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Gonadal-independent developmental changes in activation of N-methyl-D-aspartate receptors involved in gonadotropin-releasing hormone secretion.

Using hypothalamic explants of male rats, we have shown that the N-methyl-D-aspartate (NMDA) receptors involved in a stimulatory control of gonadotropin-releasing hormone (GnRH) secretion were transiently activated at 25 days around the time of onset of puberty. This was evidenced by studying the dose-related inhibition of veratridine-induced GnRH secretion by MK-801, a use dependent antagonist of NMDA receptors. An increase in sensitivity of GnRH secretion to the inhibitory effect of MK-801 was used as a marker of increased activation of NMDA receptors involved in stimulation of GnRH secretion. Here, we report on data obtained in intact and castrated rats at different ages. The aim was to determine whether the absence of gonads would affect the developmental changes in activation of NMDA receptors that we described recently. In pubertal (50-day-old) rats, orchidectomy resulted in an activation of NMDA receptors which was nonsignificant after 4 days but significant after 13 days. In prepubertal rats orchidectomized at 5 or 10 days and studied 10 days later, the NMDA receptors involved in GnRH secretion were also more activated than in intact animals. Using explants of intact and castrated animals, a similar increase in activation of NMDA receptors was observed between 15 and 25 days of age, a period preceding onset of puberty. Subsequently, between 25 and 50 days, a reduction in NMDA receptor activation was seen. This decrease was observed in intact rats showing normal sexual development and in castrated rats as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The prolactin gene hypersensitive sites are present early in development and are not induced by estrogen administration.

We have previously shown that two DNase I-hypersensitive sites are present upstream of the PRL gene in pituitary tumors of Fischer 344 rats. In this paper we present a method for examining hypersensitive sites in nontumorous pituitaries where PRL-producing lactotrophs comprise a small percentage of the total cell population. Using this method we are able to show that DNase I-hypersensitive sites in the PRL gene chromatin remain present even when estrogen is withdrawn from animals and PRL synthesis is markedly decreased. Furthermore, the hypersensitive sites appear before sexual development in female rats, and estrogen administration does not affect the appearance of the sites.

Animals↗

Sex determination genes control the development of the Drosophila genital disc, modulating the response to Hedgehog, Wingless and Decapentaplegic signals.

In both sexes, the Drosophila genital disc contains the female and male genital primordia. The sex determination gene doublesex controls which of these primordia will develop and which will be repressed. In females, the presence of Doublesex(F) product results in the development of the female genital primordium and repression of the male primordium. In males, the presence of Doublesex(M) product results in the development and repression of the male and female genital primordia, respectively. This report shows that Doublesex(F) prevents the induction of decapentaplegic by Hedgehog in the repressed male primordium of female genital discs, whereas Doublesex(M) blocks the Wingless pathway in the repressed female primordium of male genital discs. It is also shown that Doublesex(F) is continuously required during female larval development to prevent activation of decapentaplegic in the repressed male primordium, and during pupation for female genital cytodifferentiation. In males, however, it seems that Doublesex(M) is not continuously required during larval development for blocking the Wingless signaling pathway in the female genital primordium. Furthermore, Doublesex(M) does not appear to be needed during pupation for male genital cytodifferentiation. Using dachshund as a gene target for Decapentaplegic and Wingless signals, it was also found that Doublesex(M) and Doublesex(F) both positively and negatively control the response to these signals in male and female genitalia, respectively. A model is presented for the dimorphic sexual development of the genital primordium in which both Doublesex(M) and Doublesex(F) products play positive and negative roles.

Animals↗

In utero immobilization stress and its effects on the development, behavior and sexual maturity of the rat.

The effect of prenatal stress from psychophysical immobilization, the applied during gestation, has been studied as well as its consequences on the development, behavior and sexual maturity in the offspring. Modifications in development were slight, even when intensified at four months of age. Whereas male sexual behavior showed only slight variation, female sexual maturity was markedly changed in experimental animals as compared to controls. From the present results, the psychopathological action from immobilization stress in utero on offspring is questionable.

Animals↗

Sexual performance and longevity.

Sexually inactive ("low-performing," LP) and highly active ("high-performing," HP) rats were selected from a sexually inexperienced population. Saline control LP rats (n = 44) lived 134.58 +/- 2.29 weeks, their HP peers (n = 49) lived 151.24 +/- 1.36 weeks. Life-long treatment with 0.25 mg/kg (-)deprenyl, a selective inhibitor of MAO-B that also stimulates action potential-transmitter release coupling in the catecholaminergic neurons in the brain (catecholaminergic activity enhancer, CAE, effect), enhanced the sexual and learning performance of both LP and HP rats and prolonged their life. LP rats (n = 48) treated with (-)deprenyl lived 152.54 +/- 1.36 weeks and HP rats on (-)deprenyl (n = 50) lived 185.30 +/- 1.96 weeks. As an indicator of the basic activity of catecholaminergic neurons, the resting release of dopamine from the striatum, substantia nigra, and tuberculum olfactorium, and of norepinephrine from the locus coeruleus, was measured in 2-, 4-, 8-, 16-, and 32-week-old male and female rats. The release of transmitters between weaning and the second month of age, i.e., during the crucial developmental phase of life, was significantly higher than either before or after that period, indicating that a CAE mechanism starts working with high intensity after weaning, lasts until the completion of full scale sexual development, and shows an unparalleled decay thereafter. It was concluded that the CAE regulation in the brain, stimulated by (-)deprenyl, controls general activity and consequently the longevity of rats.

Animals↗

Low-dose bisphenol A does not affect reproductive organs in estrogen-sensitive C57BL/6N mice exposed at the sexually mature, juvenile, or embryonic stage.

Bisphenol A (BPA) is used on a large scale in the manufacture of polycarbonate plastics. BPA has been shown to bind weakly to both estrogen receptor (ER) alpha and ER beta. The objective of this study was to evaluate the effects of low-dose BPA on male sexual development after exposure at various stages of development. Mice of the estrogen-sensitive strain C57BL/6N were exposed to BPA orally at doses of 2, 20, or 200 microg/kg at various stages, i.e. adulthood, the immature stage just after weaning, or the embryonic/fetal stage, to evaluate the effects of low-dose BPA on male reproductive organs. Body weight changes, weights of reproductive organs (testes, epididymides, seminal vesicles), cauda epididymal sperm density, and histology of reproductive organs including the ventral prostate were not affected by exposure to BPA at any dose examined. The results of this study indicate that exposure of estrogen-sensitive C57BL/6N mice to low-dose BPA did not reduce sperm density or disrupt development of the male reproductive organs.

Air Pollutants, Occupational↗

Effect of constant and of changing photoperiods on age at first egg and related traits in pullets.

1. The effects of constant photoperiods and of single (5 h) changes in photoperiod applied at 12 or 17 weeks of age upon age at first egg (AFE) were studied using ISA Brown and Shaver 288 pullets. 2. Birds reared from 2 d of age until after maturity on constant 10 h photoperiods matured 8 d earlier than birds reared on constant 8 h and 5 d earlier than the average for 13 or 18 h photoperiods. 3. A single increment in photoperiod from 8 to 13 h advanced AFE by 23 d (compared to 8 h constant day controls) when applied at 84 d, but by only 6 d when given at 119 d. An increase in photoperiod from 13 to 18 h advanced AFE by only 4 d, averaged across breeds and age at increase. A reduction in photoperiod from 13 to 8 h delayed AFE by 22 d when given at 84 d and by 16 d at 119 d. A similar 5 h reduction in photoperiod, but from 18 to 13 h, retarded maturity by 11 d in ISA Brown pullets, but only when given at 84 d, and delayed AFE in Shaver 288 by 12 d, but only when given at 119 d. This interaction may be partly explained by the different physiological stages reached by the two breeds when the photoperiod was changed. 4. Under constant daylengths cumulative food intake before first egg was positively correlated with photoperiod, but the early AFE for birds on 10 h photoperiods resulted in this group having the lowest cumulative food intake to first egg. 5. A 5 h increase in photoperiod at 84 d significantly reduced the food consumed to first egg, but had no effect when given at 119 d. A 5 h decrease in photoperiod generally increased the food consumed to first egg, but the effect was only significant when the daylength was reduced from 13 to 8 h at 119 d. Food intake to first egg in birds subjected to a change in photoperiod was highly correlated with AFE. 6. The data confirm that sexual development in growing pullets responds more to changes in photoperiod than to the absolute daylength, that changes made at different daylengths are not equivalent and that sensitivity changes with age.

Aging↗

Strategies for optimizing immunosuppression in adolescent transplant recipients: a focus on liver transplantation.

Adolescence is a difficult time for transplant recipients; they must learn to take responsibility for their own behavior and medication, and to balance their developing sexuality in a body that has been transformed by the adverse effects of immunosuppression. More than 80% of children survive transplantation to adolescence and adulthood, thus long-term outcome and tailoring of immunosuppression is of great importance. To date, the most experience with long-term immunosuppression regimens is cyclosporine, which is well tolerated and effective. Long-term adverse effects include hypertension, nephrotoxicity, and post-transplant lymphoproliferative disease (PTLD). The recent development of tacrolimus has improved the cosmetic adverse effects related to cyclosporine, but has similar rates of hypertension and nephrotoxicity, and possibly a higher rate of PTLD. There has been a recent, welcome development in renal sparing drugs, such as mycophenolate mofetil, which has no cosmetic adverse effects, does not require drug level monitoring and is thus particularly attractive to teenagers. Recent surveys demonstrate recovery of renal function with mycophenolate mofetil, if started prior to irreversible renal dysfunction. There are currently little published data on the use of sirolimus (rapamycin) in the pediatric population, but preliminary studies suggest that the future use of interleukin-2 receptor antibodies may be beneficial for immediate post-transplant induction of immunosuppression. It is important when planning immunosuppression for adolescents to consider the effects of drug therapy on both males and females in order to maintain fertility and to ensure safety in pregnancy. Noncompliance is a problem in this age group, but adequate practical measures and support should reduce noncompliance, and allow good, long-term graft function.

Adolescent↗

Exposure to internet pornography among children and adolescents: a national survey.

Estimates suggest that up to 90% or more youth between 12 and 18 years have access to the Internet. Concern has been raised that this increased accessibility may lead to a rise in pornography seeking among children and adolescents, with potentially serious ramifications for child and adolescent sexual development. Using data from the Youth Internet Safety Survey, a nationally representative, cross-sectional telephone survey of 1501 children and adolescents (ages 10-17 years), characteristics associated with self-reported pornography seeking behavior, both on the Internet and using traditional methods (e.g., magazines), are identified. Seekers of pornography, both online and offline, are significantly more likely to be male, with only 5% of self-identified seekers being female. The vast majority (87%) of youth who report looking for sexual images online are 14 years of age or older, when it is developmentally appropriate to be sexually curious. Children under the age of 14 who have intentionally looked at pornography are more likely to report traditional exposures, such as magazines or movies. Concerns about a large group of young children exposing themselves to pornography on the Internet may be overstated. Those who report intentional exposure to pornography, irrespective of source, are significantly more likely to cross-sectionally report delinquent behavior and substance use in the previous year. Further, online seekers versus offline seekers are more likely to report clinical features associated with depression and lower levels of emotional bonding with their caregiver. Results of the current investigation raise important questions for further inquiry. Findings from these cross-sectional data provide justification for longitudinal studies aimed at parsing out temporal sequencing of psychosocial experiences.

Adolescent↗

Effect of final photoperiod and twenty-week body weight on sexual maturity and early egg production in broiler breeders.

Cobb broiler breeder pullets, grown to achieve 2.19 kg (normal growth) or 2.41 kg (faster growth) BW at 20 wk, were given continuous light during the first 2 d posthatch, were reared on 8-h photoperiods between 2 d and 20 wk of age, and were then transferred abruptly to 10-, 11-, 12-, 14-, 16-, or 18-h photoperiods at 20 wk. Controls remained on 8 h at 20 wk. The birds were reared on a litter-floor from 1 d and transferred at 15 wk to individual cages. Mean age at first egg (AFE) was advanced by 12 d, compared with controls, for the transfer to 10 h, and progressively earlier for longer photoperiods until a 25-d advance for 14 h; AFE was similar for pullets transferred to 14, 16, and 18 h. A quadratic regression indicated that a transfer to 15 h would induce the earliest maturity. On average, accelerating growth by about 10 d advanced AFE by 4 d, but the difference was larger for transfers to a more stimulatory photoperiod. Body weight at first egg increased by about 20 g for each 1-d delay in first egg and was 110 g heavier for the faster growth pullets than for controls. Egg numbers to 39 wk increased by 0.75 for each 1-d earlier AFE. Mean egg weight was negatively related to photoperiod, decreasing by 0.3 g per 1-h, but positively linked to AFE, increasing by 0.1 g for each 1-d delay in AFE. Faster growth did not significantly increase egg numbers or mean egg weight, but it did increase egg output to 39 wk by 150 g. The data suggest that broiler breeders reared on 8-h daylengths do not need more than a 14-h photoperiod in the laying period to optimize sexual development or egg production. Typically recommended BW targets for broiler breeders (2.1 to 2.2 kg) appear to be optimal for egg production. Responses to the lighting treatments were independent of those to 20-wk BW.

Animals↗

Acceleration of puberty in female mice by a chemosignal from pregnant and lactating females: circadian rhythm effects.

Two experiments were designed to test whether the urinary chemosignal excreted by pregnant and lactating female mice that accelerates puberty in young females is affected by circadian rhythms. The experiments also measured the possible influence of circadian rhythms on the response of the young recipient females. For urine from both pregnant and lactating females there was no difference in the effectiveness for accelerating puberty in urine collected during all 24 h. However, pregnancy urine used for treatment at 1800 and 0000 h, and lactation urine used for treatment at 1800, 0000 and 0600 h, all resulted in significantly earlier mean ages for puberty than pregnancy urine treatment at 0600 or 1200 h, or lactation urine treatment at 1200 h. There was also a significant interaction between the time of urine collection and the time of urine treatment for each urine source; urine was generally more effective in accelerating sexual development when used for treating young females at the same hour at which it had been collected, or at the time interval(s) just before or after the time at which it had been collected.

Analysis of Variance↗

Sex determination in mythology and history.

The history of ideas on how the sexes became divided spans at least three thousand years. The biblical account of the origin of Eve, and the opinions of the philosophers of classical Greece, have unexpected bearings on present-day ideas. The scientific study of sex determination can be said to have begun in the 17th century with the discovery of spermatozoa, but the origin and function of the "spermatic animalcules" eluded investigators until 1841. The mammalian egg was discovered in 1827, and in the last quarter of the century fertilization was observed. The view current at that time, that sex determination was under environmental control, gave way to the idea of chromosomal determination in the first quarter of the 20th century. The study of human and other mammalian chromosomes during the third quarter of the century, and the discovery of sex-chromosome abnormalities, emphasized the importance of the Y chromosome for male sex determination. The last quarter of the century witnessed a hunt for the "testis-determining" gene, thought to be responsible for the differentiation of Sertoli cells, and culminating in the isolation of SRY (Sry in the mouse). However, an increasing number of additional genes and growth factors were found to be required for the establishment of male sex. During the same period evidence emerged that male development was accompanied by enhanced growth, both of gonads and whole embryos. An unexpected finding was the demonstration of temperature-dependent sex determination in reptiles. With the advent of the 21st century, it was shown that Sry induces cell proliferation in fetal mouse gonads, and it has been suggested that male sex differentiation in mammals requires a higher metabolic rate. These insights could lead to a better understanding and improved treatment of abnormalities of sexual development.

Female↗

The isolation and characterization of nrc-1 and nrc-2, two genes encoding protein kinases that control growth and development in Neurospora crassa.

Using an insertional mutagenesis approach, a series of Neurospora crassa mutants affected in the ability to control entry into the conidiation developmental program were isolated. One such mutant, GTH16-T4, was found to lack normal vegetative hyphae and to undergo constitutive conidiation. The affected gene has been named nrc-1, for nonrepressible conidiation gene #1. The nrc-1 gene was cloned from the mutant genomic DNA by plasmid rescue, and was found to encode a protein closely related to the protein products of the Saccharomyces cerevisiae STE11 and Schizosaccharomyces pombe byr2 genes. Both of these genes encode MAPKK kinases that are necessary for sexual development in these organisms. We conclude the nrc-1 gene encodes a MAPKK kinase that functions to repress the onset of conidiation in N. crassa. A second mutant, GTH16-T17, was found to lack normal vegetative hyphae and to constitutively enter, but not complete, the conidiation program. The affected locus is referred to as nrc-2 (nonrepressible conidiation gene #2). The nrc-2 gene was cloned and found to encode a serine-threonine protein kinase. The kinase is closely related to the predicted protein products of the S. pombe kad5, and the S. cerevisiae YNRO47w and KIN82 genes, three genes that have been identified in genome sequencing projects. The N. crassa nrc-2 gene is the first member of this group of kinases for which a phenotype has been defined. We conclude a functional nrc-2-encoded serine/threonine kinase is required to repress entry into the conidiation program.

Amino Acid Sequence↗

Identification of a subtelomeric gene family expressed during the asexual-sexual stage transition in Plasmodium falciparum.

For malaria transmission, the parasite must undergo sexual differentiation into mature gametocytes. However, the molecular basis for this critical transition in the parasites life cycle is unknown. Six previously uncharacterized genes, Pfg14.744, Pfg14.745, Pfg14.748, Pfg14.763, Pfg14.752 and Pfg6.6 that are members of a 36 gene Plasmodium falciparum-specific subtelomeric superfamily were found to be expressed in parasites that are committed to sexual development as suggested by co-expression of Pfs16 and Pfg27. Northern blots demonstrated that Pfg14.744 and Pfg14.748 were first expressed before the parasites differentiated into morphologically distinct gametocytes, transcription continued to increase until stage II gametocytes were formed and then rapidly decreased. Immunofluorescence assays indicated that both proteins were only produced in the subpopulation of ring stage parasites that are committed to gametocytogenesis and both localized to the parasitophorous vacuole (PV)b of the early ring stage parasites. As the parasites continued to develop Pfg14.748 remained within the parasitophorous vacuole, while Pfg14.744 was detected in the erythrocyte. The 5' flanking region of either gene alone was sufficient to drive early gametocyte specific expression of green fluorescent protein (GFP). In parasites transfected with a plasmid containing the Pfg14.748 5' flanking region immediately upstream of GFP, fluorescence was observed in a small number of schizonts the cycle before stage I gametocytes were observed. This expression pattern is consistent with commitment to sexual differentiation prior to merozoite release and erythrocyte invasion. Further investigation into the role of these genes in the transition from asexual to sexual differentiation could provide new strategies to block malaria transmission.

Amino Acid Sequence↗

Changes in the premarital and marital sexual life of Czechoslovak women born between 1911 and 1970.

Using the interview method, three sexologists examined, over a period of 36 years, the sexual development and life of 2,425 gynecological patients who were sent to Franzensbad for after-treatment of conditions following gynecological inflammations or surgery. They had all been married at least 1 year and when interviewed were 20-40 years old. The average age at the time of the first coitus dropped from 20.75 among the women born in the decade 1911-1920 to 17.8 among those born between 1961 and 1970. As far as premarital sexual life is concerned, the number of young women with numerous coital partners before marriage has continuously increased since 1931. About 50% of young brides today had premarital sexual contacts with 1-3 partners. Over the decades between 1921 and 1970, the number of women with 4-10 premarital coital partners has increased from 1% to 12%. Among women born in the decade 1961-1970, there has been a distinct increase in those who achieve coital orgasm only rarely to 26%. This is the highest percentage of this type of insufficient sexual reactivity since 1911. This unfavorable change in sexual life of young married women is discussed in the context of negative social environmental factors in Czechoslovakia today. The study concludes with the opinion that frequency of coital orgasm in women is a sensitive indicator of social environmental influences in a given society.

Adolescent↗

[Complete androgen insensitivity syndrome in 16-year-old girl with female phenotype].

We present a case of a 16-year-old girl who attended Endocrinology Clinic in Kraków. Her main complains were amenorrhea and lack of pubic and axillary hair development. Breast development was normal. Based on those features, male karyotype (46, XY) as well as high levels of blood testosterone and lack of uterus on ultrasound examination allowed for establishing the diagnosis of complete androgen insensitivity syndrome. The authors emphasize the possibility of diagnosing severe disorders of sex differentiation, such as sex reversal, not earlier than in teenage patients with delayed puberty. In such cases the diagnosis can be established based on physical examination with evaluation of sexual development, basic blood hormonal tests and karyotype results. Reliable knowledge of male sex differentiation physiology is needed for their correct interpretation.

Adolescent↗

Use of molecular and ultrastructural markers to evaluate stage conversion of Toxoplasma gondii in both the intermediate and definitive host.

Toxoplasma gondii has a complex life cycle involving definite (cat) and intermediate (all warm blooded animals) hosts. This gives rise to four infectious forms each of which has a distinctive biological role. Two (tachyzoite and merozoite) are involved in propagation within a host and two (bradyzoite and sporozoite) are involved in transmission to new hosts. The various forms can be identified by their structure, host parasite relationship and distinctive developmental processes. In the present in vivo study, the various stages have been evaluated by electron microscopy and immunocytochemistry using a panel of molecular markers relating to surface and cytoplasmic molecules, metabolic iso-enzymes and secreted proteins that can differentiate between tachyzoite, bradyzoite and coccidian development. Tachyzoites were characterised as being positive for surface antigen 1, enolase isoenzyme 2, lactic dehydrogenase isoenzyme 1 and negative for bradyzoite antigen 1. In contrast, bradyzoites were negative for SAG1 but positive for BAG1, ENO1 and LDH2. When stage conversion was followed in brain lesion at 10 and 15 days post-infection, tachyzoites were predominant but a number of single intermediate organisms displaying tachyzoite and certain bradyzoite markers were observed. At later time points, small groups of organisms displaying only bradyzoite markers were also present. A number (9) of dense granule proteins (GRA1-8, NTPase) have also been identified in both tachyzoites and bradyzoites but there were differences in their location during parasite development. All the dense granule proteins extensively label the parasitophorous vacuole during tachyzoite development. In contrast the tissue cyst wall displays variable staining for the dense granule proteins, which also expresses an additional unique cyst wall protein. The molecular differences could be identified at the single cell stage consistent with conversion occurring at the time of entry into a new cell. These molecular differences were reflected in the structural differences in the parasitophorous vacuoles observed by electron microscopy. Stage conversion to enteric (coccidian) development was limited to the enterocytes of the cat small intestine. Although no specific markers were available, this form of development can be identified by the absence of specific tachyzoite (SAG1) and bradyzoite (BAG1) markers although the isoenzymes ENO2 and LHD1 were expressed. There was also a significant difference in the expression of the dense granule proteins. The coccidian stages and merozoites only expressed two (GRA7 and NTPase) of the nine dense granule proteins and this was reflected in significant differences in the structure of the parasitophorous vacuole. The coccidian stages also undergo conversion from asexual to sexual development. The mechanism controlling this process is unknown but does not involve any change in the host cell type or parasitophorous vacuole and may be pre-programmed, since the number of asexual cycles was self-limiting. In conclusion, it was possible using a combination of molecular markers to identify tachyzoite, bradyzoite and coccidian development in tissue sections.

Animals↗