Biomedical subjects

Jorma Toppari

Publications and source records attributed to Jorma Toppari.

At least 19 recordsLinked to original sources

PubMed2007

From mother to child: investigation of prenatal and postnatal exposure to persistent bioaccumulating toxicants using breast milk and placenta biomonitoring.

The exposure levels of placenta and paired breast milk samples to selected organochlorine compounds and pesticides from Danish and Finnish samples have been investigated. p,p'-DDE is the dominant pollutant, beta-HCH, hexachlorobenzene, endosulfan-I, dieldrin, oxychlordane, cis-heptachlor epoxide and p,p'-DDT being the other major constituents. Their concentrations are linearly correlated between milk and placenta in similar patterns for Danish and Finnish samples. Milk samples have higher levels of these pollutants than placenta on lipid base. However, the apparently not correlated compounds, such as alpha-HCH, pentachlorobenzene, pentachloroanisole and methoxychlor, are generally accumulated more in placenta, which may suggest a tissue specific metabolic activity. Thus, depending on the compound of interest, biomonitoring may be done in placenta only or in both matrices.

Adult↗

PubMed2007

GATA-4 is required for sex steroidogenic cell development in the fetal mouse.

The transcription factor GATA-4 is expressed in Sertoli cells, steroidogenic Leydig cells, and other testicular somatic cells. Previous studies have established that interaction between GATA-4 and its cofactor FOG-2 is necessary for proper Sry expression and all subsequent steps in testicular organogenesis, including testis cord formation and differentiation of both Sertoli and fetal Leydig cells. Since fetal Leydig cell differentiation depends on Sertoli cell-derived factors, it has remained unclear whether GATA-4 has a cell autonomous role in Leydig cell development. We used two experimental systems to explore the role of GATA-4 in the ontogeny of testicular steroidogenic cells. First, chimeric mice were generated by injection of Gata4-/- ES cells into Rosa26 blastocysts. Analysis of the resultant chimeras showed that in developing testis Gata4-/- cells can contribute to fetal germ cells and interstitial fibroblasts but not fetal Leydig cells. Second, wild-type or Gata4-/- ES cells were injected into the flanks of intact or gonadectomized nude mice and the resultant teratomas examined for expression of steroidogenic markers. Wild-type but not Gata4-/- ES cells were capable of differentiating into gonadal-type steroidogenic lineages in teratomas grown in gonadectomized mice. In chimeric teratomas derived from mixtures of GFP-tagged Gata4+/+ ES cells and unlabeled Gata4-/- ES cells, sex steroidogenic cell differentiation was restricted to GFP-expressing cells. Collectively these data suggest that GATA-4 plays an integral role in the development of testicular steroidogenic cells.

Animals↗

PubMed2006

Differential expression of members of the E2F family of transcription factors in rodent testes.

BACKGROUND: The E2F family of transcription factors is required for the activation or repression of differentially expressed gene programs during the cell cycle in normal and abnormal development of tissues. We previously determined that members of the retinoblastoma protein family that interacts with the E2F family are differentially expressed and localized in almost all the different cell types and tissues of the testis and in response to known endocrine disruptors. In this study, the cell-specific and stage-specific expression of members of the E2F proteins has been elucidated. METHODS: We used immunohistochemical (IHC) analysis of tissue sections and Western blot analysis of proteins, from whole testis and microdissected stages of seminiferous tubules to study the differential expression of the E2F proteins. RESULTS: For most of the five E2F family members studied, the localizations appear conserved in the two most commonly studied rodent models, mice and rats, with some notable differences. Comparisons between wild type and E2F-1 knockout mice revealed that the level of E2F-1 protein is stage-specific and most abundant in leptotene to early pachytene spermatocytes of stages IX to XI of mouse while strong staining of E2F-1 in some cells close to the basal lamina of rat tubules suggest that it may also be expressed in undifferentiated spermatogonia. The age-dependent development of a Sertoli-cell-only phenotype in seminiferous tubules of E2F-1 knockout males corroborates this, and indicates that E2F-1 is required for spermatogonial stem cell renewal. Interestingly, E2F-3 appears in both terminally differentiated Sertoli cells, as well as spermatogonial cells in the differentiative pathway, while the remaining member of the activating E2Fs, E2F-2 is most concentrated in spermatocytes of mid to late prophase of meiosis. Comparisons between wildtype and E2F-4 knockout mice demonstrated that the level of E2F-4 protein displays a distinct profile of stage-specificity compared to E2F-1, which is probably related to its prevalence and role in Sertoli cells. IHC of rat testis indicates that localization of E2F-5 is distinct from that of E2F-4 and overlaps those of E2F-1 and E2F-2. CONCLUSION: The E2F-1 represents the subfamily of transcription factors required during stages of DNA replication and gene expression for development of germ cells and the E2F-4 represents the subfamily of transcription factors that help maintain gene expression for a terminally differentiated state within the testis.

Animals↗

PubMed2006

Mild gestational diabetes as a risk factor for congenital cryptorchidism.

CONTEXT: Cryptorchidism is the most common malformation in newborn boys. Maternal diabetes has previously been suggested to be a risk factor for this disorder in one epidemiological study. OBJECTIVE: Evaluation of the prevalence of maternal glucose metabolism disorders during pregnancy in newborn boys having normal testicular descent or congenital cryptorchidism. DESIGN: Postnatal analysis of maternal history concerning glucose metabolism abnormalities during pregnancy among cryptorchid and healthy Finnish boys. SETTING AND PARTICIPANTS: The material of this case-control study comprises 1163 boys with normal testicular descent at birth and 125 boys with congenital cryptorchidism. All these singleton Finnish boys were born in Turku University Central Hospital (1997-2001) and were examined at birth and/or at the expected date of delivery. MAIN OUTCOME MEASURES: Information about maternal diabetes diagnosis and abnormality of the result of a 2-h 75-g oral glucose tolerance test during pregnancy were obtained from the hospital records after delivery. RESULTS: After adjustment for possible confounding factors, i.e. maternal smoking during pregnancy, maternal age at delivery, and risk factors of cryptorchidism, e.g. prematurity and weight for gestational age, abnormal maternal glucose metabolism was significantly more common in the group of cryptorchid boys [diet-treated gestational diabetes, P = 0.0001; odds ratio, 3.98 (95% confidence interval, 1.97-8.05); diet-treated gestational diabetes or only an abnormal result in oral glucose tolerance test, P = 0.0016; odds ratio, 2.44 (95% confidence interval, 1.40-4.25)] when compared with boys with normal testicular descent. CONCLUSIONS: Mildly abnormal glucose metabolism during pregnancy was associated with an increased risk for congenital cryptorchidism. The mechanism remains to be elucidated.

Adult↗

PubMed2006

Expression and localization of androgen receptor-interacting protein-4 in the testis.

Androgen receptor-interacting protein 4 (ARIP4) belongs to the SNF2 family of proteins involved in chromatin remodeling, DNA excision repair, and homologous recombination. It is a DNA-dependent ATPase, binds to DNA and mononucleosomes, and interacts with androgen receptor (AR) and modulates AR-dependent transactivation. We have examined in this study the expression and cellular localization of ARIP4 during postnatal development of mouse testis. ARIP4 was detected by immunohistochemistry in Sertoli cell nuclei at all ages studied, starting on day 5, and exhibited the highest expression level in adult mice. At the onset of spermatogenesis, ARIP4 expression became evident in spermatogonia, pachytene, and diplotene spermatocytes. Immunoreactive ARIP4 antigen was present in Leydig cell nuclei. In Sertoli cells ARIP4 was expressed in a stage-dependent manner, with high expression levels at stages II-VI and VII-VIII. ARIP4 expression patterns did not differ significantly in testes of wild-type, follicle-stimulating hormone receptor knockout, and luteinizing hormone receptor knockout mice. In testes of hypogonadal mice, ARIP4 was found mainly in interstitial cells and exhibited lower expression in Sertoli and germ cells. In vitro stimulation of rat seminiferous tubule segments with testosterone, FSH, or forskolin did not significantly change stage-specific levels of ARIP4 mRNA. Heterozygous ARIP4(+/-) mice were haploinsufficient and had reduced levels of Sertoli-cell specific androgen-regulated Rhox5 (also called Pem) mRNA. Collectively, ARIP4 is an AR coregulator in Sertoli cells in vivo, but the expression in the germ cells implies that it has also AR-independent functions in spermatogenesis.

Adenosine Triphosphatases↗

PubMed2006

Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes.

In somatic cells, integrity of cell division is safeguarded by the spindle checkpoint, a signaling cascade that delays the separation of sister chromatids in the presence of misaligned chromosomes. Aurora kinases play important roles in this process by promoting centrosome maturation, chromosome bi-orientation, spindle checkpoint signaling, and cytokinesis. To investigate the functions of Aurora kinases in male meiosis, we applied a small molecule Aurora inhibitor, ZM447439, to seminiferous tubules in vitro. Primary and secondary spermatocytes exposed to ZM447439 exhibit defects in the spindle morphology and fail to align their chromosomes at the metaphase plate. Moreover, the treated spermatocytes undergo a forced exit from the meiotic M-phase without cytokinesis. These results suggest that the activities of Aurora kinases are required for normal spindle assembly as well as for establishment and maintenance of proper microtubule-kinetochore attachments and spindle checkpoint signaling in male mammalian meiosis.

Animals↗

PubMed2006

Effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on rat follicular steroidogenesis.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant and causes adverse effects on female reproduction when administered to rats. Our aims were to study effects of gestational and lactational exposure to TCDD on ovarian steroidogenesis and steroidogenic enzyme expression of offspring on postnatal day (PND) 14 in the rat and sensitivity of enzymatically isolated ovarian follicles to TCDD in vitro. Synthetic estrogen diethylstilbestrol (DES) was used as a treatment control. Serum progesterone (P4) level in offspring increased significantly on PND 14 in the TCDD (1 microg/kg)-exposed group while body weight, FSH and E2 levels were not changed. In ovarian follicles of offspring on PND 14 in the TCDD-exposed groups, protein expression of cytochrome P-450 aromatase, cytochrome P-450 cholesterol side-chain cleavage, steroidogenic acute regulatory protein, 3beta-hydroxy-steroid-dehydrogenase/Delta(5)-Delta(4) isomerase type 1, or P4 receptor was not affected. TCDD decreased E2 and P4 production in ex vivo follicle culture. DES at a dose level of 0.1mg/kg was dystocic while a dose 0.02 mg/kg increased ovarian ex vivo E2 and testosterone production without affecting P450arom activity indicating stimulation of early steps of steroidogenic pathway. Data suggests that TCDD has multiple targets in ovarian steroidogenesis, but the inhibitory action represented as decreased follicular steroid hormone production ex vivo is not apparent at the ovarian protein expression. Furthermore, TCDD had no direct effect on immature rat ovarian steroidogenesis in vitro suggesting that the follicle culture method is not a sensitive method to study the mechanisms of TCDD action.

Animals↗

PubMed2006

Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys.

CONTEXT: Recent studies showed that male reproductive health problems, such as cryptorchidism, hypospadias, testicular cancer, and low sperm quality, are more prevalent in Denmark than in Finland. OBJECTIVES: We hypothesized that, if fetal testicular dysgenesis contributed to these observations, differences in gonadal development and the hypothalamus-pituitary-testis axis would already be detectable perinatally. Thus, we investigated healthy newborn boys in both countries. DESIGN: This was a prospective, longitudinal population-based study. SETTING: Two primary obstetric centers were included at the University Hospitals of Copenhagen, Denmark, and Turku, Finland. PARTICIPANTS: The participants of the study included 633 Danish and 1044 Finnish boys, born at term with appropriate weight for gestational age. INTERVENTIONS: Ultrasound determination of testis size at 0, 3, and 18 months and blood sampling (n = 727) at 3 months were analyzed. MAIN OUTCOME MEASURES: Testicular volume and reproductive hormones were measured. RESULTS: Testis volume was significantly higher at all ages in Finnish than in Danish boys (medians, 98 vs. 95, 185 vs. 119, and 188 vs. 136 mm(3), respectively; P < 0.00001). Testis growth from birth to 3 months was larger in Finnish than in Danish boys (mean, 75 vs. 26 mm(3); P < 0.0001). Serum hormone levels were higher in Finnish than Danish boys for inhibin B (median, 456 vs. 385 pg/ml; P < 0.0001), FSH (1.33 vs. 1.21 IU/liter; P < 0.036), and SHBG (143 vs. 136 nmol/liter; P < 0.022). Inhibin B was significantly positively correlated to testicular volume (r = 0.25; P < 0.006). CONCLUSIONS: The larger testes and higher inhibin B levels most likely represent a bigger volume of seminiferous tubules in Finnish compared with Danish boys. Although this phenomenon may be attributable to a genetic difference between the two countries, it may also reflect environmental factors influencing testicular development.

Adult↗

PubMed2006

Effects of neonatal exposure to 4-tert-octylphenol, diethylstilbestrol, and flutamide on steroidogenesis in infantile rat testis.

Exposure of neonatal testis, populated by fetal-type Leydig cells, to endocrine-active compounds may have far-reaching consequences. Our aim was to resolve the sensitivity of testosterone synthesis of infant rat (Sprague-Dawley) testis to diethylstilbestrol (DES; 0.1-1.0 mg/kg), 4-tert-octylphenol (OP; 10-100 mg/kg), and Flutamide (FLU; 2.0-25 mg/kg) given by daily sc injections from birth to postnatal day 4. Testes and serum were collected on day 14 when body and testis weight, testicular histology, circulating testosterone, LH and FSH levels, and steroidogenic acute regulatory protein (StAR) and 3beta-hydroxy-steroid-dehydrogenase (3beta-HSD) protein levels were determined. DES at each dose and FLU at 25 mg/kg dose reduced testis weight and the diameter of seminiferous cords. FLU caused some Leydig cell hyperplasia. Plasma testosterone was reduced in all DES animals, LH elevated in DES 0.5 mg/kg and FLU 25 mg/kg animals, and FSH reduced in the DES 1.0 mg/kg group. Basal testicular ex vivo progesterone and human chorionic gonadotropin (hCG)-stimulated testosterone production were decreased in DES animals. Despite a decrease in hCG-induced cyclic adenosine-3',5'-monophosphate (cAMP) production, intratesticular testosterone was increased in the FLU 10 and 25 mg/kg groups. OP 100 mg/kg elevated hCG-induced progesterone production only. No changes were seen in 3beta-HSD protein levels in any treatment group. StAR levels were reduced in DES animals. The results indicate the sensitivity of postnatal fetal-type Leydig cells to endocrine-active compounds. Suppression of StAR expression level was an early sign of the DES-induced steroidogenic lesion. FLU-induced changes suggest the importance of androgen receptor-mediated regulation of testosterone synthesis in the postnatal rat testis. Octylphenol appeared less effective in bringing about acute steroidogenic changes.

Androgen Antagonists↗

PubMed2006

Hormonal changes in 3-month-old cryptorchid boys.

CONTEXT: Hormonal dysregulation has been suggested to be one of many etiological factors of cryptorchidism. OBJECTIVES: The objective of this study was to assess the hypothalamic-pituitary-testicular axis in cryptorchid boys during the postnatal hormonal surge. DESIGN: This was a prospective, longitudinal, population-based study. SETTING: The study was performed at two primary obstetric centers. PARTICIPANTS: Study participants included 388 Finnish and 433 Danish boys (88 and 34 with cryptorchidism, respectively). INTERVENTIONS: Clinical examinations were performed at 0 and 3 months. Blood samples were taken at 3 months. MAIN OUTCOME MEASURES: The main outcome measures were testis position and reproductive hormone levels. RESULTS: Finnish cryptorchid boys had significantly higher FSH [1.59 (0.50-3.53) vs. 1.30 (0.49-2.92) IU/liter; P < 0.0001] and lower inhibin B [426 (254-770) vs. 459 (266-742) pg/ml; P < 0.015] levels than Finnish control boys [median (2.5th-97.5th percentiles)]. Danish cryptorchid boys had higher FSH levels than controls [1.47 (0.54-3.89) vs. 1.18 (0.41-3.04) IU/liter; P = 0.018]. Inhibin B levels in healthy Danish boys were lower than those in Finnish boys [380 (233-637) pg/ml; P < 0.0001] and were not reduced in Danish crypt-orchid boys [392 (236-672) pg/ml; P = 0.851]. Changes in hormone levels were strongest in boys with severe, persistent cryptorchidism, but were also detectable in mild and transient cryptorchidism. Effects on Leydig cell function were subtle, with an increase in LH in Finnish (but not Danish) cryptorchid boys vs. controls [1.97 (0.77-5.91) vs. 1.75 (0.58-4.04) IU/liter; P < 0.021], but testosterone levels remained within the normal range. CONCLUSIONS: Our results support the hypothesis that cryptorchidism is associated with a primary testicular disorder, which could be a cause or a consequence of cryptorchidism. This malfunction is reflected by low inhibin B production in the Finnish cohort and high gonadotropin drive in both the Finnish and Danish cohorts.

Child↗

PubMed2006

Is human fecundity declining?

Summary The decreasing trends in fertility rates in many industrialized countries are now so dramatic that they deserve much more scientific attention. Although social and behavioural factors undoubtedly play a major role for these trends, it seems premature, and not based on solid information, to conclude that these trends can be ascribed to social and behavioural changes alone. There is evidence to suspect that changing lifestyle and increasing environmental exposures, e.g. to endocrine disrupters, are behind the trends in occurrence of male reproductive health problems, including testis cancer, undescended testis and poor semen quality. These biological factors may also contribute to the extremely low fertility rates. However, the necessary research is complex and requires non-traditional collaboration between demographers, epidemiologists, clinicians, biologists, wild life researchers, geneticists and molecular biologists. This research effort can hardly be carried out without major support from governments and granting agencies making it possible to fund collaborative projects within novel research networks of scientists.

Environmental Pollutants↗

PubMed2006

Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age.

UNLABELLED: Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.

Adult↗

PubMed2006

Persistent pesticides in human breast milk and cryptorchidism.

INTRODUCTION: Prenatal exposure to some pesticides can adversely affect male reproductive health in animals. We investigated a possible human association between maternal exposure to 27 organochlorine compounds used as pesticides and cryptorchidism among male children. DESIGN: Within a prospective birth cohort, we performed a case-control study; 62 milk samples from mothers of cryptorchid boys and 68 from mothers of healthy boys were selected. Milk was collected as individual pools between 1 and 3 months postpartum and analyzed for 27 organochlorine pesticides. RESULTS: Eight organochlorine pesticides were measurable in all samples (medians; nanograms per gram lipid) for cases/controls: 1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene (p,p -DDE) : 97.3/83.8; beta-hexachlorocyclohexane (beta-HCH) : 13.6/12.3; hexachlorobenzene (HCB) : 10.6/8.8; alpha-endosulfan: 7.0/6.7; oxychlordane: 4.5/4.1; 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (p,p -DDT) : 4.6/4.0; dieldrin: 4.1/3.1 ; cis-heptachloroepoxide (cis-HE) : 2.5/2.2. Five compounds [octachlorostyrene (OCS); pentachlorobenzene, 1,1-dichloro-2,2-bis(4-chlorophenyl) ethane(p,p -DDD) ; o,p -DDT ; mirex] were measurable in most samples (detection rates 90.8-99.2%) but in lower concentrations. For methoxychlor, cis-chlordane, pentachloroanisole (PCA), gamma-HCH, 1,1-dichloro-2-(2-chlorophenyl) -2,2(4-chlorophenyl) ethane, trans-chlordane, alpha-HCH, and o,p -DDE, both concentrations and detection rates were low (26.5-71.5%). Heptachlor, HCH (lc delta, epsilon), aldrin, beta-endosulfan and trans-heptachloroepoxide were detected at negligible concentrations and low detection rates and were not analyzed further. Seventeen of 21 organochlorine pesticides [p,p -DDT, p,p-DDE, p,p-DDD, o,p-DDT, HCH (alpha, beta, gamma), HCB, PCA, alpha-endosulfan, cis-HE, chlordane (cis-, trans-) oxychlordane, methoxychlor, OCS, and dieldrin] were measured in higher median concentrations in case milk than in control milk. Apart from trans-chlordane (p = 0.012), there were no significant differences between cryptorchid and healthy boys for individual chemicals. However, combined statistical analysis of the eight most abundant persistent pesticides showed that pesticide levels in breast milk were significantly higher in boys with cryptorchidism (p = 0.032). CONCLUSION: The association between congenital cryptorchidism and some persistent pesticides in breast milk as a proxy for maternal exposure suggests that testicular descent in the fetus may be adversely affected.

Adult↗

PubMed2006

Postnatal penile length and growth rate correlate to serum testosterone levels: a longitudinal study of 1962 normal boys.

OBJECTIVE: Infant boys show a brief activation of their hypothalamic-pituitary-gonadal axis shortly after birth, the physiological significance of which is poorly understood. The objective of the study was to investigate the correlation between endogenous testosterone levels and penile size and growth. DESIGN: Prospective, longitudinal population-based study taking place at two large primary obstetric centres at the University Hospitals of Copenhagen, Denmark, and Turku, Finland. METHODS: Infant boys, 728 Danish and 1234 Finnish, underwent clinical examinations at 0, 3, 18 and 36 months in Denmark and at 0, 3 and 18 months in Finland with blood samples taken at 3 months (n = 630). Penile length and growth were registered and reproductive hormones (testosterone, sex hormone binding globulin, oestradiol) were analysed. RESULTS: Penile length increased from birth (3.49+/-0.4 cm) to 3 years of age (4.53+/-0.51 cm) with the highest growth velocity from birth to 3 months (1.0 mm/month). Penile length and growth were significantly, positively correlated to serum testosterone (r = 0.31 and 0.076, P = 0.006 and 0.001 respectively) and to free testosterone index (r = 0.385 and 0.094, P = 0.0001 and 0.0001 respectively). CONCLUSIONS: We found that endogenous testosterone was significantly associated with penile size and growth rate in infant boys. Thus, the postnatal surge in reproductive hormones appears to be important for genital growth. Our data may serve as an updated reference for normal penile length in Caucasian boys up to 3 years of age.

Aging↗

PubMed2005

The regulated expression of c-IAP1 and c-IAP2 during the rat seminiferous epithelial cycle plays a role in the protection of germ cells from Fas-mediated apoptosis.

The inhibitor of apoptosis proteins, c-IAP1 and c-IAP2, are highly expressed in rat testis and potentially play a regulatory role in testicular apoptosis. To better understand their functions during spermatogenesis, we have analyzed their spatio-temporal distribution in rat testis, how their expression is controlled by the paracrine stem-cell factor (SCF) and how they affect Fas-mediated apoptosis. Both c-IAP1 and c-IAP2 showed cycles of transcriptional expression, throughout the seminiferous epithelial cycle. c-IAP1 protein showed a diffuse nuclear distribution in type B spermatogonia, preleptotene, leptotene, and zygotene spermatocytes. In pachytene spermatocytes, c-IAP1 colocalized with SUMO-1 in the XY-body. c-IAP2 protein was cytoplasmic in spermatocytes, from stage VI pachytene onwards, round spermatids, elongated spermatids and Leydig cells. Its expression was upregulated by SCF. Inhibition of IAP activity resulted in a greater sensitivity of germ cells to Fas-mediated apoptosis. These results suggest an important role for IAPs in the regulation of spermatogenic apoptosis.

Animals↗

PubMed2005

Fetal but not adult Leydig cells are susceptible to adenoma formation in response to persistently high hCG level: a study on hCG overexpressing transgenic mice.

We have previously demonstrated that male transgenic (TG) mice overexpressing human chorionic gonadotropin (hCG+) develop reproductive organ defects, but no tumors, in adult age. In this study, the effects of persistently elevated hCG were followed in TG males between day 5 postpartum and adulthood. Leydig cell (LC) adenomas were found in prepubertal mice, most prominently at the age of 10 days, but not in adult age. Serum testosterone concentrations were significantly increased in TG males at all ages studied. The phenotype of the prepubertal hCG+ males resembled that found in boys upon expression of constitutively activating luteinizing hormone (LH) receptor mutations. The temporal expression patterns of the fetal LC marker gene, thrombospondin 2, and those of adult LCs, hydroxysteroid dehydrogenase-6, delta5-3-beta and prostaglandin D synthase, were similar in wild-type and hCG+ males. Hence, the postnatal adenomas resemble functionally fetal LCs, and only these cells are susceptible to hCG-induced tumorigenesis. Our findings demonstrate a novel intriguing difference between the fetal and adult LC populations and provide further insight into the potential tumorigenic effects of gonadotropins.

3-Hydroxysteroid Dehydrogenases↗

PubMed2005

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 (Ins l3)-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 Ins l3 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 Ins l3, manifest the same phenotype as Ins l3 knockout mutants. Even though mutations found in Ins l3 and LGR8/GREAT genes are not a common cause of cryptorchidism in patients, it remains to be resolved whether low Ins l3 levels during development are associated with cryptorchidism. Cryptorchidism may reflect foetal testicular dysgenesis that may later manifest as subfertility or testicular cancer.

Androgens↗

PubMed2005

Enantiomeric ratios as an indicator of exposure processes for persistent pollutants in human placentas.

The enantiomeric ratios (ER) of alpha-HCH and o,p'-DDT ((+)-isomer concentration/(-)-isomer concentration) and o,p'-DDD (first eluting enantiomer/second enantiomer) were investigated in 112 human placentas from Finnish boys collected 1997-2001. Both o,p'-DDD and alpha-HCH showed changes in their ER depending on the total concentration of the compound in the sample. Their ERs are approaching a value close to racemic mixture (ER=1) at high concentrations. At low concentrations they often differ from 1. The relationship between concentration and ER is clearly identified and it has been shown that it is not affected by analytical uncertainty. This relationship appears to be important for assessing tissue- and species-specific exposure and risk and it may indicate whether net uptake or metabolic activity is dominant in exposure for the resulting exposure of the enantiomers.

DDT↗