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In brief
Atrazine, like oestrogen, disorganises laminin formation and reduces the number of germ cells and Sertoli cells in the developing testes of the tammar wallaby. This study suggests that interfering with the balance of androgen and oestrogen affects the integrity of laminin structure and testis differentiation.
Abstract
The herbicide atrazine was banned in Europe in 2003 due to its endocrine disrupting activity but remains widely used. The integrity of the laminin structure in fetal testis cords requires oestrogen signalling but overexposure to xenoestrogens in the adult can cause testicular dysgenesis. However, whether xenoestrogens affect laminin formation in developing testes has not been investigated. Here we examined the effects of atrazine in the marsupial tammar wallaby during early development and compare it with the effects of the anti-androgen flutamide, oestrogen, and the oestrogen degrader fulvestrant. The tammar, like all marsupials, gives birth to altricial young, allowing direct treatment of the developing young during the male programming window (day 20–40 post partum (pp)). Male pouch young were treated orally with atrazine (5 mg/kg), flutamide (10 mg/kg), 17β-oestradiol (2.5 mg/kg) and fulvestrant (1 mg/kg) daily from day 20 to 40 pp. Distribution of laminin, vimentin, SOX9 and DDX4, cell proliferation and mRNA expression of SRY, SOX9, AMH, and SF1 were examined in testes at day 50 post partum after the treatment. Direct exposure to atrazine, flutamide, 17β-oestradiol, and fulvestrant all disorganised laminin but had no effect on vimentin distribution in testes. Atrazine reduced the number of germ cells and Sertoli cells when examined at day 40–50 pp and day 20 to 40 pp, respectively. Both flutamide and fulvestrant reduced the number of germ cells and Sertoli cells. Atrazine also downregulated SRY expression and impaired SOX9 nuclear translocation. Our results demonstrate that atrazine can compromise normal testicular differentiation during the critical male programming window.
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Valosin-containing protein (VCP; aka p97), a member of the AAA (ATPases Associated with various cellular Activities) family, has been associated with a wide range of cellular functions. While previous evidence has shown its presence in mammalian sperm, our study unveils its function in mouse sperm. Notably, we found that mouse VCP does not undergo tyrosine phosphorylation during capacitation and exhibits distinct localization patterns. In the sperm head, it resides within the equatorial segment and, following acrosomal exocytosis, it is released and cleaved. In the flagellum, VCP is observed in the principal and midpiece. Furthermore, our research highlights a unique role for VCP in the cAMP/PKA pathway during capacitation. Pharmacological inhibition of sperm VCP led to reduced intracellular cAMP levels that resulted in decreased phosphorylation in PKA substrates and tyrosine residues and diminished fertilization competence. Our results show that in mouse sperm, VCP plays a pivotal role in regulating cAMP production, probably by the modulation of soluble adenylyl cyclase activity.
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health,Shandong University, Jinan, Shandong, China
Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
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Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
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Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
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Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
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Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
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Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
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Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, China
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In brief
Ovarian aging results in reactive oxygen species accumulation and mitochondrial deterioration. During the aging process, GRSF1 deficiency attenuates mitochondrial function in aging granulosa cells.
Abstract
Ovarian aging critically influences reproductive potential, with a marked decrease in oocyte quality and quantity and an increase in oxidative stress and mitochondrial dysfunction. This study elucidates the role of guanine-rich RNA sequence binding factor 1 (GRSF1) in the aging of ovarian granulosa cells (GCs). We observed a significant reduction in GRSF1 within GCs correlating with patient age, utilizing clinical samples from IVF patients. Using an siRNA-mediated knockdown technique, we established that diminished GRSF1 expression exacerbates mitochondrial dysfunction, elevates reactive oxygen species, and impairs ATP production. Furthermore, RNA immunoprecipitation revealed GRSF1’s interaction with superoxide dismutase 2 (SOD2) mRNA, a key antioxidant enzyme, suggesting a mechanism whereby GRSF1 modulates oxidative stress. Downregulation of SOD2 reversed the protective effects of GRSF1 overexpression on mitochondrial function. These insights into the role of GRSF1 in ovarian aging may guide the development of interventions to improve fertility outcomes in advanced age.
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Department of Health Promotion in Nursing and Midwifery, Innovative Nursing for Life Course, Graduate School of Nursing, Chiba University, Inohana, Chuo-ku, Chiba-shi, Chiba, Japan
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In brief
Mammalian spermatozoa actively generate reactive oxygen species (ROS) during capacitation, a maturational process necessary for fertilization in vivo. This study shows that hypotaurine, a precursor of taurine present in the oviduct, is incorporated and concentrated in hamster sperm cells via the taurine transporter, TauT, for cytoprotection against self-produced ROS.
Abstract
To achieve fertilization competence, mammalian spermatozoa undergo capacitation, during which they actively generate reactive oxygen species (ROS). Therefore, mammalian spermatozoa must protect themselves from these self-generated ROS. The mammalian oviductal fluid is rich in hypotaurine, a taurine precursor, which reportedly protects mammalian spermatozoa, including those of hamsters, from ROS; however, its precise mechanism remains unknown. This study aimed to elucidate the mechanism underlying hypotaurine-mediated protection of spermatozoa from ROS using hamsters, particularly focusing on the taurine/hypotaurine transporter TauT. The effect of hypotaurine on sperm motility and ROS levels was tested using sperm motility analysis and the CellROX dye and luminol assays. RNA sequencing analysis was performed to verify TauT expression. We found that hypotaurine was necessary for maintaining sperm motility and hyperactivated motility. Hypotaurine did not scavenge extracellular ROS but lowered intracellular ROS levels and was incorporated and concentrated in hamster spermatozoa. TauT was detected at both mRNA and protein levels. β-Alanine blocked hypotaurine transport, increased intracellular ROS levels, and inhibited hyperactivation. Elimination of Na+ or Cl− ions inhibited hypotaurine transport and increased intracellular ROS levels. Thus, these results indicated that hamster spermatozoa incorporated and concentrated hypotaurine in sperm cells via TauT to protect themselves from self-generated ROS.
State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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Shandong Medicine and Health Key Laboratory of Birth Defect Prevention and Genetic Medicine, Jinan, Shandong, China
Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Jinan, Shandong, China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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In brief
Abnormal glucose metabolism may be involved in the pathogenesis of endometriosis. The present study identifies that highly expressed H19 leads to increased aerobic glycolysis and histone lactylation levels in endometriosis.
Abstract
Previous studies from our group and others have shown increased IncRNA H19 expression in both the eutopic endometrium and the ectopic endometriosis tissue during endometriosis. In this study, we use immunofluorescence, immunohistochemistry, and protein quantification to determine that levels of aerobic glycolysis and histone lactylation are increased in endometriosis tissues. In human endometrial stromal cells, we found that high H19 expression resulted in abnormal glucose metabolism by examining the levels of glucose, lactate, and ATP and measuring protein levels of enzymes that participate in glycolysis. At the same time, immunofluorescence and western blotting demonstrated increased histone lactylation in H19 overexpressing cells. Altering aerobic glycolysis and histone lactylation levels through the addition of sodium lactate and 2-deoxy-d-glucose demonstrated that increased aerobic glycolysis and histone lactylation levels resulted in enhanced cell proliferation and cell migration, contributing to endometriosis. To validate these findings in vivo, we constructed an endometriosis mouse model, demonstrating similar changes in endometriosis tissues in vivo. Both aerobic glycolysis and histone lactylation levels were elevated in endometriotic lesions. Taken together, these data demonstrate elevated expression levels of H19 in endometriosis patients promote abnormal glucose metabolism and elevated histone lactylation levels in vivo, enhancing cell proliferation and migration and promoting the progression of endometriosis. Our study provides a functional link between H19 expression and histone lactylation and glucose metabolism in endometriosis, providing new insights into disease mechanisms that could result in novel therapeutic approaches.
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The pituitary gland is crucial for regulating many physiological systems, including reproduction. Clear evidence suggests pituitary function could be impaired by exposure to endocrine disrupting chemicals (EDCs). Humans and animals are exposed to EDCs throughout life but exposure during critical periods when the pituitary is developing could have more damaging consequences. In this review we summarize the development of the pituitary gland, including the impact of hormone signals, and describe how in vivo EDC exposure during development might alter pituitary function. These include changes in pituitary hormone, mRNA and protein expression levels, as well as pituitary cell number and population balance. We focus on reproductive hormone-producing cells as well as the other endocrine and pituitary stem/progenitor cells. We reveal the current gaps in knowledge and suggest future directions in terms of understanding effects of developmental EDC exposure directly on the pituitary gland.
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Over the past 50 years, there has been a concerning decline in male reproductive health and an increase in male infertility which is now recognised as a major health concern globally. While male infertility can be linked to some genetic and lifestyle factors, these do not fully explain the rate of declining male reproductive health. Increasing evidence from human and animal studies suggests that exposure to chemicals found ubiquitously in the environment may in part play a role. Many studies on chemical exposure, however, have assessed the effects of exposure to individual environmental chemicals (ECs), usually at levels not relevant to everyday human exposure. There is a need for study models which reflect the ‘real-life’ nature of EC exposure. One such model is the biosolids-treated pasture (BTP) sheep model which utilises biosolids application to agricultural land to examine the effects of exposure to low-level mixtures of chemicals. Biosolids are the by-product of the treatment of wastewater from industrial and domestic sources and so their composition is reflective of the ECs to which humans are exposed. Over the last 20 years, the BTP sheep model has published multiple effects on offspring physiology including consistent effects on the male reproductive system in fetal, neonatal, juvenile, and adult offspring. This review focuses on the evidence from these studies which strongly suggests that low-level EC exposure during gestation can alter several components of the male reproductive system and highlights the BTP model as a more relevant model to study real-life EC exposure effects.
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Nutrition College, Universidade Federal de Pelotas, Pelotas, RS, Brazil
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Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
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Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
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In brief
Recent reports suggest a relationship between ovarian inflammation and functional declines, although it remains unresolved if ovarian inflammation is the cause or consequence of ovarian aging. In this review, we compile the available literature in this area and point to several current knowledge gaps that should be addressed through future studies.
Abstract
Ovarian aging results in reduced fertility, disrupted endocrine signaling, and an increased burden of chronic diseases. The factors contributing to the natural decline of ovarian follicles throughout reproductive life are not fully understood. Nevertheless, local inflammation may play an important role in driving ovarian aging. Inflammation progressively rises in aged ovaries during the reproductive window, potentially affecting fertility. In addition to inflammatory markers, recent studies show an accumulation of specific immune cell populations in aging ovaries, particularly lymphocytes. Other hallmarks of the aging ovary include the formation and accumulation of multinucleated giant cells, increased collagen deposition, and increased markers of cellular senescence. Collectively, these changes significantly impact the quantity and quality of ovarian follicles and oocytes. This review explores recent literature on the alterations associated with inflammation, fibrosis, cell senescence, and the accumulation of immune cells in the aging ovary.
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In brief
Chromosome missegregation and declining energy metabolism are considered to be unrelated features of oocyte ageing that contribute to poor reproductive outcomes. Given the bioenergetic cost of chromosome segregation, we propose here that altered energy metabolism during ageing may be an underlying cause of age-related chromosome missegregation and aneuploidy.
Abstract
Advanced reproductive age in women is a major cause of infertility, miscarriage and congenital abnormalities. This is principally caused by a decrease in oocyte quality and developmental competence with age. Oocyte ageing is characterised by an increase in chromosome missegregation and aneuploidy. However, the underlying mechanisms of age-related aneuploidy have not been fully elucidated and are still under active investigation. In addition to chromosome missegregation, oocyte ageing is also accompanied by metabolic dysfunction. In this review, we integrate old and new perspectives on oocyte ageing, chromosome segregation and metabolism in mammalian oocytes and make direct links between these processes. We consider age-related alterations to chromosome segregation machinery, including the loss of cohesion, microtubule stability and the integrity of the spindle assembly checkpoint. We focus on how metabolic dysfunction in the ageing oocyte disrupts chromosome segregation machinery to contribute to and exacerbate age-related aneuploidy. More specifically, we discuss how mitochondrial function, ATP production and the generation of free radicals are altered during ageing. We also explore recent developments in oocyte metabolic ageing, including altered redox reactions (NAD+ metabolism) and the interactions between oocytes and their somatic nurse cells. Throughout the review, we integrate the mechanisms by which changes in oocyte metabolism influence age-related chromosome missegregation.
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Departments of Psychiatry & Behavioral Sciences, and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Division of Endocrinology, Nationwide Children’s Hospital, Columbus, Ohio, USA
Center for Biobehavioral Health, Abigail Wexner Research Institute, Columbus, Ohio, USA
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In brief
Transgender and gender diverse (TGD) youth demonstrate low utilization of fertility preservation before medical and surgical gender-affirming interventions. However, a significant number of TGD youth have goals for parenthood and/or recognize that their attitude toward future family-building goals may change over time. In this narrative review, we conclude that TGD young people should have ongoing opportunities to discuss their family-building goals and options for fertility preservation. Validated decision tools can help facilitate these discussions.
Abstract
The number of transgender and gender diverse (TGD) youth seeking care continues to increase, necessitating comprehensive counseling about potential long-term effects of gender-affirming medical interventions on fertility. The objective of this narrative review was to examine fertility-related knowledge, attitudes, and decision-making (including factors influencing decisions, decision regret, and decision tools) among TGD youth. We searched PubMed, PsycInfo, and Google Scholar for original, peer-reviewed research investigating TGD youth attitudes and knowledge of fertility and fertility preservation, perspectives on fertility counseling and fertility preservation decision-making, as well as fertility-related decision tools. We reviewed 106 studies; eight were included in this narrative review. Four studies assessed TGD youth knowledge and attitudes of fertility and fertility preservation, three examined perspectives on fertility counseling and fertility preservation decision-making, and three discussed development of decision tools. Key findings were that: (1) many TGD youth are aware of potential fertility-related impacts of gender-affirming treatments, but there are still unmet informational needs, (2) some TGD youth report an interest in future biological parenthood, and of those who are not currently interested in biological parenthood, many acknowledge their desires may change over time, (3) ongoing discussions about fertility and fertility preservation are critical, and (4) decision tools are in development. In conclusion, TGD youth and their caregivers should receive ongoing, comprehensive fertility counseling and decision tools may be helpful to facilitate these discussions and decisions in each youth’s gender-affirming care journey.
