the WW domains of YAP, competitively inhibiting LATS1-mediated YAP phosphorylation. This interaction stabilizes YAP by suppressing ubiquitination and promotes its nuclear translocation dependent on MLH1's nuclear localization signal. Additionally, MLH1 facilitates YAP-TEAD complex formation, enabling expression of testicular development genes, including Wt1, Sox9, and Ctgf. These functions are independent of the MMR activity of MLH1. Mlh1-deficient mice show elevated YAP phosphorylation, reduced target gene expression, and impaired proliferation in developing testes. Pharmacological inhibition of the Hippo pathway kinases MST1/2 partially rescues testis hypoplasia in Mlh1-/- mice. These findings establish MLH1 as a Hippo pathway regulator and resolve its long-standing role in male gonad development.

Male↗
PubMed2001

Hemicentin, a conserved extracellular member of the immunoglobulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions.

him-4 mutations cause a novel syndrome of tissue fragility, defective cell migration and chromosome instability in Caenorhabditis elegans. Null mutants have abnormal escape reflex, mispositioning of the vas deferens and uterus, and mitotic chromosome loss and multinucleate cells in the germline. The him-4 gene product, hemicentin, is a conserved extracellular matrix protein with 48 tandem immunoglobulin repeats flanked by novel terminal domains. Secreted from skeletal muscle and gonadal leader cells, hemicentin assembles into fine tracks at specific sites, where it contracts broad regions of cell contact into oriented linear junctions. Some tracks organize hemidesmosomes in the overlying epidermis. Hemicentin tracks facilitate mechanosensory neuron anchorage to the epidermis, gliding of the developing gonad along epithelial basement membranes and germline cellularization.

Amino Acid Sequence↗
PubMed1998

Long-term, quantitative analysis of gametogenesis in autotriploid rainbow trout, Oncorhynchus mykiss.

A long-term, quantitative analysis was conducted on the gametogenesis of autotriploid rainbow trout (Oncorhynchus mykiss) to quantify their degree of germline development and reproductive potential. Triploid and diploid (control) trout siblings were raised separately under identical conditions and sampled randomly for histological analysis. Triploid males underwent testicular development and proliferation of germ cells by mitosis and meiosis, progressing through initial phases of spermatogenesis at a similar pace to diploid controls. The effects of triploidy on males were most evident during the final stages of spermatogenesis, when all diploid males contained free spermatozoa in the lumen of most tubules (average relative frequency, ARF = 68.5%), whereas triploid males contained predominantly spermatocytes (ARF = 36.3%) and morphologically abnormal spermatozoa (ARF = 31.8%). In contrast, the gonadal development of triploid females was affected during its early stages; the major patterns observed were the arrest of the oogonia within oogonial clusters (ARF = 30.4-71.1%), the appearance of small numbers (ARF = 1.5-6.0%) of previtellogenic and early vitellogenic follicles, and the proliferation of non-follicular elements (vascular lacunae, fibrosis and tubular adenomas). In agreement with previous reports on the ovarian development of chromosomally female (3A:ZZW) triploid chickens, male-differentiating areas (ARF = 0.2-12.2%) were observed in most triploid females examined, which by the end of the sampling period appeared as gonadal hermaphrodites. It is hypothesized that the lack of proper somatic-to-germ cell interactions prevents the segregation of the oocytes from the gonial clusters and may explain the early blockage observed during the gonadal morphogenesis of autotriploid female rainbow trout.

Aging↗
PubMed1998

The Dazh gene is expressed in male and female embryonic gonads before germ cell sex differentiation.

The autosomal homologs of the human Y-chromosomal DAZ gene (DAZH and Dazh in human and mouse, respectively) are strong candidate for Azoospermia factor and encode a testis specific RNA-binding proteins. We studied the expression pattern of the mouse Dazh during embryonic development by using Northern-blotting of developing gonads. In the mouse, we have detected 3.5 kb and 4.5 kb transcripts in male and female embryonic gonads at 12.5 dpc (days post coitum). During this period, the only germ cells present in the gonad are primordial germ cells. Dazh transcripts were not detected in embryonic gonads of mice that lack germ cells because of mutation in W gene, suggesting that expression is limited to germ-cells. In females, oogonia enter meiosis at 13.5-14.5 dpc: at this time Dazh transcription levels are similar to those of the male (when prospermatogonia are in the male gonad). Transcription levels decrease steadily after birth as the number of oocytes is depleted and is hardly detectable by puberty. A human DAZH transcript was also detected by Northern-blotting in the human ovary in levels which are of about 100 fold lower than those observed in the human testis. The expression of the Dazh in male and female gonad before germ cell sex differentiation suggests that these genes may act at the first phase of male and female gametogenesis.

Adult↗
PubMed1998

Transgenic mouse models for gonadal tumorigenesis.

The versatile transgenic (TG) techniques allow the production of in vivo animal models for a variety of diseases, including malignant tumors, through tissue-specific expression of oncogenes. We have created a TG mouse model for gonadal somatic cell tumors by expressing the powerful viral oncogene, Simian virus 40 T-antigen (Tag) under regulation of the murine inhibin alpha-subunit promoter (inh alpha). Ovarian granulosa and theca cell tumors were formed in the female, and those of testicular Leydig cells, in the male TG mice at the age of 5-6 months, with 100% penetrance. The tumors produced high levels of inhibin peptides, especially the alpha-subunit, and were steroidogenically active, mainly producing progesterone. The gonadal tumorigenesis was gonadotropin-dependent, since TG mice rendered gonadotropin-deficient by crossbreeding them into the hypogonadotropic hpg genetic background, or by treating them with a gonadotropin-releasing hormone (GnRH) antagonist, did not develop tumors. In order to study the possibility of using the tumor mouse model for testing gene therapy, we created another TG mouse model expressing under the same inhibin-alpha promoter the Herpes Simplex virus (HSV) thymidine kinase (TK) transgene. The inh alpha/HSV-TK mice were crossbred with the inh alpha/Tag mice and the double mutant mice also developed gonadal tumors. When they were treated with antiherpes drugs (acyclovir or gancyclovir), further growth of the tumors was blocked. These preliminary findings prove the principle that tumor ablation in our TG mouse model can be achieved by transduction of the HSV-TK gene into the tumor cells. Besides studies of formation, regulation and therapy of the tumors in vivo, immortalized cell lines derived from them provide models for studies of gonadal somatic cell functions in vitro.

Animals↗
PubMed1999

Sexual dimorphism in the neonatal gonad.

The neonatal gonad has two distinct forms (i.e., is sexually dimorphic), as judged by morphological and endocrine characteristics. The dimorphic process begins early in embryogenesis. It is well established by the time of birth, by which time the genital ridge has developed into either a testis or an ovary. The mechanisms involved in sex determination involve the Y chromosome, autosomal genes, transcription factors and possibly other unidentified control networks. This review paper describes the morphological changes that occur and the endocrine functions in the developing gonads. It highlights a number of important differences in fetal and neonatal gonadal function. The testis has early histological definition, several determining genes, delayed germ cell maturation, early autonomous steroid secretion, luteinizing hormone (LH) receptor and steroid enzyme expression, high fetal testicular testosterone content, prominent postnatal Leydig and Sertoli cells and high postnatal serum testosterone levels. The ovary has a prolonged monomorphic state, probably one determining gene, germ cells in early meiotic arrest, delayed expression of LH receptor and aromatase, low ovarian oestradiol content, prominent postnatal follicles and low postnatal serum oestradiol levels.

Embryonic and Fetal Development↗
PubMed2002

Pleiotropic activity of hepatocyte growth factor during embryonic mouse testis development.

The hepatocyte growth factor (HGF) is a pleiotropic cytokine whose action is mediated by c-met, a glycoproteic receptor with tyrosine kinase activity which transduces its multiple biological activities including cell proliferation, motility and differentiation. During embryonic development HGF acts as a morphogenetic factor as previously demonstrated for metanephric and lung development. Recently, culturing male genital ridges, we demonstrated that HGF is able to support in vitro testicular cord formation. In the present paper we report the expression pattern of the HGF gene during embryonic testis development and the multiple roles exerted by this factor during the morphogenesis of this organ. Northern blot analysis reveals a positive signal in urogenital ridges isolated from 11.5 days post coitum (dpc) embryos and in testes isolated from 13.5 and 15.5 dpc male embryos. On the contrary HGF mRNA is undetectable in ovaries isolated from 13.5 and 15.5 dpc embryos. Moreover, we demonstrate that HGF is synthesized and secreted by the male gonad and is biologically active. These data indicate a male specific biological function of HGF during embryonic gonadal development. This hypothesis is supported by the in vitro demonstration that HGF acts as a migratory factor for male mesonephric cells which is a male specific event. In addition we demonstrate that during testicular development, HGF acts as a morphogenetic factor able to reorganize dissociated testicular cells which, under HGF stimulation, form a tridimensional network of cord-like structures. Finally, we demonstrate that HGF induces testicular cell proliferation in this way being responsible for the size increase of the testis. All together the data presented in this paper demonstrate that HGF is expressed during the embryonic development of the testis and clarify the multiple roles exerted by this factor during the morphogenesis of the male gonad.

Animals↗
PubMed1995

Stimulation of spermatogenesis or of sex reversal according to the dose of exogenous estradiol-17 beta in juvenile males of protandrous black porgy, Acanthopagrus schlegeli.

The objective was to investigate the effects of various doses of estradiol-17 beta (E2) on gonadal development, gametogenesis, and plasma levels of sex steroids in 1-year-old protandrous male black porgy, Acanthopagrus schlegeli. Juvenile black porgy were divided into four groups, fed with control diet or diet mixed with E2 (0.25, 1.0, or 4.0 mg/kg feed) for 7 months, respectively. Significantly higher gonadosomatic index was observed in the 0.25- and 1.0-mg E2 groups compared to that in the control and 4.0-mg E2 groups during the spawning season. E2 at 4.0 mg completely suppressed spermiation, while lower doses of E2 (0.25 and 1.0 mg) delayed spermatogenesis but increased the number of spermiating fish and spermiation volume. Sperm concentrations were similar in spermiating black porgy. At 10 months and older, gonads in all the groups except E2 (4.0-mg)-treated fish underwent an intensive spermatogenesis while spermatids were not observed until 11 and 12 months in the 0.25- and 1.0-mg E2 groups, respectively. Primary oocytes appeared in the 10- and 11-month-old gonads in testicular tissue of the 1.0- and 4.0-mg E2 groups. After 5 months of 4-mg E2 treatment, testicular tissue regressed and ovarian tissue with primary oocytes developed. Elevated levels of plasma E2 were observed only in the 4.0-mg E2 group while low levels of E2 and testosterone (T) were observed in the control and other E2-treated groups. Significantly higher levels of plasma 11-ketotestosterone (11-KT) were observed in the 0.25- and 1.0-mg E2-treated groups during the spawning season. Plasma vitellogenin levels showed a dose-dependent effect of E2 treatment. The present data suggest that exogenous E2 could stimulate the development of either testicular or ovarian tissues, depending on the dosage of E2. Plasma 11-KT but not T concentrations closely correlate with testicular development and spermiation in black porgy.

Animals↗
PubMed2004

Arrested development in Xenopus laevis tadpoles: how size constrains metamorphosis.

Xenopus laevis tadpoles that arrest development and remain as larvae for several years sometimes occur spontaneously in laboratory populations. These tadpoles cease development at an early hindlimb stage, but continue to grow and develop into grossly deformed giants. Giant tadpoles lack thyroid glands, and differ in morphology and behaviour from normal larvae. They are negatively buoyant, typically with small and partially solidified lungs, and have greatly enlarged fat bodies. Giant tadpoles have mature gonads with eggs and sperm, whereas normal tadpoles of the same stage have undifferentiated gonads. Larval reproduction has never been reported in anurans, but gonadal development decoupled from metamorphosis brings these giants the closest of any anurans to being truly neotenic. We discuss behavioural and morphological factors that may hinder both reproduction in giant Xenopus larvae and the evolution of neoteny in anurans in general. Experimental treatment with exogenous thyroid hormone induces some, but not complete, metamorphic changes in these giants. The limbs and head progress through metamorphosis; however, all tadpoles die at the stage when the tail would normally be resorbed. The disproportionate growth of tissues and organs in giant tadpoles may preclude complete metamorphosis, even under exogenous thyroid hormone induction.

Analysis of Variance↗
PubMed1995

Gonadal dysgenesis in del(18p) syndrome.

We report on a girl with syndromal gonadal dysgenesis and a de novo del(18p). Genetic factors controlling gonadal development are located not only on the X chromosome, but also on autosomes. The present case suggests that one of these genes is situated on 18p. We conclude that patients with del(18p) syndrome should be evaluated for gonadal dysgenesis.

Child, Preschool↗
PubMed2000

Expression of estrogen receptor beta is developmentally regulated in reproductive tissues of male and female mice.

By the use of ribonuclease protection assay (RPA) combined with immunohistochemical techniques, the expression of estrogen receptor (ER) alpha and ERbeta was mapped in the developing gonads and reproductive tracts of male and female mice from fetal day 14 to postnatal day 26 (PND 26). This study was designed to determine the pattern of expression of both ER subtypes in specific tissue compartments during development. In ovaries, ERalpha mRNA was detected at all ages examined; ERbeta mRNA was seen as early as PND 1, and its expression increased with age. Immunolocalization showed ERbeta in differentiating granulosa cells of the ovary, whereas ERalpha was predominantly seen in interstitial cells. The remainder of the female reproductive tract showed ERalpha mRNA at all ages examined with little or no significant levels of ERbeta, except on PND 1 when a low level of message appeared. In males, ERalpha and ERbeta mRNA were detected in the fetal testis; however, ERbeta gradually increased until PND 5 and subsequently diminished to undetectable levels by PND 26. Immunolocalization showed ERalpha in the interstitial compartment of the testis, whereas ERbeta was seen predominantly in developing spermatogonia. The remainder of the male reproductive tract showed varying amounts of both receptors by RPA and immunostaining throughout development. These studies provide information useful in studying the role of both ER subtypes in normal differentiation, and they provide indications of differential tissue expression during development.

Animals↗
PubMed1993

WT-1 is required for early kidney development.

In humans, germline mutations of the WT-1 tumor suppressor gene are associated with both Wilms' tumors and urogenital malformations. To develop a model system for the molecular analysis of urogenital development, we introduced a mutation into the murine WT-1 tumor suppressor gene by gene targeting in embryonic stem cells. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos revealed a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. Our results establish a crucial role for WT-1 in early urogenital development.

Alkaline Phosphatase↗
PubMed2003

Insulin-like growth factor I (IGF-I) regulates endocrine activity of the embryonic testis in the mouse.

Insulin-like growth factor I (IGF-I) is important for gonadal and reproductive functions in mammals, although the physiological role of this growth factor during gonadal development in rodents remains largely unknown. Here, we examined the steady-state levels of IGF-I mRNA by the reverse transcriptase polymerase chain reaction (RT-PCR). IGF-I protein expression was also detected by Western blot. The effect of IGF-I as promoter of 17alpha-hydroxylase/C17-20 lyase and 17beta-hydroxysteroid dehydrogenase enzyme activity in vitro was evaluated by radioimmunoassay. Onset of IGF-I gene expression was on day E10 (urogenital ridge stage). IGF-I mRNA expression was markedly reduced on days E12 and E13 (testicular differentiation stage). IGF-I transcripts increased on day E14 and their transcription levels were maintained throughout the stages analyzed. Several IGF-I protein bands of 31-100 kDa were observed. Culture experiments demonstrated that 17alpha-hydroxyprogesterone and testosterone (T) secretion levels increased in the presence of IGF-I on days E11-E17. Additive effects of IGF-I plus (Bu)2cAMP were also seen during testicular development. It is proposed that IGF-I regulates the expression of key steroidogenic enzymes important for endocrine activity of the testis during prenatal development leading to establishment of the male phenotype and fertility.

17-Hydroxysteroid Dehydrogenases↗
PubMed2007

TRPM channel function in Caenorhabditis elegans.

The nematode Caenorhabditis elegans contains over 20 genes for TRP (transient receptor potential) channels which include members of all of the subclasses identified in mammalian cells. These proteins include three members of the TRPM (TRP melastatin) family: gon-2 (abnormal gonad development), gtl-1 (gon-2-like 1) and gtl-2. Although studies of these genes are at an early stage, we are beginning to understand their functions in the life of C. elegans. Mutations in gon-2 have defective gonad formation because of failures in the cell division of the somatic gonad precursor cells. gon-2 and gtl-1 are both expressed in the intestine of the animal. Experiments on gon-2,gtl-1 double mutants show that they have a severe growth defect that is ameliorated by the addition of high levels of Mg(2+) to the growth medium. gon-2,gtl-1 double mutants have defective magnesium homoeostasis and also have altered sensitivity to toxic levels of Ni(2+). Furthermore gon-2 mutants have reduced levels of I(ORCa) (outwardly rectifying calcium current) in the intestinal cells. Thus these two channels appear to play an important role in cation homoeostasis in C. elegans. In addition, perturbing the function of gon-2 and gtl-1 disrupts the ultradian defecation rhythm in C. elegans, suggesting that these channels play an important role in regulating this calcium-dependent rhythmic process. The tractability of C. elegans as an experimental animal and its amenability to techniques such as RNAi (RNA interference) and in vivo imaging make it an excellent system for an integrative analysis of TRPM function.

Animals↗