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PubMed2003

Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain.

Hypothalamic astroglial erbB tyrosine kinase receptors are required for the timely initiation of mammalian puberty. Ligand-dependent activation of these receptors sets in motion a glia-to-neuron signaling pathway that prompts the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development, from hypothalamic neuroendocrine neurons. The neuronal systems that may regulate this growth factor-mediated back signaling to neuroendocrine neurons have not been identified. Here we demonstrate that hypothalamic astrocytes contain metabotropic receptors of the metabotropic glutamate receptor 5 subtype and the AMPA receptor subunits glutamate receptor 2 (GluR2) and GluR3. As in excitatory synapses, these receptors are in physical association with their respective interacting/clustering proteins Homer and PICK1. In addition, they are associated with erbB-1 and erbB-4 receptors. Concomitant activation of astroglial metabotropic and AMPA receptors results in the recruitment of erbB tyrosine kinase receptors and their respective ligands to the glial cell membrane, transactivation of erbB receptors via a mechanism requiring metalloproteinase activity, and increased erbB receptor gene expression. By facilitating erbB-dependent signaling and promoting erbB receptor gene expression in astrocytes, a neuron-to-glia glutamatergic pathway may represent a basic cell-cell communication mechanism used by the neuroendocrine brain to coordinate the facilitatory transsynaptic and astroglial input to LHRH neurons during sexual development.

Animals↗
PubMed1995

Effects of sex hormones on oncogene expression in the vagina and on development of sexual dimorphism of the pelvis and anococcygeus muscle in the mouse.

Neonatal treatment of female mice with diethystilbestrol (DES) is known to induce ovary-independent persistent proliferation and cornification of vaginal epithelium. This irreversibly changed vaginal epithelium persistently expressed higher levels of c-jun and c-fos mRNAs, which was not altered by postpubertal estrogen. Sexual dimorphism was encountered in mouse pelvis and anococcygeus muscle. Postpubertal estrogen changed the shape of the pelvis to the female type and postpubertal androgen changed it to the male type. Neonatal exposure to DES and to the antiestrogen tamoxifen altered the developmental pattern of the pelvis, which contained lower concentrations of calcium and phosphorus than controls. The size of anococcygeus muscle was increased by postpubertal androgen but decreased by postpubertal estrogen. However, neonatal estrogen (DES) exposure permanently enlarged the anococcygeus muscle. Thus, neonatal treatment of mice with estrogen and antiestrogen results in irreversible changes in nonreproductive as well as reproductive structures.

Animals↗
PubMed1999

Coping with sexual abuse: development and evaluation of a videotape intervention for nonoffending parents.

OBJECTIVE: The aims of the study were: (1) to develop, apply, and evaluate a videotape intervention that targeted the development of supportive behaviors in mothers of children who were being examined because of suspected molestation; and (2) to examine the relationship between mothers' reported responses to and beliefs about the molestation and their children's perceptions of support. METHOD: Mothers (N = 87) who had children 4 to 12 years of age were recruited and randomly assigned to view either a treatment or control videotape during the time when their child was being examined. Observers who were blinded to this assignment observed and rated parent-child interactions in the waiting room prior to and again after the mothers viewed the videotape. One week after this brief intervention, 64 of the mothers and 30 of the children (8- to 12-years-old) were interviewed. RESULTS: Mothers who viewed the treatment tape were more likely to engage in supportive behaviors with their child immediately after viewing the tape, and were able to identify more supportive behaviors at the 1-week followup. In addition, mothers' reports of how they responded to the molestation (including perceived blame) was related to child perceptions of parental support. CONCLUSIONS: The findings indicate that children who have been sexually molested are sensitive to the initial reactions of their nonoffending parent to the disclosure. In addition, there is some evidence that we can design and deliver cost-effective interventions during the early disclosure period that promote more positive (or supportive) responses by the nonoffending parent.

Adaptation, Psychological↗
PubMed1999

The divergence-homogenization duality in the evolution of the b1 mating type gene of Coprinus cinereus.

The A mating type locus of the fungus Coprinus cinereus is a complex, multigenic locus which regulates compatibility and subsequent sexual development. Genes within the A locus such as the b1 gene studied here exhibit extreme sequence variation. In this work, we asked how b1 alleles have evolved high levels of variation and, at the same time, conserved function. We compared sequence variation in 17 alleles characterized as belonging to seven different compatibility classes. Comparison of sequence variation between representatives of these seven classes shows that different regions of the b1 gene have been subject to varying levels of substitution, recombination, and structural/functional constraints. The N-terminal region of the encoded protein, which has been previously demonstrated to govern self/nonself recognition, exhibited hypervariability with levels of amino acid identity as low as 41%. We used a novel analysis of neutral mutations accumulating in this gene to rule out the possibility that the N-terminal region is hypermutable. In contrast, the C-terminal region displayed heterogeneous levels of variation, with functional motifs being better conserved. In fact, there is a duality in the b1 gene between variability and conservation; recombination events have homogenized the C-terminal region, while recombination events are undetectable in the N-terminal region. The ability to regulate sexual development is maintained in all of the mating compatibility alleles studied, and these data suggest that some functional motifs may tolerate high levels of substitution.

Alleles↗
PubMed2004

Laser-captured single digoxigenin-labeled neurons of gonadotropin-releasing hormone types reveal a novel G protein-coupled receptor (Gpr54) during maturation in cichlid fish.

GPR54 is a novel G protein-coupled receptor speculated to be essential for sexual development. However, its role in the regulation of GnRH types is unknown. To address this issue, we cloned GPR54 from the brain of a cichlid fish (tilapia Oreochromis niloticus) and determined its expression in immature and mature males using our newly developed technique: laser-captured microdissection of single digoxigenin-labeled GnRH neurons coupled with real-time quantitative PCR. The tilapia GPR54 cDNA contains an open reading frame of 1131 bp encoding 377 amino acids and exhibits 56% identity to human GPR54. Absolute copies of GnRH1 and GnRH3, not GnRH2, mRNAs were significantly high in mature compared with immature males. At the single-cell level, only in mature males, GnRH1 mRNA levels were inversely related to GPR54 mRNA (P < 0.002). GPR54 was expressed in a significantly high percentage (45.0-60.0%) of mature GnRH1, GnRH2, and GnRH3 neurons and in immature GnRH3 neurons, which had migrated to the vicinity of their final locations in the brain; on the contrary, only 5.0% of immature GnRH1 and GnRH2 neurons had GPR54 transcripts (P < 0.001). Thus, using a novel innovative single-cell gene profiling technique, we provide evidence of the structure of a nonmammalian GPR54, which is highly conserved during evolution and is expressed in GnRH1, GnRH2, and GnRH3 neurons. Furthermore, we propose that the expression of GPR54 is a "stop signal" for GnRH1, GnRH2, and GnRH3 neuronal migration, leading to suppression of cell growth and modulation of GnRH secretion, which is important for normal sexual development.

Amino Acid Sequence↗
PubMed1994

A B-type cyclin negatively regulates conjugation via interacting with cell cycle 'start' genes in fission yeast.

In the fission yeast Schizosaccharomyces pombe, the cdc10+/SWI family members constitute the cell cycle 'start' genes. res1+ and res2+ are the newly identified members of this family and encode putative association partners of the Cdc10 protein. The Pat1 kinase plays a pivotal role in switching between vegetative growth and sexual development, and its inactivation in haploid cells induces unconditional growth arrest and subsequent meiosis. We have identified as an extragenic suppressor of a temperature sensitive pat1-114 mutant, a new B-type cyclin that negatively regulates conjugation by interacting with these 'start' genes. This cyclin, named Cyc17, is highly homologous with Cdc13, but has no detectable activity as a mitotic cyclin. Deletion of cyc17+ markedly enhances conjugation, despite the presence of nitrogen source, and accelerates growth arrest in G1 upon nitrogen starvation. Conversely, overexpression of the cyc17+ gene strongly inhibits conjugation. The cyc17+ gene is transcribed into 3.2 kb poly(A)+ and 3.0 kb poly(A)- RNAs. Only the poly(A)+ species is expressed during vegetative growth and periodically with a peak in the G1 and S phases of the cell cycle. On the other hand, the poly(A)- transcript is highly induced during conjugation. This induction is lost in res2- cells, whereas the poly(A)+ transcript is significantly reduced in res1- cells. However, the mating inhibition as well as the ability to rescue the pat1 mutation by overexpression of res1+ and res2+ are totally abolished in cyc17- cells. Thus, in S.pombe, a B-type cyclin, regulated by the newly identified cell cycle 'start' genes, plays a crucial role in the control of sexual development.

Amino Acid Sequence↗
PubMed1984

[Changes in plasma 2-hydroxyestrone levels in pubertal females and correlation with sex hormones].

Plasma levels of 2-hydroxyestrone (2-OHE1) were measured by specific radioimmunoassay during puberty to elucidate the physiological role of this hormone on female sexual development. Plasma levels of FSH, LH, PRL and estradiol (E2) were also measured with an RI-kit. 67 girls between aged 6 and 16 were selected for this study. Blood samples were collected into tubes containing 0.1W/V% EDTA and 0.1W/V% ascorbic acid and immediately centrifuged. 2-OHE1 in plasma was extracted and separated with a Sephadex LH-20 column. RIA was applied using anti 2-OHE1-17-CMO-BSA. Plasma 2-OHE1 levels before menarche were low (6-7 pg/ml) until 10 years of age. The levels started to increase from 11 and reached 11.2 +/- 5.8pg/ml at 16 years of age. The levels of 2-OHE1 in girls after menarche were significantly higher than that before menarche (p less than 0.01). There was a significant correlation between 2-OHE1 and E2 in girls before menarche (p less than 0.001, r = 0.5416). However, the 2-OHE1 to E2 ratio decreased significantly from 9 to 10 years of age. These results indicate that during this period, the E2 increase is more predominant than that of 2-OHE1. There was a significant negative correlation between 2-OHE1 and PRL after menarche while no correlation between 2-OHE1 and FSH, LH was noticed. These results suggested that 2-OHE1 may play a role in sexual development after menarche rather than in the initiation of menarche.

Adolescent↗
PubMed1995

[Analysis of luteinizing hormone pulses in men with idiopathic hypogonadotropic hypogonadism].

In order to test the defect of luteinizing hormone (LH) pulses and its relationship with sexual development in patients with idiopathic hypogonadotropic hypogonadism (IHH), fourteen male IHH patients and five healthy adult men were investigated. Blood samples were withdrawn at 10 minute intervals for 24h for analysis of LH pulse. LH pulse frequency ranged from 0-13 pulses/24h. Testosterone (T) level was 1.3-8.7 nmol/L in the 14 IHH patients and higher in the 5 healthy controls (all P < 0.01). Two of the patients with IHH had no detectable LH pulsations (apulsatile pattern), no history of puberty and a small testicular volume of less than 1ml. Most of the IHH patients (n = 9) had less pulse frequency (4-13 pulses/24h) and lower mean amplitude (1.3-2.2IU/L) than the healthy controls (14-20 pulses/24h and 3.81-2.46IU/L, P < 0.01). A patient with IHH had 10 pulses/24h and more or less the same mean amplitude (4.2 +/- 1IU/L) as the healthy controls; his T level was the lowest among the 14 patients due probably to biological inactivity of LH. Two IHH patients had detectable LH pulsations with normal mean amplitude (P > 0.05) present predominantly during the night, this pattern of LH pulse resembles that of peripuberty boy. Our results indicate that (1) LH pulse pattern varies widely among IHH patients and it is related to the sex characteristics; (2) frequency of LH pulses is essential for sexual development. but adequate amplitude is more important in this respect.

Adolescent↗
PubMed1986

The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in peripubertal males.

Oxandrolone (Ox) and testosterone (T) are used as growth-promoting agents in the therapy of boys with constitutional delay of growth and adolescence. Although the mechanism of action of these androgens is not known, it is recognized that T enhances GH release during GH stimulation tests. We studied the effects of T and Ox on the mean concentration of GH, the pattern of GH secretion, and somatomedin-C (SmC) concentrations in boys with short stature and/or delayed sexual development to determine whether their growth-promoting effects might be mediated through endogenous GH release. Ten boys received Ox (0.1 mg/kg . day, orally) for 65 +/- 5 days (mean +/- SD), and five boys received T propionate (7.5 mg, im, for 7 days), followed by T enanthate (100 mg, im, monthly for 3 months). Serum GH was measured in samples obtained at 20-min intervals for 24 h before and 65 +/- 5 days (mean +/- SD) after the initiation of therapy. SmC levels were measured twice during the same 24-h period before and 65 +/- 5 days (mean +/- SD) after initiation of therapy. In the boys treated with T, there were significant increases in the mean concentration of GH (mean increase, 4.3-fold; range, 2-12), in the number of GH pulses 10 ng/ml or greater [1.6 +/- 2.0 vs. 4.8 +/- 1.5/24 h (mean +/- SD)], and in the SmC levels [0.82 +/- 0.46 vs. 2.3 +/- 0.4 mu/ml (mean +/- SD)]. There were, however, no significant changes in the boys treated with Ox. Both Ox and T significantly improved the growth rates; however, T increased the growth rate by 0.95 +/- 0.24 (mean +/- SD) cm/months, and Ox increased the growth rate by 0.24 +/- 0.26 (mean +/- SD) cm/month. These results indicate that T, but not Ox, at the doses tested increases GH secretion in boys with short stature and/or delayed sexual development. This increase in GH secretion may contribute to the increased growth rate in males at puberty.

Adolescent↗
PubMed2006

DMRT gene cluster analysis in the platypus: new insights into genomic organization and regulatory regions.

We isolated and characterized a cluster of platypus DMRT genes and compared their arrangement, location, and sequence across vertebrates. The DMRT gene cluster on human 9p24.3 harbors, in order, DMRT1, DMRT3, and DMRT2, which share a DM domain. DMRT1 is highly conserved and involved in sexual development in vertebrates, and deletions in this region cause sex reversal in humans. Sequence comparisons of DMRT genes between species have been valuable in identifying exons, control regions, and conserved nongenic regions (CNGs). The addition of platypus sequences is expected to be particularly valuable, since monotremes fill a gap in the vertebrate genome coverage. We therefore isolated and fully sequenced platypus BAC clones containing DMRT3 and DMRT2 as well as DMRT1 and then generated multispecies alignments and ran prediction programs followed by experimental verification to annotate this gene cluster. We found that the three genes have 58-66% identity to their human orthologues, lie in the same order as in other vertebrates, and colocate on 1 of the 10 platypus sex chromosomes, X5. We also predict that optimal annotation of the newly sequenced platypus genome will be challenging. The analysis of platypus sequence revealed differences in structure and sequence of the DMRT gene cluster. Multispecies comparison was particularly effective for detecting CNGs, revealing several novel potential regulatory regions within DMRT3 and DMRT2 as well as DMRT1. RT-PCR indicated that platypus DMRT1 and DMRT3 are expressed specifically in the adult testis (and not ovary), but DMRT2 has a wider expression profile, as it does for other mammals. The platypus DMRT1 expression pattern, and its location on an X chromosome, suggests an involvement in monotreme sexual development.

Amino Acid Sequence↗
PubMed1998

Development and sexual difference in embryonic heart rates in pregnancies resulting from in vitro fertilization.

The purpose of this study was to investigate the gestational change of embryonic heart rates (EHRs) and to estimate the influence of embryonic sex on the EHR in pregnancies resulting from in vitro fertilization in the early first trimester. With transvaginal ultrasonography, we performed 92 and 105 examinations, on 27 male and 30 female embryos, respectively. The EHR increased gradually from 87 beats per min at 38 days of gestation to 189 beats per min at 62 days of gestation. The relationship between gestational age and EHR was explored by regression analysis: male EHR (beats per min) = 3.78 x gestational age (days) - 51.30 (r = 0.95), female EHR = 3.65 x gestational age - 44.56 (r = 0.95). These regression lines were mutually included in the 95% confidence intervals for each other. Our results indicate both a close positive correlation between the EHR and gestational age and no statistically significant difference in the EHR between male and female embryos. These findings suggest that the EHR measurement is a novel method for very early ultrasound dating with the identical EHR criterion without regard to embryonic sex.

Embryonic and Fetal Development↗
PubMed2002

Comparison of the developmental and reproductive toxicity of diethylstilbestrol administered to rats in utero, lactationally, preweaning, or postweaning.

The objective of the study was to determine which period of exposure produces the most marked effects on the reproductive capacity and sexual development of the rat, with particular emphasis on the relative sensitivity of in utero and postnatal exposures. The endocrine active chemical, diethylstilbestrol (DES) was used as an agent known to affect many of the endpoints examined. Hitherto, such comparisons have been made between studies, rather than within a study. Our data will be helpful in the interpretation of future multigenerational assay data. In preliminary studies, DES was shown to be active in the immature rat uterotrophic assay with a lowest detected dose of 0.05 mg DES/kg body weight by sc injection and 10 mg DES/l (1.6 mg DES/kg body weight) by administration in drinking water. A dose of 60 microg DES/l drinking water ( approximately 6.5mg DES/kg body weight/day) was selected for the main study since this represented the midpoint of the drinking water uterotrophic dose response and produced no overt maternal toxicity. The study used 10 groups of concomitantly pregnant animals, including 2 control groups. The first comparison was between the effects of exposure to DES in utero, and exposure from conception to weaning. Another group of animals was exposed to DES in utero and cross-fostered to untreated pregnant females to prevent lactational transfer of DES to pups. Two groups were exposed to DES neonatally, either from birth to postnatal day (PND) 10 (pups thus having only lactational exposure), or from birth until weaning (PND 21; pups thus having both lactational exposure and self-exposure via drinking water). In addition, a dose response study to DES was conducted on animals exposed from weaning to PND 100, when the first phase of the study was terminated. Pups exposed to DES in utero and pups exposed from weaning to PND 100 were bred to assess fertility of the F1 animals and the sexual development of F2 offspring. This last comparison was to determine the extent to which weanling rats could be used in endocrine toxicity studies to assess their potential to show activity in utero. The most sensitive period of exposure for inducing developmental effects in F1 animals was from weaning onwards. The neonatal to weaning period (PND 1-21) was the next most sensitive. Essentially no effects were induced in F1 animals exposed in utero. No effects of any kind were observed in animals only exposed over the early neonatal period of PND 1-10. The mean day of vaginal opening, testes descent, and prepuce separation was only altered in groups where postnatal exposure to DES continued beyond PND 10, or was started at weaning. No changes were observed in anogenital distance or caudal sperm counts. Some changes in organ weights were observed, but the interpretation of these was often confused by concomitant changes in body weight. In general, histopathological examination of tissues yielded no additional information. In breeding studies with animals exposed to DES in utero, or from weaning, reduced litter sizes and marginal advances in the day of vaginal opening were observed in the offspring, together with changes in organ weights. However, no unique sensitivity was noted for exposure in utero. Evaluation of the several exposure periods and the many markers monitored in this study may have individual strengths in individual cases, but when rigorously compared using the reference estrogen DES, many preconceptions regarding their absolute or relative value were not upheld. Further, each of these markers is subject to natural variability, as demonstrated by comparisons made among the 5 separate control groups available in parts of the present study. This variability increases the chance that small changes observed in endocrine toxicity studies employing small group sizes and a single control group, or no concomitant control group, may be artifactual. The most marked effects observed in this study were on the developmental landmarks in the F1 animals induced by exposures after PND 10. Some effects on developmental landmarks and organ weights were observed in F2 animals following exposure either in utero or postweaning. This study therefore does not establish a unique role for exposures in utero or during the early neonatal period.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Sex determination and female reproductive development in the genus Schistosoma: a review.

Parasites of the genus Schistosoma were among the first metazoans to develop separate sexes, which is chromosomally determined in the fertilized egg. Despite the occurrence of specific sex chromosomes, the females of most Schistosomatidae species do not complete their somatic development and reach no sexual maturity without the presence of males. Indeed, the most controversial and at the same time most fascinating aspect about the sexual development of Schistosoma females lies on discover the nature of the stimulus produced by males that triggers and controls this process. Although the nature of the stimulus (physical or chemical) is a source of controversy, there is agreement that mating is a necessary requirement for maturation to occur and for migration of the female to a definitive final site of residence in the vascular system of the vertebrate host. It has also been proposed that the stimulus is not species-specific and, in some cases, not even genus-specific. Despite a vast literature on the subject, the process or processes underlying the meeting of males and females in the circulatory system have not been determined and as yet no consensus exists about the nature of the stimulus that triggers and maintains female development. In the studies about their role, Schistosoma males have been considered, at times pejoratively, the brother, the muscles or even the liver of females. Indeed, it still remains to be determined whether the stimulus responsible for female maturation involves the transfer of hormones, nutrients, neuromediators, mere tactile stimulation or a combination of chemotactic and thigmotactic factors.

Animals↗
PubMed1980

Sex among siblings: a survey on prevalence, variety, and effects.

In a survey of 796 undergraduates at six New England colleges and universities, 15% of the females and 10% of the males reported some type of sexual experience involving a sibling. Fondling and touching of the genitals were the most common activities in all age categories. One-fourth of the experiences could be described as exploitative either because force was used or because there was a large age disparity between the partners. Reactions to the experiences were equally divided among those who considered them positive and those who considered them negative. Females were more likely than males to have been exploited and feel badly about it. Few participants of either sex ever told anyone. The research finds evidence that such experience may have long-term effects on sexual development. Females who report sibling sexual experiences, both positive and negative, have substantially higher levels of current sexual activity. Their level of sexual self-esteem may also have been affected, but more selectively. Those with positive sibling experiences after age 9 have more sexual self-esteem. However, experiences with much older siblings taking place before age 9 are associated with generally lower levels of self-esteem and no increase in current sexual activity.

Adolescent↗
PubMed1997

Growth, development, and sexual dimorphism in vervet monkeys (Cercopithecus aethiops) at four sites in Kenya.

Body weight and ten body segment measurements were collected from 367 wild-trapped vervet monkeys (Cercopithecus aethiops) in central and southern Kenya. The animals represent between 70 and 95% of the animals in each of 30 troops at four geographical locations separated by 80 to 380 km. The capture sites differed in altitude, mean annual rainfall and temperature. Two questions are addressed: (1) what are the differences in male and female growth patterns, and (2) what is the relationship between size, climate, and availability of food? Each animal was assigned to an age class based on dental examination. Means for all variables do not diverge for males and females from birth to age class 4 (15-18 months). After this, male and female growth rates diverge. This sexual dimorphism in growth pattern may reflect timing of entry into the reproductive community. A nested analysis of variance (ANOVA) was employed to compare sites, groups within sites and individuals within groups. Statistically significant differences between sites in body weight and body segment measurements are found for adult females. Except for tail length, these differences do not follow Bergmann's or Allen's Rules correlating size differences and temperature, but rather may reflect proximity to cultivated areas or tourist lodges with greater access to human food.

Age Determination by Teeth↗