- Proceedings of the National Academy of Sciences of the United States of America
- Published about 1 year ago
Concern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named “compensated hypogonadism,” a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism.
Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1-F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the “plastics” or “lower dose plastics” mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.
To conduct a nationwide study of associations between removal of all ovarian tissue versus conservation of at least one ovary at the time of hysterectomy and important health outcomes (ischaemic heart disease, cancer, and all cause mortality).
Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5.
Along with the increasing application of nanoparticles (NPs) in many walks of life, environmental exposure to NPs has raised considerable health concerns. When NPs enter a pregnant woman’s body through inhalation, venous injection, ingestion or skin permeation, maternal toxic stress reactions such as reactive oxygen species (ROS), inflammation, apoptosis and endocrine dyscrasia are induced in different organs, particularly in the reproductive organs. Recent studies have shown that NPs disturb the developing oocyte by invading the protective barrier of theca cells, granulosa cell layers and zona pellucida. NPs disrupt sex hormone levels through the hypothalamic-pituitary-gonadal axis or by direct stimulation of secretory cells, such as granule cells, follicle cells, thecal cells and the corpus luteum. Some NPs can cross the placenta into the fetus by passive diffusion or endocytosis, which can trigger fetal inflammation, apoptosis, genotoxicity, cytotoxicity, low weight, reproductive deficiency, nervous damage, and immunodeficiency, among others. The toxicity of these NPs depend on their size, dosage, shape, charge, material and surface-coating. We summarize new findings on the toxic effect of various NPs on the ovary and on oogenesis and embryonic development. Meanwhile, we highlight the problems that need to be studied in the future. This manuscript will also provide valuable guidelines for protecting the female reproductive system from the toxicity of NPs and provide a certain reference value for NP application in the area of ovarian diseases.
Safe clinical hormone replacement (HR) will likely become increasingly important in the growing populations of aged women and cancer patients undergoing treatments that ablate the ovaries. Cell-based HRT (cHRT) is an alternative approach that may allow certain physiological outcomes to be achieved with lower circulating hormone levels than pharmacological means due to participation of cells in the hypothalamus-pituitary-ovary feedback control loop. Here we describe the in vivo performance of 3D bioengineered ovarian constructs that recapitulate native cell-cell interactions between ovarian granulosa and theca cells as an approach to cHRT. The constructs are fabricated using either Ca++ or Sr++ to crosslink alginate. Following implantation in ovariectomized (ovx) rats, the Sr++-cross-linked constructs achieve stable secretion of hormones during 90 days of study. Further, we show these constructs with isogeneic cells to be effective in ameliorating adverse effects of hormone deficiency, including bone health, uterine health, and body composition in this rat model.
The development of new method to cryopreserve human ovarian cortex tissues without damage is needed for the improvement of quality of life (QOL) of female cancer patients. Here we show novel cryopreservation method of human ovarian cortex tissues by using supercooling (S.C.) procedure. Our method will be helpful in order to preserve fertility of female cancer patients.
The endocrine system dynamically controls tissue differentiation and homeostasis, but has not been studied using dynamic tissue culture paradigms. Here we show that a microfluidic system supports murine ovarian follicles to produce the human 28-day menstrual cycle hormone profile, which controls human female reproductive tract and peripheral tissue dynamics in single, dual and multiple unit microfluidic platforms (Solo-MFP, Duet-MFP and Quintet-MPF, respectively). These systems simulate the in vivo female reproductive tract and the endocrine loops between organ modules for the ovary, fallopian tube, uterus, cervix and liver, with a sustained circulating flow between all tissues. The reproductive tract tissues and peripheral organs integrated into a microfluidic platform, termed EVATAR, represents a powerful new in vitro tool that allows organ-organ integration of hormonal signalling as a phenocopy of menstrual cycle and pregnancy-like endocrine loops and has great potential to be used in drug discovery and toxicology studies.
Temperature-dependent sex determination (TSD) was described nearly 50 years ago. Researchers have since identified many genes that display differential expression at male- versus female-producing temperatures. Yet, it is unclear whether these genes are 1) involved in sex determination per se, 2) downstream effectors involved in differentiation of ovaries and testes, or 3) thermo-sensitive but unrelated to gonad development. Here we present multiple lines of evidence linking CIRBP to sex determination in the snapping turtle, Chelydra serpentine. We demonstrate significant associations between a single nucleotide polymorphism (SNP) (c63A>C) in CIRBP, transcript levels in embryonic gonads during specification of gonad fate, and sex in hatchlings from a thermal regime that produces mixed sex ratios. The A allele was induced in embryos exposed to a female-producing temperature, while expression of the C allele did not differ between female- and male-producing temperatures. In accord with this pattern of temperature-dependent, allele-specific expression, AA homozygotes were more likely to develop ovaries than AC heterozygotes, which, in turn, were more likely to develop ovaries than CC homozygotes. Multiple regression using SNPs in CIRBP and adjacent loci suggests that c63A>C may be the causal variant or closely linked to it. Differences in CIRBP allele frequencies among turtles from northern Minnesota, southern Minnesota, and Texas reflect small and large-scale latitudinal differences in TSD pattern. Finally, analysis of CIRBP protein localization reveals that CIRBP is in a position to mediate temperature effects on the developing gonads. Together, these studies strongly suggest that CIRBP is involved in determining the fate of the bipotential gonad.
Short stature and later maturation of youth artistic gymnasts are often attributed to the effects of intensive training from a young age. Given limitations of available data, inadequate specification of training, failure to consider other factors affecting growth and maturation, and failure to address epidemiological criteria for causality, it has not been possible thus far to establish cause-effect relationships between training and the growth and maturation of young artistic gymnasts. In response to this ongoing debate, the Scientific Commission of the International Gymnastics Federation (FIG) convened a committee to review the current literature and address four questions: (1) Is there a negative effect of training on attained adult stature? (2) Is there a negative effect of training on growth of body segments? (3) Does training attenuate pubertal growth and maturation, specifically, the rate of growth and/or the timing and tempo of maturation? (4) Does training negatively influence the endocrine system, specifically hormones related to growth and pubertal maturation? The basic information for the review was derived from the active involvement of committee members in research on normal variation and clinical aspects of growth and maturation, and on the growth and maturation of artistic gymnasts and other youth athletes. The committee was thus thoroughly familiar with the literature on growth and maturation in general and of gymnasts and young athletes. Relevant data were more available for females than males. Youth who persisted in the sport were a highly select sample, who tended to be shorter for chronological age but who had appropriate weight-for-height. Data for secondary sex characteristics, skeletal age and age at peak height velocity indicated later maturation, but the maturity status of gymnasts overlapped the normal range of variability observed in the general population. Gymnasts as a group demonstrated a pattern of growth and maturation similar to that observed among short-, normal-, late-maturing individuals who were not athletes. Evidence for endocrine changes in gymnasts was inadequate for inferences relative to potential training effects. Allowing for noted limitations, the following conclusions were deemed acceptable: (1) Adult height or near adult height of female and male artistic gymnasts is not compromised by intensive gymnastics training. (2) Gymnastics training does not appear to attenuate growth of upper (sitting height) or lower (legs) body segment lengths. (3) Gymnastics training does not appear to attenuate pubertal growth and maturation, neither rate of growth nor the timing and tempo of the growth spurt. (4) Available data are inadequate to address the issue of intensive gymnastics training and alterations within the endocrine system.