Premature Reproductive Senescence Research Articles

Premature reproductive aging in female rats after developmental exposure to mixtures of endocrine disrupters

Premature reproductive aging in female rats after developmental exposure to mixtures of endocrine disrupters

Scrambled and fried: Cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress

Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction.

Glutathione-Deficient Mice Have Increased Sensitivity to Transplacental Benzo[a]pyrene-Induced Premature Ovarian Failure and Ovarian Tumorigenesis

Polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (BaP) are ubiquitous environmental pollutants found in tobacco smoke, air pollution, and grilled foods. Prenatal exposure to BaP causes premature reproductive senescence in mice, and other PAHs are transplacental ovarian carcinogens. Glutathione (GSH) is critical for detoxification of the reactive metabolites of PAHs. Therefore, we hypothesized that mice that are genetically deficient in GSH synthesis, due to deletion of the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have increased destruction of oogonia, premature ovarian failure, and ovarian tumorigenesis after transplacental BaP exposure compared with Gclm(+/+) females. Gclm(+/-) female and male mice were mated, and dams were treated with 0, 2, or 10 mg/kg/d BaP in sesame oil by gavage from gestational days 7 to 16. Compared with oil-treated F1 females of the same genotype, Gclm(-/-) prenatally BaP-treated females had significantly greater decrements in offspring production than Gclm(+/+) BaP-treated females. Similarly, we observed significant BaP dose × Gclm genotype interactions on ovarian follicle counts and ovarian tumor multiplicity at 7.5 months of age, with Gclm(-/-) females having greater decrements in follicle numbers and more ovarian tumors in response to prenatal BaP exposure than Gclm(+/+) females. The ovarian tumors were positive for the epithelial marker cytokeratin. Our results show that prenatal exposure of females to BaP causes premature ovarian failure and ovarian tumorigenesis and that embryonic GSH deficiency due to deletion of Gclm increases sensitivity to these transplacental ovarian effects of BaP.

Follicular Stage-Specific Gene Expression Analysis in Rat Ovary.

It is well established that endocrine-disrupting chemical (EDC) exposures during early development can cause ovarian dysfunction by adulthood. Studies with the organochlorine pesticide methoxychlor (MXC), a model EDC with estrogenic and anti-estrogenic activities, have demonstrated that neonatal and fetal exposure [embryonic day 18 to postnatal day (PND) 7] lead to accelerated puberty, irregular estrus cycles, reduced litter sizes, reduced superovulatory response to gonadotropins, and premature reproductive aging. In PND 50-60 ovaries, there was a disruption of follicular progression with a large number of follicles found in the early antral follicle stage with a concomitant reduction in corpora lutea. Furthermore, immunohistochemical studies showed that MXC-treated ovaries had decreased levels of CYP11A1 and LHR proteins in mid-late antral follicle stages and reduced ESR2 expression in the preantral and early antral follicles. Interestingly, there was no significant effect on ESR2 expression at earlier follicular stages such as primary and secondary follicles. Other studies with granulosa cell (GC) cultures demonstrated an enhanced effect of HPTE (a major metabolite of MXC) only in cells stimulated with FSH suggesting that gonadotropin responsive stages of follicles/GCs were more likely to exhibit the MXC mediated detrimental effects. Therefore, to identify the specific stages and the molecular/epigenetic mechanisms involved in EDC-associated effects, follicular isolations were performed. The objectives were (1) to establish a robust follicle separation method by enzymatic digestion and (2) to compare the gene expression patterns at the various follicular stages. Enzymatic digestions were performed with Collagenase Type I and various size beads (Polysciences, Inc.) were utilized to categorize the follicles into three groups: (1) “small” (50-180 μm, up to and including early pre-antral), (2) “medium” (180-300 μm, late pre-antral and early antral), and (3) “large” (300-700, mid- and late-antral follicles. Granulosa cells were collected from the large follicles by puncturing them prior to the enzymatic digestion. In this manner, approximately 25-30 small, 10-20 medium follicles and ~6 x 10-5 GCs from large follicles, per rat (n = 3), were obtained and RNA was isolated. Gene expression analyses were conducted after whole transcriptome amplification and QPCR with Taqman assays. Small follicles had a 100- to 200-fold enrichment ( p < 0.001) of Gdf9 and Bmp15 transcripts while GC from the large follicles had an enrichment of 100- to 500-fold ( p < 0.001) in steroidogenic enzyme transcripts such as Cyp11a1, Cyp19a1, and Hsd17b1 . These data validated our isolation techniques. Currently these data are being compared to those obtained from laser capture microdissection technique. Together they provide a useful tool for future studies of EDC exposed ovaries wherein gonadotropin responsive follicular stage-dependent gene expression and epigenetic analyses can be performed. Supported by R56 ES017059 from NIEHS (MU) and TUBITAK– BIDEB 2219 International Postdoctoral Fellowship Program (KA).

Early Life Exposure to Endocrine-Disrupting Chemicals Causes Lifelong Molecular Reprogramming of the Hypothalamus and Premature Reproductive Aging

Gestational exposure to the estrogenic endocrine disruptor methoxychlor (MXC) disrupts the female reproductive system at the molecular, physiological, and behavioral levels in adulthood. The current study addressed whether perinatal exposure to endocrine disruptors re-programs expression of a suite of genes expressed in the hypothalamus that control reproductive function and related these molecular changes to premature reproductive aging. Fischer rats were exposed daily for 12 consecutive days to vehicle (dimethylsulfoxide), estradiol benzoate (EB) (1 mg/kg), and MXC (low dose, 20 μg/kg or high dose, 100 mg/kg), beginning on embryonic d 19 through postnatal d 7. The perinatally exposed females were aged to 16-17 months and monitored for reproductive senescence. After euthanasia, hypothalamic regions [preoptic area (POA) and medial basal hypothalamus] were dissected for real-time PCR of gene expression or pyrosequencing to assess DNA methylation of the Esr1 gene. Using a 48-gene PCR platform, two genes (Kiss1 and Esr1) were significantly different in the POA of endocrine-disrupting chemical-exposed rats compared with vehicle-exposed rats after Bonferroni correction. Fifteen POA genes were up-regulated by at least 50% in EB or high-dose MXC compared with vehicle. To understand the epigenetic basis of the increased Esr1 gene expression, we performed bisulfite conversion and pyrosequencing of the Esr1 promoter. EB-treated rats had significantly higher percentage of methylation at three CpG sites in the Esr1 promoter compared with control rats. Together with these molecular effects, perinatal MXC and EB altered estrous cyclicity and advanced reproductive senescence. Thus, early life exposure to endocrine disruptors has lifelong effects on neuroendocrine gene expression and DNA methylation, together with causing the advancement of reproductive senescence.

Molecular profiling of human oocytes after vitrification strongly suggests that they are biologically comparable with freshly isolated gametes

To assess the effects of vitrification on the biomolecular profile of oocytes, we analyzed through real-time reverse transcriptase-polymerase chain reaction eight genes encoding critically important proteins for embryo development and compared this partial transcriptome with that of freshly collected gametes isolated from the same women. The comparison of the molecular profiles demonstrated that our vitrification protocol does not alter the biomolecular quality of oocytes: in fact, between the two groups we found the absence of statistically significant variations. Accordingly, this cryopreservation technique might be helpful in preserving women's fertility.

Telomere Length and Reproductive Aging

Previous studies have suggested an association between rates of biological and reproductive aging. Short telomere length is a marker for cellular aging and may occur more frequently in women with poor oocyte quality and a history of premature reproductive senescence. Telomere length, however, has been both positively and negatively associated with different measures of reproductive aging in a number of studies. In the present study, the investigators tested the hypothesis that women with a history of premature reproductive aging have a shorter average telomere length than women without such a history. Telomere length in peripheral blood leukocytes was measured in 2 groups of women with evidence of premature reproductive aging: Group 1 (n = 34) was comprised of women with idiopathic premature ovarian failure (POF) who experienced menopause before 40 years of age and group 2 (n = 95) contained women with a history of recurrent miscarriage (RM). The 2 control groups were healthy women of reproductive age from the general population (C1, n = 108) and women who had had a healthy pregnancy after 37 years of age (C2, n = 46). Telomere length was measured using telomere-specific quantitative PCR. The age-adjusted mean telomere length was shorter among women in the RM group than among those in both control groups (8.46 kb for RM vs. 8.92 kb for C1, [P = 0.0004] and 9.11 kb for C2, [P = 0.02]), respectively. However, this effect was not specifically confined to women known to have experienced trisomic pregnancies. Contrary to expectation, women in the POF group did not have a shorter age-adjusted mean telomere length than those in the controls: Telomere length in POF women was longer compared to C1 (9.58 vs. 8.92 kb, P = 0.01) and not significantly different than C2. These findings suggest that both the opposing association of RM and POF with telomere length, and lack of an association of trisomic pregnancy―as manifestations of different types of reproductive aging―may result from unique physiological factors. The results require confirmation in studies with larger and more defined patient populations.

Accelerated Ovarian Aging in the Absence of the Transcription Regulator TAF4B in Mice1

The mammalian ovary is unique in that its reproductive life span is limited by oocyte quantity and quality. Oocytes are recruited from a finite pool of primordial follicles that are usually exhausted from the ovary during midadult life. If regulation of this pool is perturbed, the reproductive capacity of the ovary is compromised. TAF4B is a gonad-enriched subunit of the TFIID complex required for female fertility in mice. Previous characterization of TAF4B-deficient ovaries revealed several reproductive deficits that collectively result in infertility. However, the etiology of such fertility defects remains unknown. By assaying estrous cycle, ovarian pathology, and gene expression changes in young Taf4b-null female mice, we show that TAF4B-deficient female mice exhibit premature reproductive senescence. The rapid decline of ovarian function in Taf4b-null mice begins in early postnatal life, and follicle depletion is completed by 16 wk of age. To uncover differences in gene expression that may underlie accelerated ovarian aging, we compared genome-wide expression profiles of 3-wk-old, prepubescent Taf4b-null and wild-type ovaries. At 3 wk of age, decreased gene expression in Taf4b-null ovaries is similar to that seen in aged ovaries, revealing several molecular signatures of premature reproductive senescence, including reduced Smc1b. One significantly reduced transcript in the young TAF4B-null ovary codes for MOV10L1, a putative germline-specific RNA helicase that is related to the Drosophila RNA interference protein, armitage. We show here that Mov10l1 is expressed in mouse oocytes and that its expression is sensitive to TAF4B level, linking TAF4B to the posttranscriptional control of ovarian gene expression.

Premature Reproductive Senescence in Mice Expressing a Constitutively Active Luteinizing Hormone Receptor.

Premature Reproductive Senescence in Mice Expressing a Constitutively Active Luteinizing Hormone Receptor.

Maternal Characteristics versus Egg Size and Energy Density: Do Stocked Lake Trout in Lake Ontario Experience Premature Reproductive Senescence

Observations from September 1994 and 1997 collections of hatchery-origin, mature female lake trout (Salvelinus namaycush) from Lake Ontario indicated that egg mass decreased with age, fueling the notion that stocked fish experienced premature reproductive senescence. Supplemental collections during September 2002 and November 2002–2004 were combined with the 1994 and 1997 samples to examine whether sample date or maternal age, body mass, condition (K), egg count, or strain were related to egg mass or energy content (percentage dry mass [%DM]). Body mass was correlated with egg mass for age ≥ 8 lake trout sampled in September, and egg count was correlated with egg mass for September age-6 lake trout only. Within each month, egg mass was not related to K or egg %DM, however, egg %DM was 1.52% greater (P ≤ 0.0247) in November than in September which is equivalent to a 110 cal/g difference. Samples were grouped for the three most abundant strains (Seneca, Superior, and Ontario) after finding no strain or year effects from our 1994 and 1997 samples and based on life history data from the literature and our assessment sampling. Further analysis indicated that September egg masses were greater for fish ages ≤ 6 than for fish ages ≥ 8. The age effect disappeared in November when mean egg mass across all ages (0.078 g) was greater than September means (P < 0.0005) for ages-5 (0.054 g), -6 (0.057 g) and ≥ 8 (0.041 g). Our results indicate that the decrease in egg mass with female age in September was not due to senescence, but to oogenesis being closer to completion in young age-5 and -6 fish than in older individuals.

Advancement of reproductive senescence and changes in the early expression of estrogen, progesterone and µ-opioid receptors induced by neonatal hypoxia in the female rat

Perinatal hypoxia is a frequent birth complication, and although its early consequences on brain development have been well studied, few studies address any long-term effects. Postnatal insults producing small disturbances in endocrine function can have marked and long-lasting effects. In the present work we studied the effects of two types of perinatal brain injury: global hypoxia (H, 6.5% O 2 for 50 min) and hypoxia plus ischemia (HI, ligature of the right carotid artery) on female rat reproductive performance and expression of mediobasal hypothalamus-preoptic area (MBH-PO) estrogen, progesterone and µ-opioid receptors at different times after injury, measuring the mRNA (by semiquantitative RT-PCR) and protein (by Western blot). H or HI advanced approximately 3 months after the appearance of blunted preovulatory LH surges and cyclic irregularities (prolonged estrus) characteristic of the early stages of reproductive senescence. 48 h after H or HI we observed decreases in ERβ, µOR and PR (only in the H group) mRNAs and in total ER and µOR proteins, followed by increased PR levels (mRNA and protein) 7 days post-injury and by increased µOR protein and ERβ mRNA in the H group and ERα, ERβ and µOR mRNAs and ER protein in the HI group 30 days post-injury. Thus, an episode of hypoxia suffered during early postnatal life induces premature reproductive senescence on the female rats, accompanied by early changes in some MBH-PO hormone receptors (µOR, ER and PR), whose expression is intimately involved in the regulation of gonadotropin secretion and female sexual cyclicity.

Maternal Characteristics versus Egg Size and Energy Density: Do Stocked Lake Trout in Lake Ontario Experience Premature Reproductive Senescence?

Observations from September 1994 and 1997 collections of hatchery-origin, mature female lake trout ( Salvelinus namaycush) from Lake Ontario indicated that egg mass decreased with age, fueling the notion that stocked fish experienced premature reproductive senescence. Supplemental collections during September 2002 and November 2002-2004 were combined with the 1994 and 1997 samples to examine whether sample date or maternal age, body mass, condition (K), egg count, or strain were related to egg mass or energy content (percentage dry mass [%DM]). Body mass was correlated with egg mass for age ≥ 8 lake trout sampled in September, and egg count was correlated with egg mass for September age-6 lake trout only. Within each month, egg mass was not related to K or egg %DM, however, egg %DM was 1.52% greater (P ≤ 0.0247) in November than in September which is equivalent to a 110 cal/g difference. Samples were grouped for the three most abundant strains (Seneca, Superior, and Ontario) after finding no strain or year effects from our 1994 and 1997 samples and based on life history data from the literature and our assessment sampling. Further analysis indicated that September egg masses were greater for fish ages ≤ 6 than for fish ages ≥ 8. The age effect disappeared in November when mean egg mass across all ages (0.078 g) was greater than September means (P < 0.0005) for ages-5 (0.054 g), -6 (0.057 g) and ≥ 8 (0.041 g). Our results indicate that the decrease in egg mass with female age in September was not due to senescence, but to oogenesis being closer to completion in young age-5 and -6 fish than in older individuals.

USE OF A SYNGENEIC ORTHOTOPIC OVARY TRANSPLANTATION MODEL TO ASSESS THE RELATIVE IMPACT OF OVARIAN VS. EXTRAOVARIAN AND DEVELOPMENTAL VS. ADULT ACTIVATION OF THE ARYL HYDROCARBON RECEPTOR PATHWAY

Chronic exposure to environmentally relevant concentrations of the aryl hydrocarbon receptor-specific toxicant 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) causes premature reproductive senescence in female rats through what appear to be preferential actions on the ovary. In an effort to definitively localize these chronic actions of TCDD on the female reproductive axis, adult pregnant Lewis rat dams (n=24) were dosed with corn oil vehicle or TCDD (50 ng kg-1 wk-1) to provide in utero and lactational (IUL) exposure to pups. Female pups were weaned on postnatal day 21 and dosed with TCDD or vehicle weekly. Ovaries from donor animals treated with TCDD or vehicle were harvested at 3 weeks of age and transplanted into the ovarian bursae of similarly treated recipient females. Following ovary transplantation, rats (n=6–8 per group) received weekly TCDD or vehicle until reproductive senescence in a factorial design for IUL vs. adult and ovarian vs. extraovarian exposure to TCDD. Beginning at vaginal opening, reproductive cyclicity was monitored by vaginal cytology for 10 days each month. Blood samples were collected across the estrous cycle at 3 and 8–9 months of age. Procedural controls included naïve and sham-operated females treated with TCDD or vehicle. Ovary transplantation resulted in precocious vaginal opening regardless of treatment group. Ovarian cyclicity following transplantation was less regular than for sham or naïve controls. IUL ovarian exposure to TCDD was more detrimental to subsequent reproductive cyclicity than extraovarian and adult exposures. The immature ovary appears to be a sensitive developmental target of the AhR during environmental endocrine disruption. (platform)

Ovarian Endocrine Disruption Underlies Premature Reproductive Senescence Following Environmentally Relevant Chronic Exposure to the Aryl Hydrocarbon Receptor Agonist 2,3,7,8-Tetrachlorodibenzo-p-Dioxin1

The aryl hydrocarbon receptor (AHR) mediates the effects of many endocrine disruptors and contributes to the loss of fertility in polluted environments. While previous work has focused on mechanisms of short-term endocrine disruption and ovotoxicity in response to AHR ligands, we have shown recently that chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces premature reproductive senescence in female rats without depletion of ovarian follicular reserves. In the current study, premature reproductive senescence was induced using a range of low-dose exposure to TCDD (0, 1, 5, 50, and 200 ng kg(-1) wk(-1)) beginning in utero and continuing until the transition to reproductive senescence. Doses of 50 and 200 ng TCDD kg(-1) wk(-1) delayed the age at vaginal opening and accelerated the loss of normal reproductive cyclicity with age without depletion of follicular reserves. Serum estradiol concentrations were decreased in a dose-dependent fashion (> or = 5 ng kg(-1) wk(-1)) across the estrous cycle in perisenescent rats still displaying normal cyclic vaginal cytology. Serum FSH, LH, and progesterone profiles were unchanged by TCDD. The loss of reproductive cyclicity following chronic exposure to TCDD was not accompanied by decreased responsiveness to GnRH. Ovarian endocrine disruption is the predominant functional change preceding the premature reproductive senescence induced by chronic exposure to low doses of the AHR-specific ligand TCDD.

Effects of Acute and Chronic Exposure to the Aryl Hydrocarbon Receptor Agonist 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the Transition to Reproductive Senescence in Female Sprague-Dawley Rats1

Activation of the aryl hydrocarbon receptor (AHR) can occur in polluted environments, either from smoking-related toxicants or from endogenous ligands. We tested whether acute or chronic exposure to the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the transition to reproductive senescence in female Sprague-Dawley rats. In experiment 1, rats (n = 6 per experimental group) received a single dose of 0 or 10 mug/kg of TCDD orally (p.o.) on Postnatal Day 29. Vaginal cytology was monitored for 1 wk each month until rats were killed at 1 yr of age. The single prepubertal exposure to TCDD hastened the transition to reproductive senescence in female rats and was associated with delayed puberty, abnormal cyclicity, and premature reproductive senescence. In a second experiment, rats were exposed to TCDD chronically through weekly dosing (0, 50, or 200 ng kg(-1) wk(-1) p.o., n = 7 each dose) beginning in utero. Lifelong exposure to these lower doses of TCDD induced a dose- and time-dependent loss of normal cyclicity and significantly hastened the onset of the transition to reproductive senescence (P < 0.05). This premature transition to reproductive senescence was associated with prolonged estrous cycles and, at the highest dose of TCDD, persistent estrus or diestrus. The number and size of ovarian follicles were not altered by TCDD. Diestrous concentrations of LH in rats exposed chronically to TCDD were similar to those in controls, whereas progesterone tended to be elevated at both doses of the dioxin (P < 0.08). Serum FSH was elevated in the group exposed to 50 ng/kg of TCDD (P < 0.02), whereas estradiol was decreased at both doses of dioxin (P < 0.01). Data thus far support endocrine disruption rather than depletion of follicular reserves as a primary mechanism of the premature transition to reproductive senescence following activation of the AHR pathway by TCDD in female rats.

Mental Illness Takes Heavy Toll on Youth

changes in the ovary (including the presence of multi-oocyte follicles) that were associated with a 35% incidence of uterine tumors in animals at 18 months of age. “These animals had premature reproductive senescence,” said Newbold. “Their ovaries were malformed and not completely functional.” According to one report, the daily exposure of human infants to isoflavones in soy-based infant formulas is 6 to 11 times higher (based on body weight) than the dose that produces hormonal effects in adults consuming soy foods (Setchell et al. Lancet. 1997; 350:23-27). But for now, said Newbold, researchers don’t know how animal findings about genistein translate to the human population. “I think we have to be cautious,” she added. “Humans are exposed to a number of estrogenic or endocrine-disrupting compounds and it makes sense to decrease those exposures as much as possible.”

Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia.

Fanconi Anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents. Recent studies suggest that FA proteins share a common pathway with BRCA proteins. To study the in vivo role of the FA group A gene (Fanca), gene-targeting techniques were used to generate Fanca(tm1Hsc) mice in which Fanca exons 1-6 were replaced by a beta-galactosidase reporter construct. Fanca(tm1.1Hsc) mice were generated by Cre-mediated removal of the neomycin cassette in Fanca(tm1Hsc) mice. Fanca(tm1.1Hsc) homozygotes display FA-like phenotypes including growth retardation, microphthalmia and craniofacial malformations that are not found in other Fanca mouse models, and the genetic background affects manifestation of certain phenotypes. Both male and female mice homozygous for Fanca mutation exhibit hypogonadism, and homozygous females demonstrate premature reproductive senescence and an increased incidence of ovarian cysts. We showed that fertility defects in Fanca(tm1.1Hsc) homozygotes might be related to a diminished population of primordial germ cells (PGCs) during migration into the gonadal ridges. We also found a high level of Fanca expression in pachytene spermatocytes. Fanca(tm1Hsc) homozygous males exhibited an elevated frequency of mispaired meiotic chromosomes and increased apoptosis in germ cells, implicating a role for Fanca in meiotic recombination. However, the localization of Rad51, Brca1, Fancd2 and Mlh1 appeared normal on Fanca(tm1Hsc) homozygous meiotic chromosomes. Taken together, our results suggest that the FA pathway plays a role in the maintenance of reproductive germ cells and in meiotic recombination.

Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad

Oocyte loss, either directly through attrition (germ cell death) or indirectly through follicular atresia (somatic or granulosa cell death), is a fundamental event associated with defining the time of normal or premature reproductive senescence in females. Although apoptosis has been reported to function as the underlying mechanism responsible for death of both germ cells and somatic cells in the ovary, the final molecular steps which commit ovarian cells to death have not been fully elucidated. To examine if death repressor activity of the bcl-2 gene product is important for germ cell survival, we conducted studies using a Bcl-2 loss-of-function (bcl-2 -/-) transgenic mouse model. Histological analyses revealed that ovaries collected from bcl-2 -/- mice possessed numerous aberrantly formed primordial follicle-like structures containing a single layer of granulosa cells without an oocyte. Additionally, the total number of primordial follicles present which contained a healthy oocyte was markedly reduced in bcl-2 -/- mice as compared to heterozygote (bcl-2 -/+) or wild-type (bcl-2 +/+) mice, suggesting that expression of the bcl-2 death repressor gene is critical for endowment of a normal complement of germ cells and primordial follicles in the mammalian ovary.

Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad.

Oocyte loss, either directly through attrition (germ cell death) or indirectly through follicular atresia (somatic or granulosa cell death), is a fundamental event associated with defining the time of normal or premature reproductive senescence in females. Although apoptosis has been reported to function as the underlying mechanism responsible for death of both germ cells and somatic cells in the ovary, the final molecular steps which commit ovarian cells to death have not been fully elucidated. To examine if death repressor activity of the bcl-2 gene product is important for germ cell survival, we conducted studies using a Bcl-2 loss-of-function (bcl-2 -/-) transgenic mouse model. Histological analyses revealed that ovaries collected from bcl-2 -/- mice possessed numerous aberrantly formed primordial follicle-like structures containing a single layer of granulosa cells without an oocyte. Additionally, the total number of primordial follicles present which contained a healthy oocyte was markedly reduced in bcl-2 -/- mice as compared to heterozygote (bcl-2 -/+) or wild-type (bcl-2 +/+) mice, suggesting that expression of the bcl-2 death repressor gene is critical for endowment of a normal complement of germ cells and primordial follicles in the mammalian ovary.

The evolution of premature reproductive senescence and menopause in human females

Reproductive senescence in human females takes place long before other body functions senesce. This fact presents an evolutionary dilemma since continued reproduction should generally be favored by natural selection. Two commonly proposed hypotheses to account for human menopause are (a) a recent increase in the human lifespan and (b) a switch to investment in close kin rather than direct reproduction. No support is found for the proposition that human lifespans have only recently increased. Data from Ache hunter-gatherers are used to test the kin selection hypothesis. Ache data do not support the proposition that females can gain greater fitness benefits in old age by helping kin rather than continuing to reproduce. Nevertheless, one crucial parameter in the model, when adjusted to the highest value within the measured 95% confidence interval, would lead to the evolution of reproductive senescence at about 53 years of age. Further investigation is necessary to determine whether the kin selection hypothesis of menopause can account for its current maintenance in most populations.