A 17-year oscillation in cancer mortality birth cohorts on three continents – synchrony to cosmic ray modulations one generation earlier

Cross-generational effects (grandmother effects) associated with epigenetic imprinting, environmental exposures, and lifestyle choices are beginning to be explored by various investigators. The possibility that low-level background radiation can be a driver of such effects has been suggested previously and is explored further in this study. Age-period-cohort analysis was performed on United States (US), United Kingdom (UK), and Australian (AU) female breast cancer mortality of the twentieth century, as well as on UK female total cancer mortality, to extract the high-frequency oscillations in the birth cohort time series. US fetal and infant congenital mortality were examined to extend the birth cohorts to modern times. A ∼17-year cycle was detected in all birth cohort series, which spanned approximately 180 years from 1820 to 2000. This suggests a global, environmental cause. To mimic previous work in examining a possible link to cosmic radiation, the 17- to 18-year cycles of the cosmogenic nuclide ¹⁴C, the sunspot double-cycle, neutron monitors, and a compilation of ground-based magnetic field observations were examined in the birth cohort and germ cell cohort time frames. Evidence is presented that optimal alignments with extraterrestrial oscillations occur in the time frame of the germ-cell cohort, one generation before the birth cohorts. Furthermore, the alignment is optimized by accounting for the changes in the maternal age distribution over time. These findings have potential importance to the mechanisms of disease as well as species adaptation and evolution.     

Trends in the incidence of testicular germ cell cancer in Ontario by histologic subgroup, 1964-1996

BACKGROUND: Testicular cancer is rare but is notable because it affects mainly young men. The incidence of this disease has been increasing in developed countries throughout the world for several decades. The authors examined trends in the incidence of testicular germ cell cancer in Ontario for the period 1964-1996 according to the 2 main histologic groups, seminoma and non-seminoma. METHODS: Data on incident cases of testicular germ cell cancer diagnosed in Ontario residents aged 15-59 years between 1964 and 1996 were extracted from the population-based Ontario Cancer Registry. Annual rates of testicular cancer for the 2 histologic groups were analysed by means of log-linear regression to estimate average annual percent change. RESULTS: Between 1964 and 1996 the incidence of testicular germ cell cancer increased by 59.4%, from 4.01 to 6.39 per 100,000. This corresponded to an average annual increase of about 2% for both nonseminoma and seminoma. The relative increase in incidence was greatest in the lowest age group (15-29 years) for both histologic groups, although the data suggest that the incidence of nonseminoma cancer in this age group began to decline in the early 1990s. The increase in incidence appears to be due to a birth cohort effect, with more recent cohorts of men at increased risk. INTERPRETATION: The rise in the incidence of testicular germ cell cancer, not only in Ontario but also in many developed countries, requires investigation. The search for explanatory factors should focus on exposures whose prevalence may have increased over the past few decades and that are common enough to affect population incidence. The similarity of trends for seminoma and nonseminoma cancer suggests that the underlying risk factors are likely the same.     

From primordial germ cell to primordial follicle: mammalian female germ cell development

In mammals, the final number of oocytes available for reproduction of the next generation is defined at birth. Establishment of this oocyte pool is essential for fertility. Mammalian primordial germ cells form and migrate to the gonad during embryonic development. After arriving at the gonad, the germ cells are called oogonia and develop in clusters of cells called germ line cysts or oocyte nests. Subsequently, the oogonia enter meiosis and become oocytes. The oocyte nests break apart into individual cells and become packaged into primordial follicles. During this time, only a subset of oocytes ultimately survive and the remaining immature eggs die by programmed cell death. This phase of oocyte differentiation is poorly understood but molecules and mechanisms that regulate oocyte development are beginning to be identified. This review focuses on these early stages of female germ cell development.     

Cytological evaluation of the germ cell development strategy within the testis of the American alligator, Alligator mississippiensis

The cytological changes to germ cells were investigated within the seminiferous epithelium of the American alligator (Alligator mississippiensis). Testicular tissues were collected, embedded in plastic, sectioned on an ultramicrotome, and stained with the periodic acid–Schiff+ procedure followed by a haematoxylin counterstain. Alligators have a prenuptial pattern of germ cell development, where spermatogenesis begins in early spring and sperm is mature by the time mating begins in May. Consistent spatial relationships between germ cells are absent within the seminiferous epithelium of the alligator. Their germ cells progress through the phases of spermatogenesis as a single cohort, leading to one continuous spermiation event that occurs during their mating season (May–June). This temporal germ cell development is different from the consistent spatial development seen within seasonally breeding birds and mammals but is similar to the recently described germ cell development strategies of two other temperate breeding reptiles, the slider turtle and the European wall lizard. The germ cell development strategy shared by these three temperate reptiles representing three different taxa within the class Reptilia is reminiscent of the temporal strategy seen within the anamniotic testis. Thus, alligators and at least two other temperate reptiles exhibit primitive spermatogenic cycles within derived amniotic testes and may be consider intermediates in terms of testicular organization, which may have significance phylogenetically.     

Cancer mortality among German aircrew: second follow-up

Aircrew members are exposed to cosmic radiation and other specific occupational factors. In a previous analysis of a large cohort of German aircrew, no increase in cancer mortality or dose-related effects was observed. In the present study, the follow-up of this cohort of 6,017 cockpit and 20,757 cabin crew members was extended by 6 years to 2003. Among male cockpit crew, the resulting all-cancer standardized mortality ratio (SMR) (n = 127) is 0.6 (95% CI 0.5–0.8), while for brain tumors it is 2.1 (95% CI 1.0–3.9). The cancer risk is significantly raised (RR = 2.2, 95% CI 1.2–4.1) among cockpit crew members employed 30 years or more compared to those employed less than 10 years. Among both female and male cabin crew, the all-cancer SMR and that for most individual cancers are close to 1. The SMR for breast cancer among female crew is 1.2 (95% CI 0.8–1.8). Non-Hodgkin’s Lymphoma among male cabin crew is increased (SMR 4.2; 95% CI 1.3–10.8). However, cancers associated with radiation exposure are not raised in the cohort. It is concluded that among cockpit crew cancer mortality is low, particularly for lung cancer. The positive trend of all cancer with duration of employment persists. The increased brain cancer SMR among cockpit crew requires replication in other cohorts. For cabin crew, cancer mortality is generally close to population rates. Cosmic radiation dose estimates will allow more detailed assessments, as will a pooling of updated aircrew studies currently in planning.     

Thyroid cancer risk in Belarus after the Chernobyl accident: Comparison with external exposures

Within the time period 1990–1993, childhood thyroid cancer incidence due to the Chernobyl accident increased dramatically in Belarus, especially with regard to the birth cohort January 1, 1971, to May 31, 1986. This rise subsequently slowed down, i.e. during the period 1994–1996. The respective data were analysed and compared with the results of an analysis on the time dependence of thyroid cancer incidence in a pooled cohort of persons who had been exposed during childhood to external radiation with high dose rates. Concerning the period of 5–10 years following exposure, the excess absolute cancer risk per unit thyroid dose in the latter (external) exposure group was found to exceed the one in the Belarus group by a factor of two. This difference, however, is not statistically significant. The age-adjusted average excess absolute risk per unit thyroid dose for the period of 5–50 years following external childhood exposure was found to be 8 female and 14 male cases per 10⁴ person-year · Gy, which is a factor about 2.5 times higher than for the non-adjusted risk in the pooled cohort, as reported by Ron et al. in 1995. Assessments of future excess thyroid cancer cases due to the Chernobyl accident were done on the basis of the time dependence of thyroid cancer risk following external exposure. The thyroid cancer incidence among the birth cohort considered in Belarus and for a period starting from the cessation of the available observation data (1 January 1997) and extending to 50 years after the Chernobyl accident has been estimated to be about 15,000 cases, with an uncertainty range of 5000–45,000 cases. According to our calculations, 80% of these cases exceed the baseline risk under enhanced thyroid surveillance. Received: 8 June 1999 / Accepted in revised form: 20 November 1999     

Abnormal germ cell development in cryptorchidism.

BACKGROUND: Previous studies suggest that two fundamental, probably androgen-dependent, steps in maturation of germ cells normally occur in the prepubertal testis: the disappearance of gonocytes (the fetal stem cell pool) and the appearance of adult dark spermatogonia (the adult stem cell pool) at 2-3 months of age and the appearance of primary spermatocytes (the onset of meiosis) at 4-5 years. Previous studies of small series of cryptorchid boys suggest that both steps are defective in undescended testes and to a lesser degree in descended testes contralateral to unilaterally undescended testes. The purpose of this study is to confirm the previous findings of defective germ cell maturation in a large series of boys with unilateral undescended testes. PATIENTS: Seven hundred and sixty-seven boys with unilateral cryptorchidism who had orchidopexy and bilateral testicular biopsies between birth and 9 years of age were studied. MATERIALS AND METHODS: Total and differential germ cell counts were performed on semithin histologic sections of the biopsies. The results from the undescended and contralateral descended testes were compared using the Wilcoxon signed-rank test and the Wilcoxon-Whitney-Mann U test. RESULTS: Gonocytes failed to disappear and adult dark spermatogonia failed to appear in undescended testes under 1 year of age indicating a defect in the first step in maturation at 2-3 months resulting in failure to establish an adequate adult stem cell pool. Primary spermatocytes failed to appear in undescended testes and appeared in only 19% of contralateral descended testes at 4-5 years of age indicating a defect in the onset of meiosis. CONCLUSION: Unilaterally undescended testes fail to establish an adequate adult stem cell pool which normally occurs at 2-3 months of age and fail to establish adequate meiosis which normally occurs at 4-5 years of age. Similar but less severe changes are seen in the contralateral descended testes. Defects in the two pubertal steps in germ cell maturation are associated with reduced total germ cell counts.     

Establishment of the germ cell lineage in mammals

The germ cell lineage in mice becomes lineage-restricted about 7.2 days postcoitum. Its progenitors have migrated from the proximal region of the epiblast. Cells from the distal region of the epiblast will also give rise to germ cells, if they are transplanted to the proximal region at the appropriate time. Cells in this region are subject to a predisposing signal from the adjacent extra-embryonic ectoderm. It appears that this and other signals determine the emergence of germ cells: unlike in some other organisms, this event is not predetermined.     

Birth weight, breast cancer and the potential mediating hormonal environment

Background

Previous studies have shown that woman’s risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother’s own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer.

Methods and Findings

Risk of breast cancer in relation to a first infant’s birth weight, mother’s own birth weight and breast cancer risk factors were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3), anti-estrogen alpha-fetoprotein (AFP), and pregnancy-associated plasma protein-A (PAPP-A) were measured in 23,824 pregnant women from a separate prospective cohort, the FASTER trial. During follow-up (median, 14 years) 31 women (7.6 %) were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile) had a higher breast cancer risk compared to other women (hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.2–5.2; P = 0.012). The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.5; 95% CI, 1.2–5.6; P = 0.021). An infant’s birth weight had a strong positive relationship with the mother’s serum E3/AFP ratio and PAPP-A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships.

Conclusions

Giving birth to an infant with high birth weight was associated with increased breast cancer risk in later life, independently of mother’s own birth weight and breast cancer risk factors and was also associated with a hormonal environment during pregnancy favoring future breast cancer development and progression.     

Short term increase in risk of breast cancer after full term pregnancy.

To determine whether there is a short term increase in the risk of breast cancer after a full term birth data from two hospital based, case-control studies in Italy were pooled. Analysis was restricted to women aged under 50 with two or more children (573 women with cancer and 570 controls). A relative risk for breast cancer of 2.66 was seen in women who had given birth during the three years preceding the interview compared with women whose last birth had occurred 10 or more years before, after adjustment for age, age at first birth, and parity. The relative risk slowly decreased for women who had last given birth three to 10 years before. Multivariate analyses confirmed the protective effect of an early age at first birth and the age dependent effect of parity on the risk of breast cancer--that is, a direct relation below age 40 and an inverse one in older women. These data provide epidemiological evidence that a full term birth is followed by a transient increase in the risk of breast cancer, which for some time contrasts with and overcomes the long term protection of pregnancy at an early age. They therefore confirm predictions from animal studies and theoretical models that pregnancy prevents the early stages of breast carcinogenesis but promotes the late stages of the process.     

PRDM在生殖细胞发育中的作用

生殖细胞特化是发育和遗传的基础。原始生殖细胞（精子和卵子的前体细胞）的特化包括3个主要事件：体细胞程序的抑制、潜在全能性的获得、基因组范围内的表观遗传重编程。含PR域蛋白1（PR domain-containing1,PRDM1）和PRDM14是生殖细胞系产生的关键转录调节因子。PRDMl要抑制体细胞程序,而PRDM14主要调节潜在全能性的获得及表观遗传学重编程。此外,PRDM家族蛋白PRDM9在生殖细胞减数分裂中有重要作用。     

Incidence and Mortality Trends in German Women with Breast Cancer Using Age,Period and Cohort 1999 to 2008

Longitudinal analysis investigates period (P), often as years. Additional scales of time are age (A) and birth cohort (C) Aim of our study was to use ecological APC analysis for women breast cancer incidence and mortality in Germany. Nation-wide new cases and deaths were obtained from Robert Koch Institute and female population from federal statistics, 1999–2008. Data was stratified into ten 5-years age-groups starting 20–24 years, ten birth cohorts starting 1939–43, and two calendar periods 1999–2003 and 2004–2008. Annual incidence and mortality were calculated: cases to 100,000 women per year. Data was analyzed using glm and apc packages of R. Breast cancer incidence and mortality increased with age. Secular rise in breast cancer incidence and decline in mortality was observed for period1999-2008. Breast cancer incidence and mortality declined with cohorts; cohorts 1950s showed highest incidence and mortality. Age-cohort best explained incidence and mortality followed by age-period-cohort with overall declining trends. Declining age-cohort mortality could be probable. Declining age-cohort incidence would require future biological explanations or rendered statistical artefact. Cohorts 1949–1958 could be unique in having highest incidence and mortality in recent time or future period associations could emerge relatively stronger to cohort to provide additional explanation of temporal change over cohorts.     

Necrosis and necroptosis in germ cell depletion from mammalian ovary

The maximum number of germ cells is present during the fetal life in mammals. Follicular atresia results in rapid depletion of germ cells from the cohort of the ovary. At the time of puberty, only a few hundred (<1%) germ cells are either culminated into oocytes or further get eliminated during the reproductive life. Although apoptosis plays a major role, necrosis as well as necroptosis, might also be involved in germ cell elimination from the mammalian ovary. Both necrosis and necroptosis show similar morphological features and are characterized by an increase in cell volume, cell membrane permeabilization, and rupture that lead to cellular demise. Necroptosis is initiated by tumor necrosis factor and operated through receptor interacting protein kinase as well as mixed lineage kinase domain-like protein. The acetylcholinesterase, cytokines, starvation, and oxidative stress play important roles in necroptosis-mediated granulosa cell death. The granulosa cell necroptosis directly or indirectly induces susceptibility toward necroptotic or apoptotic cell death in oocytes. Indeed, prevention of necrosis and necroptosis pathways using their specific inhibitors could enhance growth/differentiation factor-9 expression, improve survivability as well as the meiotic competency of oocytes, and prevent decline of reproductive potential in several mammalian species and early onset of menopause in women. This study updates the information and focuses on the possible involvement of necrosis and necroptosis in germ cell depletion from the mammalian ovary.     

Hedgehog signaling in germ cell migration

The primitive gonad of the Drosophila embryo is formed from two cell types, the somatic gonad precursor cells (SGPs) and the germ cells, which originate at distant sites. To reach the SGPs the germ cells must undergo a complex series of cell movements. While there is evidence that attractive and repulsive signals guide germ cell migration through the embryo, the molecular identity of these instructive molecules has remained elusive. Here, we present evidence suggesting that hedgehog (hh) may serve as such an attractive guidance cue. Misexpression of hh in the soma induces germ cells to migrate to inappropriate locations. Conversely, cell-autonomous components of the hh pathway appear to be required in the germline for proper germ cell migration.     

Ability of trypsin in mimicking germ cell factors that affect Sertoli cell secretory function

A biological factor that inhibits the in vitro secretion of testin by Sertoli cells was purified to apparent homogeneity from conditioned medium of germ cells isolated using trypsin. Partial N-terminal amino acid sequence analysis of the purified germ cell factor revealed a sequence of NH₂-IVGGYTXAAN. Comparison of the sequence with the existing protein database revealed that it is homologous to trypsin. Immunoprecipitation experiments using either [¹⁵S]-labeled germ or Sertoli cell proteins and a monospecific anti-trypsin antibody failed to demonstrate the synthesis and secretion of trypsin by these testicular cells, suggesting the isolated factor is the residuary trypsin that was used for isolating germ cells from seminiferous tubules. Subsequent experiments revealed that trypsin per se can inhibit the secretion of Sertoli cell testin and clusterin dose-dependently, whose effect can be prohibited by soybean trypsin inhibitor (STI). In view of these findings, a nonenzymatic procedure was deemed necessary to prepare germ cell conditioned medium (GCCM) to assess whether an authentic biological factor(s) is indeed present. Four batches of conditioned medium of germ cells isolated by a mechanical procedure without the use of trypsin were fractionated by sequential Mono Q anion exchange and C8 reversed-phase HPLC. When these fractions were monitored for testin modulatory activity using an in vitro bioassay with primary cultures of Sertoli cells, it was shown that GCCM prepared by this procedure indeed contained testin modulatory bioactivity. Since testin is a novel component of specialized junctions between Sertoli and germ cells, the identification of a germ cell factor(s) that affects its secretion by Sertoli cells suggests a dynamic biochemical relationship between these cell types in the seminiferous epithelium. © 1996 Wiley-Liss, Inc.     

The ultrastructure of normal fetal and neonatal pig testis germ cells and the influence of fetal decapitation on the germ cell development

The development of germ cells in the male pig was investigated ultrastructurally in normal and decapitated fetuses. The age ranged respectively from 30 days p.c. till one month after birth and from 52 days p.c. until birth. The ultrastructural organization of the germ cells changes dramatically between 30 days p.c. and 52 days p.c. which coincides with the formation of 'true' sex cords. From 52 days p.c. onwards the morphology is rather stable: cells show a 'hydrated' appearance and typical cell bridges. There is no obvious difference in the ultrastructure of germ cells in decapitated animals, their normal littermates and control animals. Therefore germ cell development in the pig is likely to be insensitive to gonadotropins during the fetal period. The development of pig germ cells follows closely the pattern described for several species. Quantitatively there is an increase in the ratio of germ cell/Sertoli cell per cross sectional diameter in the decapitated animals.     

Protruding disordered loop of gC1qR is specifically exposed and related to antiapoptotic property in germ cell lineage

We established a monoclonal antibody (MAb), 5G9, with the use of a fixed seminoma tissue from an archival paraffin-embedded specimen, as an immunogen. Without antigen retrieval, positive 5G9-immunohistochemical staining was confined mostly to primordial germ cells, spermatogonia and various germ cell tumors. 5G9 recognized a mitochondrial 32-kD protein with an isoelectric point of pH 4.2, identified as a multifunctional ubiquitous protein, receptor for globular head of C1q (gC1qR), whose epitope was mapped in a disordered loop connecting the β3 and the β4 strands. Reflecting the ubiquitous distribution of gC1qR, with antigen retrieval, 5G9 was found reactive to a wide range of normal and tumor tissues. Since several co-precipitated and phosphorylated bands were observed in various human cell lines but not in germ cell tumor cell lines by in vitro phosphorylation assay, we speculate that the epitope of gC1qR is specifically unmasked in the germ cell lineage. By reducing gC1qR by siRNA, a significant increase was observed in the number of apoptotic cells in ITO-II and TCam-2 cell lines, but to a lesser extent in the Colo201 colon cancer cell line, showing an antiapoptotic property of gC1qR in the germ cells. Since protein–protein interaction is partially preserved by fixation, archival paraffin-embedded specimens can be a valuable source of immunogens for generating monoclonal antibodies (MAbs) that recognize tissue-specific protein conformation.     

A mini-review of familial ovarian germ cell tumors: An additional manifestation of the familial testicular germ cell tumor syndrome

Introduction While testicular germ cell tumors (TGCTs) are the most common malignancy in young men, germ cell tumors in women are uncommon. Familial clustering, epidemiologic evidence of increased risk with family or personal history of TGCT, and associations with genitourinary tract anomalies suggest an underlying genetic predisposition to TGCT, but traditional linkage studies have yet to identify a highly penetrant TGCT cancer susceptibility gene. In this paper, we investigate the familial occurrence of testicular and ovarian germ cell tumors. Methods We report a family in which a TGCT and an ovarian germ cell tumor (OGCT) occurred in two siblings, summarize the existing literature on familial occurrences of OGCT, either alone or in combination with extragonadal or TGCTs, and compare the incidence of familial and sporadic testicular and ovarian GCTs. Sporadic GCT data were obtained from the US Surveillance Epidemiology and End Results (SEER) registry. Results We identified 16 reports of OGCT occurring in conjunction with either ovarian, testicular or extragonadal GCT. In these familial cases, the mean age at onset of female dysgerminoma was younger than that noted in the general population (age 17 vs. age 24, p = 0.01). In SEER, the incidence of TGCT was 15 times higher than that of OGCT. Histologic distributions in males and females showed distinctly different patterns. Discussion Although the incidence of OGCTs in the general population is quite low, its occurrence in multiple members of the same family and in families with TGCT suggests that a gene conferring susceptibility to GCTs may exist in some families.