Gonadal Atrophy Research Articles

Anti-Müllerian hormone deficiency leads to two distinct ovarian phenotypes with different alterations of sex hormones in gynogenetic carp

Anti-Müllerian hormone (Amh) plays conserved roles in gonadal development and function in vertebrates. Previous studies have demonstrated that amh deficiency results in severe gonadal hypertrophy in teleost. Here, we report a novel phenotype of gonadal atrophy caused by amh knockout in fish. Firstly, it was found that the amh gene had three alleles and was expressed in the cytoplasm of follicle cells in gynogenetic amphiploid gibel carp (Carassius gibelio). Subsequently, we constructed a mutant line of amh and identified two distinct ovarian abnormalities in gibel carp. Most mutants exhibited hypertrophic ovaries with increased proliferation and decreased differentiation of early germ cells, which is consistent with previously reported findings. Intriguingly, a small number of mutants displayed atrophic ovaries with decreased proliferation and premature differentiation of germ cells, which represents a novel phenotype in fish species. Transcriptome analysis revealed that these two distinct ovaries of amh mutants showed different alterations in the sex hormone biosynthesis pathway, when compared with wild-type ovaries. Furthermore, diverse gonadal sex hormone levels were also detected in these two abnormal ovaries, which were consistent with the transcriptional expressions of corresponding genes in the sex hormone synthesis pathway. These findings identify a novel atrophic ovarian phenotype of amh mutants and confirm the amh function in controlling the balance between proliferation and differentiation of germ cells in fish.

The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.

The human genome contains 24 gag-like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity during aging. Analysis of donated human ovaries shows that expression of both genes declines normally with age, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

Estrogen contamination increases vulnerability of amphibians to the deadly chytrid fungus

Aquatic contaminants and infectious diseases are among the major drivers of global amphibian declines. However, the interaction of these factors is poorly explored and could better explain the amphibian crisis. We exposed males and females of the Brazilian Cururu Toad, Rhinella icterica, to an environmentally relevant concentration of the estrogen 17-alpha-ethinylestradiol (an emerging contaminant) and to the chytrid infection (Batrachochytrium dendrobatidis), in their combined and isolated forms, and the ecotoxicity was determined by multiple biomarkers: cutaneous, hematological, cardiac, hepatic, and gonadal analysis. Our results showed that Cururu toads had many physiological alterations in response to the chytrid infection, including the appearance of cutaneous Langerhans's cells, increased blood leukocytes, increased heart contraction force and tachycardia, increased hepatic melanomacrophage cells, which in turn led to gonadal atrophy. The estrogen, in turn, increased the susceptibility of the toads to the chytrid infection (higher Bd loads) and maximized the deleterious effects of the pathogen: reducing leukocytes, decreasing the contraction force, and causing greater tachycardia, increasing hepatic melanomacrophage cells, and leading to greater gonadal atrophy, which were more extreme in females. The exposure to estrogen also revealed important toxicodynamic pathways of this toxicant, as shown by the immunosuppression of exposed animals, and the induction of the first stages of feminization in males, which corroborates that the synthetic estrogen acts as an endocrine disruptor. Such an intricate relationship is unprecedented and reinforces the importance of studying the serious consequences that multiple environmental stressors can cause to aquatic populations.

Introduction of pediatric laparoscopic inguinal hernia repair in Guatemala

PurposeIntroducing new surgical techniques in a developing country can be challenging. Inguinal hernias in children are a common surgical problem, and open repair is the standard surgical approach. Laparoscopic repair has gained popularity in developed countries because of similar results. This study aimed to determine the outcomes following the introduction of laparoscopic repairs in Guatemala.MethodsThis retrospective analysis of prospectively collected data from all patients under 18 years who underwent laparoscopic repair at Corpus Christi Hospital in Patzun, Guatemala, from September 5th to September 8th, 2022.ResultsA total of 14 patients were included in the study. A board-certified pediatric surgeon and a Guatemalan physician performed all cases. The mean patient age was 7.6 years; 7 boys and 7 girls. All patients were interviewed at 7 days, 30 days, and 6 months. There were no postoperative infections, pain requiring re-evaluation, gonadal atrophy, or hernia recurrence.ConclusionUnder controlled circumstances with limited but proper equipment and disposables, laparoscopic inguinal hernia repairs can be introduced and performed in a developing country with a risk complication profile comparable to that in developed countries. This study provides promising evidence of laparoscopic repair feasibility and safety where surgical resources are limited.

First evidence of gonadal hybrid dysgenesis in Chagas disease vectors (Hemiptera, Triatominae): gonad atrophy prevents events of interspecific gene flow and introgression

BackgroundHybridization events between Triatoma spp. have been observed under both natural and laboratory conditions. The ability to produce hybrids can influence different aspects of the parent species, and may even result in events of introgression, speciation and extinction. Hybrid sterility is caused by unviable gametes (due to errors in chromosomal pairing [meiosis]) or by gonadal dysgenesis (GD). All of the triatomine hybrids analyzed so far have not presented GD. We describe here for the first time GD events in triatomine hybrids and highlight these taxonomic and evolutionary implications of these events.MethodsReciprocal experimental crosses were performed between Triatoma longipennis and Triatoma mopan. Intercrosses were also performed between the hybrids, and backcrosses were performed between the hybrids and the parent species. In addition, morphological and cytological analyzes were performed on the atrophied gonads of the hybrids.ResultsHybrids were obtained only for the crosses T. mopan♀ × T. longipennis♂. Intercrosses and backcrosses did not result in offspring. Morphological analyses of the male gonads of the hybrids confirmed that the phenomenon that resulted in sterility of the hybrid was bilateral GD (the gonads of the hybrids were completely atrophied). Cytological analyses of the testes of the hybrids also confirmed GD, with no germ cells observed (only somatic cells, which make up the peritoneal sheath).ConclusionsThe observations made during this study allowed us to characterize, for the first time, GD in triatomines and demonstrated that gametogenesis does not occur in atrophied gonads. The characterization of GD in male hybrids resulting from the crossing of T. mopan♀ × T. longipennis♂ highlights the importance of evaluating both the morphology and the cytology of the gonads to confirm which event resulted in the sterility of the hybrid: GD (which results in no gamete production) or meiotic errors (which results in non-viable gametes).Graphical

Growth, survival and gonad development of diploids, triploids and tetraploids of ‘Haida No. 3’ line of the Pacific oyster Crassostrea gigas

Selection and polyploidization are two practical tools for improving productive traits of oysters. To evaluate the aquaculture traits of diploids, triploids and tetraploids of ‘Haida No. 3’ line of the Pacific oyster Crassostrea gigas, four mating combinations (HD- diploid ‘Haida No. 3’ line ♀ × diploid ‘Haida No. 3’ line ♂, HTR- diploid ‘Haida No. 3’ line ♀ × tetraploid ‘Haida No. 3’ line ♂, HTE- tetraploid ‘Haida No. 3’ line ♀ × tetraploid of ‘Haida No. 3’ line ♂, WD- wild diploid ♀ × wild diploid ♂) were established. At both Rongcheng and Rushan sites, HD had a larger shell height and wet weight than WD. HTR outperformed HD in growth and survival, with a consistently positive value of triploid advantage (TA). On the day 480 at Rushan site, the triploid advantages in terms of shell height, wet weight and cumulative survival were 20.70%, 40.28% and 29.27%, respectively. HTE were the lowest in growth and survival compared to the other three groups. Histomorphometric analysis revealed that HTR were partial highly sterile, indicating its gonadal atrophy and gamete abnormalities. In contrast, HD and HTE were fully fertile and contained functional gametes. During the whole culture period, HTR remained 100% triploid rate while HTE maintained a tetraploid rate of over 80%. HTR and HTE exhibited rapid growth and stable black shell color, suggesting that these traits were stably inherited by the ploidy change. Overall, our results demonstrated that polyploidization based on selective line had favorable performance for aquaculture, which would have vital practical interest for oyster culture in northern China.

Wolfram Syndrome 1: A Pediatrician's and Pediatric Endocrinologist's Perspective.

Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disease caused by mutations in WFS1 and WFS2 genes that produce wolframin, a protein involved in endoplasmic reticulum calcium homeostasis and cellular apoptosis. Its main clinical features are diabetes insipidus (DI), early-onset non-autoimmune insulin-dependent diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA) and deafness (D), hence the acronym DIDMOAD. Several other features from different systems have been reported such as urinary tract, neurological, and psychiatric abnormalities. In addition, endocrine disorders that can appear during childhood and adolescence include primary gonadal atrophy and hypergonadotropic hypogonadism in males and menstrual cycle abnormalities in females. Further, anterior pituitary dysfunction with deficient GH and/or ACTH production have been described. Despite the lack of specific treatment for the disease and its poor life expectancy, early diagnosis and supportive care is important for timely identifying and adequately managing its progressive symptoms. The current narrative review focuses on the pathophysiology and the clinical features of the disease, with a special emphasis on its endocrine abnormalities that appear during childhood and adolescence. Further, therapeutic interventions that have been proven to be effective in the management of WS1 endocrine complications are discussed.

Влияние индуцированной транспозиционной активности р элементов на возраст-зависимые изменения репродуктивной системы и эмбриональную выживаемость Drosophila melanogaster

The age-dependent change in the activity of P elements in the P-M genetic system was studied by parameters of the reproductive system (fertility, gonadal atrophy, ovarian reserve) and embryonic survival of Drosophila melanogaster. The transposition activity of P elements was controlled using tests for sterility and mutability of the sn[w] locus, the results of which showed a high mobilization of functional P sequences in all age groups. An increase in the activity of transposons with age was noted in dysgenic F1 individuals obtained from aging parents in inducing crosses, as well as in 60-day-old dysgenic offspring (according to the mutability of the sn[w] locus). It was shown that the effect of P-transpositions affected only on the viability of embryos, the profile of which decreased with the aging of their dysgenic F1 parents. On the contrary, the average fecundity of dysgenic females did not change with age and was at a low level compared to non-dysgenic females. An analysis of the obtained data suggests that the observed effects are based on different mechanisms of the biological action of aging and induced P-activity.

Short communication: Photoperiod impacts ovarian extracellular matrix and metabolic gene expression in Siberian hamsters

Ovarian cyclicity is variable in adult Siberian hamsters (Phodopus sungorus), who respond to long breeding season photoperiods with follicle development and ovulation, while short photoperiods typical of the non-breeding season induce gonadal atrophy. Recent RNAseq results identified ovarian matrix components and regulators of metabolism as differentially regulated by photoperiod; however, the impact of photoperiod across a full cycle of ovarian regression and recrudescence had not been explored for additional regulators of ovarian metabolism and extracellular matrix components. We hypothesized that matrix and metabolism-related genes would be expressed differentially across photoperiods that mimic breeding and non-breeding season daylengths. Hamsters were housed in one of four photoperiod groups: long day (16 h of light per day: 8 h of dark; LD, controls), short day regressed (8 L:16D; SD, regressed), and females exposed to SD then transferred to LD to stimulate return of ovarian function for 2 (early recrudescence), or 8 (late recrudescence) weeks. Plasma leptin concentrations along with expression of ovarian versican and liver-receptor homolog-1/Nr582 mRNA decreased in SD compared to LD and late recrudescence, while vimentin mRNA expression peaked in early and late recrudescence. Ovarian expression of fibronectin and extracellular matrix protein-1 was low in LD ovaries and increased in regressed and recrudescing groups. Expression of hyaluronidase-2, nectin-2, liver-X receptors-α and-β, and adiponectin mRNA peaked in late recrudescence, with no changes noted for adiponectin receptor-1 and -2. The results offer a first look at the parallels between expression of these genes and the dynamic remodeling that occurs during ovarian regression and recrudescence.

Seasonal reproduction and gonadal function: a focus on humans starting from animal studies.

Photoperiod impacts reproduction in many species of mammals. Mating occurs at specific seasons to achieve reproductive advantages, such as optimization of offspring survival. Light is the main regulator of these changes during the photoperiod. Seasonally breeding mammals detect and transduce light signals through extraocular photoreceptor, regulating downstream melatonin-dependent peripheral circadian events. In rodents, hormonal reduction and gonadal atrophy occur quickly and consensually with short-day periods. It remains unclear whether photoperiod influences human reproduction. Seasonal fluctuations of sex hormones have been described in humans, although they seem to not imply adaptative seasonal pattern in human gonads. This review discusses current knowledge about seasonal changes in the gonadal function of vertebrates, including humans. The photoperiod-dependent regulation of hypothalamic-pituitary-gonadal axis, as well as morphological and functional changes of the gonads is evaluated herein. Endocrine and morphological variations of reproductive functions, in response to photoperiod, are of interest as they may reflect the nature of past population selection for adaptative mechanisms that occurred during evolution.

New Prospects in Neutering Male Animals Using Magnetic Nanoparticle Hyperthermia.

Controlling populations of free-roaming dogs and cats poses a huge challenge worldwide. Non-surgical neutering strategies for male animals have been long pursued, but the implementation of the procedures developed has remained limited to date. As submitting the testes to high temperatures impairs spermatogenesis, the present study investigated localized application of magnetic nanoparticle hyperthermia (MNH) to the testicles as a potential non-surgical sterilization method for animals. An intratesticular injection of a magnetic fluid composed of manganese-ferrite nanoparticles functionalized with citrate was administered followed by testicle exposure to an alternate magnetic field to generate localized heat. Testicular MNH was highly effective, causing progressive seminiferous tubule degeneration followed by substitution of the parenchyma with stromal tissue and gonadal atrophy, suggesting an irreversible process with few side effects to general animal health.

Unusual association of priapism with Wolfram syndrome

Wolfram syndrome is an autosomal recessive disorder resulting from mutation of WFS1 gene located on 4p16.1 and is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy, and sensorineural deafness with features of neurodegeneration, renal anomalies, and primary gonadal atrophy. Priapism itself is a rare disease with isolated reports in association with type-2 DM due to change in coagulation status causing endothelial dysfunction and local vascular thrombosis leading to ischemic priapism. Here, we present a case of a 14-year-old male with type-1 DM and optic atrophy who was presented to us with two episodes of priapism. He was suspected to have Wolfram syndrome and his genetic evaluation for WFS-1 gene confirmed the diagnosis. Our case suggests that priapism is an atypical association in patient with the Wolfram Syndrome due to hypercoagulability in type-1 DM which is rarely reported.

Pinealectomy and gonadectomy modulate amplitude, but not photoperiodic modulation of Clock gene expression in the Syrian hamster suprachiasmatic nuclei.

The duration of daytime light phase (photoperiod) controls reproduction in seasonal mammals. Syrian hamsters are sexually active when exposed to long photoperiod, while gonadal atrophy is observed after exposure to short photoperiod. The photorefractory period, or photorefractoriness, is a particular state of spontaneous recrudescence of sexual activity that occurs after a long-term exposure to short photoperiod. Expression of core clock genes in the master circadian clock contained in the suprachiasmatic nuclei depends on photoperiodic conditions. Interestingly, the expression of the Clock gene is also modified in photorefractory Syrian hamsters. Since melatonin and testosterone levels in seasonal species are dependent on photoperiod, photoperiodic variations of Clock mRNA levels in the suprachiasmatic clock could be a consequence of these hormonal changes. To test this hypothesis, we analysed the effects of pinealectomy on Clock mRNA changes due to long to short photoperiod transition and of gonadectomy on Clock mRNA levels in photorefractory period. Our data show that the suprachiasmatic integration of the short photoperiod (assessed by a rhythmic expression profile of Clock) is independent of the presence of melatonin. Furthermore, constitutively low expression of Clock observed during the photorefractory period does not require the presence of either melatonin or testosterone. However, we show that both hormones provide positive feedback on average levels of Clock expression. Thus, our data support the hypothesis that daily variations of Clock levels in the suprachiasmatic nuclei are influenced by photoperiodic changes and the time spent in short photoperiod, independently of seasonal modifications of melatonin or testosterone levels.

A Study of Variant Anatomy of Gonadal Arteries in 40 Adult Males: A Cross-sectional Cadaveric Study

Introduction: The surgeons are witnessing an ever-increasing range of operative procedures with increasing levels of complexity in the abdominal cavity. So, the anatomy of blood vessels of abdominal cavity has assumed much more importance. Knowledge of variations in the gonadal artery is essential during renal and gonadal surgery as these variations may influence the blood flow to the kidney and gonads and cause some pathological conditions such as varicocoele and gonadal atrophy. Aim: To assess the prevalence of variations in origin and course of the gonadal arteries and to discuss their clinical significance. Materials and Methods: This cross-sectional cadaveric study was done in 40 human cadavers which were well embalmed and allotted for under graduate teaching in the Department of Anatomy, Madurai Medical College Madurai, Tamil Nadu, India, from the year June 2010 to May 2015. The human cadavers were numbered serially from 1-40. The routine dissection of abdomen was done. The origin and course of the gonadal arteries were traced. Variations in number, origin and course of the gonadal arteries were noted. The incidence of gonadal artery arising from the renal artery was calculated. Prevalence of variant origin of gonadal artery from renal artery was noted. Software of MacBook pages was used to gather the data. Categorical data were presented as mean and percentage. Results: In the present study, in 36 cadavers (90%) the gonadal artery was normal in source of origin, and took normal course in 39 cadavers (97.5%). In the remaining cadavers different variations were observed. The variations found in this study include the gonadal arteries arising from the renal artery 4 (10%) cadavers and according with course arching of left gonadal artery over the left renal vein seen in 1 (2.5%) cadaver. In the current study, the vertebral level of origin of the artery ranged from the intervertebral disc of first and second lumbar vertebra to upper 1/3rd of the third lumbar vertebra on the right-side and between upper 1/3rd of first lumbar to lower 1/3rd of third vertebra on the left-side. Conclusion: During surgical and diagnostic interventions at the level of renal, gonadal and para aortic vessels arterial variations are clinically important to avoid risk of haemorrhage, ischaemia of particular organs. Those arterial variations are not only unilateral but also bilateral associations of vascular anomaly must be considered.

Pregabalin induced reproductive toxicity and body weight changes by affecting caspase3 and leptin expression: Protective role of wheat germ oil

Pregabalin (PGB) drug abuse is common among the youth. It substituted tramadol before its recent schedule as a controlled drug since April 2019. PGB is an antiepileptic drug acting on the central nervous system. It blocks calcium channels regulating the action of neurotransmitters and causing prolonged depolarization. The present study aimed to investigate the toxic effect of long term pregabalin abuse on the reproductive function and body weight in both male and female albino rats and to evaluate the ameliorative effect of wheat germ oil (WGO). Forty-eight rats were randomly divided into eight groups. The first four groups were males and they were treated as follows: control group (1.5 mL saline), WGO group (1.5 mL L/kg), PGB group (300 mg/kg), and protective group (PGB + WGO). All doses were administrated once per day for 60 days by gastric gavage. The second four groups were females. They were divided and treated the same as the male groups. Pregabalin caused significant weight loss, decreased serum triglyceride level, and increased leptin gene expression in all rats. PGB affected male rats reproduction by decreasing total testosterone serum level and inhibiting spermatogenesis. Reproductive toxicity in females was caused by decreasing pituitary steroids, increasing gonadal hormones, and increasing the number of atretic ovarian follicles. Mechanism of toxicity may be attributed to the PGB oxidative stress effect that induced apoptosis and caused diffuse gonadal atrophy. WGO showed a protective effect on PGB induced toxicity as all measured parameters were relatively improved.

Endocrine disruption: molecular interactions of chlorpyrifos and its degradation products with estrogen receptor

Chlorpyrifos is an extensively used organophosphate pesticide showing broad-spectrum effectiveness on various target pests. Long-term sublethal exposure to this pesticide is reported to produce detrimental effects on sex hormone metabolism and nervous system functioning. It is a suspected endocrine-disrupting chemical and causes abnormal developmental patterns, gonadal atrophy, and neurodevelopmental problems. The degradation products formed during environmental degradation of chlorpyrifos are also capable of binding with steroid hormone receptors such as estrogen receptor alpha (ER-α) and can disrupt estrogen signaling in humans. In the present study, chlorpyrifos and four of its degradation products viz. CPYO, DEC, TCP, and TMP were chosen to study their ability to bind with estrogen receptors. The molecular docking and dynamics simulation carried out to understand the molecular interaction of chlorpyrifos and its environmental degradation products with human ER reveal the risk of potential disruption in estrogen signaling in humans by these compounds.

Chronic stress impairs male spermatogenesis function and Nectin-3 protein expression in the testis.

Chronic stress is a crucial public issue that occurs when a person is repetitively stimulated by various stressors. Previous researches have reported that chronic stress induces spermatogenesis dysfunction in the reproductive system, but its molecular mechanisms remain unclear. The nectin protein family, including nectin-1 to nectin-4, is Ca(2+)-independent immunoglobulin-like cell adhesion molecules, that are widely expressed in the hippocampus, testicular tissue, epithelial cells and other sites. Nectin-3 contributes to the sperm development at the late stage, and the abnormal expression of nectin-3 impairs spermatogenesis. Some recent studies have demonstrated that stress induces a decrease in nectin-3 expression in the hippocampus via corticotropin-releasing hormone (CRH) to corticotropin-releasing hormone receptor 1 (CRHR1) pathway. Here, we tested whether chronic stress also caused a reduction in nectin-3 expression in the testis. We established a chronic social defeat stress paradigm, which provides naturalistic and complex chronic stress inmale C57BL/6 mice. After 25 days of chronic social defeat stress, the mice showed weight loss, thymic atrophy and some other typical symptoms of chronic stress (e.g.anxiety-like behavior and social avoidance behavior). We found gonad atrophy, testicular histological structure changes and semen quality reductions in the stressed mice. The stressed male mice significantly spent more time to impregnate the female mice than the control male mice. Moreover, nectin-3 protein levels in stressed mice were significantly decreased in the testes compared with those in control mice. In addition, we found that the CRHR1 expression level was increased in the testes of stressed mice. Therefore, we demonstrated a decreased level of nectin-3 expression and an increase in CRHR1 expression in the testis after exposure to chronic stress, which may provide a potential therapeutic target for the spermatogenesis dysfunction induced by chronic stress.

Hybrid dysgenesis in Drosophila virilis results in clusters of mitotic recombination and loss-of-heterozygosity but leaves meiotic recombination unaltered

BackgroundTransposable elements (TEs) are endogenous mutagens and their harmful effects are especially evident in syndromes of hybrid dysgenesis. In Drosophila virilis, hybrid dysgenesis is a syndrome of incomplete gonadal atrophy that occurs when males with multiple active TE families fertilize females that lack active copies of the same families. This has been demonstrated to cause the transposition of paternally inherited TE families, with gonadal atrophy driven by the death of germline stem cells. Because there are abundant, active TEs in the male inducer genome, that are not present in the female reactive genome, the D. virilis syndrome serves as an excellent model for understanding the effects of hybridization between individuals with asymmetric TE profiles.ResultsUsing the D. virilis syndrome of hybrid dysgenesis as a model, we sought to determine how the landscape of germline recombination is affected by parental TE asymmetry. Using a genotyping-by-sequencing approach, we generated a high-resolution genetic map of D. virilis and show that recombination rate and TE density are negatively correlated in this species. We then contrast recombination events in the germline of dysgenic versus non-dysgenic F1 females to show that the landscape of meiotic recombination is hardly perturbed during hybrid dysgenesis. In contrast, hybrid dysgenesis in the female germline increases transmission of chromosomes with mitotic recombination. Using a de novo PacBio assembly of the D. virilis inducer genome we show that clusters of mitotic recombination events in dysgenic females are associated with genomic regions with transposons implicated in hybrid dysgenesis.ConclusionsOverall, we conclude that increased mitotic recombination is likely the result of early TE activation in dysgenic progeny, but a stable landscape of meiotic recombination indicates that either transposition is ameliorated in the adult female germline or that regulation of meiotic recombination is robust to ongoing transposition. These results indicate that the effects of parental TE asymmetry on recombination are likely sensitive to the timing of transposition.

Phage constructs targeting gonadotropin-releasing hormone for fertility control: evaluation in cats.

Phage-gonadotropin-releasing hormone (GnRH) constructs with potential contraceptive properties were generated in our previous study via selection from a phage display library using neutralizing GnRH antibodies as selection targets. In mice, these constructs invoked the production of antibodies against GnRH and suppressed serum testosterone. The goal of this study was to evaluate this vaccine against GnRH for its potential to suppress reproductive characteristics in cats. Sexually mature male cats were injected with a phage-GnRH vaccine using the following treatment groups: (1) single phage-GnRH vaccine with adjuvant; (2) phage-GnRH vaccine without adjuvant and half-dose booster 1 month later; or (3) phage-GnRH vaccine with adjuvant and two half-dose boosters with adjuvant 3 and 6 months later. Anti-GnRH antibodies and serum testosterone, testicular volume and sperm characteristics were evaluated monthly for 7-9 months. All cats developed anti-GnRH antibodies following immunization. Serum antibody titers increased significantly after booster immunizations. In group 3, serum testosterone was suppressed 8 months after primary immunization. Total testicular volume decreased in group 1 by 24-42% and in group 3 by 15-36% at 7 months after immunization, indicating potential gonadal atrophy. Vacuolation of epididymides was observed histologically. Although all cats produced sperm at the conclusion of the study, normal morphology was decreased as much as 38%. Phage alone produced no local or systemic reactions. Immunization of phage with AdjuVac produced unacceptable injection site reactions. Our phage-based vaccine against GnRH demonstrated a potential for fertility impairment in cats. Future research is required to optimize vaccine regimens and identify animal age groups most responsive to the vaccine. If permanent contraception (highly desirable in feral and shelter cats) cannot be achieved, the vaccine has a potential use in zoo animals or pets where multiple administrations are more practical and/or reversible infertility is desirable.

A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans

A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or quasi-programs) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode Caenorhabditis elegans, likely result from quasi-programs. Such tumors develop from unfertilized oocytes which enter the uterus and become hypertrophic and replete with endoreduplicated chromatin masses. Tumor formation begins with ovulation of unfertilized oocytes immediately after exhaustion of sperm stocks. We show that the timing of this transition between program and quasi-program (i.e., the onset of senescence), and the onset of tumor formation, depends upon the timing of sperm depletion. We identify homology between uterine tumors and mammalian ovarian teratomas, which both develop from oocytes that fail to mature after meiosis I. In teratomas, futile activation of developmental programs leads to the formation of differentiated structures within the tumor. We report that older uterine tumors express markers of later embryogenesis, consistent with teratoma-like activation of developmental programs. We also present evidence of coupling of distal gonad atrophy to oocyte hypertrophy. This study shows how the Williams Blagosklonny model can provide a mechanistic explanation of this component of C. elegans aging. It also suggests etiological similarity between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs.