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Background: Certain phthalates can impair Leydig cell distribution and steroidogenesis in the fetal rat in utero, but it is unknown whether similar effects might occur in the human.Objectives: Our aim in this study was to investigate the effects of di(n-butyl) phthalate (DBP), or its metabolite monobutyl phthalate (MBP), on testosterone production and Leydig cell aggregation (LCA) in fetal testis explants from the rat and human, and to compare the results with in vivo findings for DBP-exposed rats. We also wanted to determine if DBP/MBP affects testosterone production in vivo in the neonatal male marmoset.Methods: Fetal testis explants obtained from the rat [gestation day (GD) 19.5] and from the human (15-19 weeks of gestation) were cultured for 24-48 hr with or without human chorionic gonadotropin (hCG) or 22R-hydroxy-cholesterol (22R-OH), and with or without DBP/MBP. Pregnant rats and neonatal male marmosets were dosed with 500 mg/kg/day DBP or MBP.Results: Exposure of rats in utero to DBP (500 mg/kg/day) for 48 hr before GD21.5 induced major suppression of intratesticular testosterone levels and cytochrome P450 side chain cleavage enzyme (P450scc) expression; this short-term treatment induced LCA, but was less marked than longer term (GD13.5-20.5) DBP treatment. In vitro, MBP (10[-3] M) did not affect basal or 22R-OH-stimulated testosterone production by fetal rat testis explants but slightly attenuated hCG-stimulated steroidogenesis; MBP induced minor LCA in vitro. None of these parameters were affected in human fetal testis explants cultured with 10[-3] M MBP for up to 48 hr. Because the in vivo effects of DBP/MBP were not reproduced in vitro in the rat, the absence of MBP effects in vitro on fetal human testes is inconclusive. In newborn (Day 2-7) marmosets, administration of a single dose of 500 mg/kg MBP significantly (p = 0.019) suppressed blood testosterone levels 5 hr later. Similar treatment of newborn co-twin male marmosets for 14 days resulted in increased Leydig cell volume per testis (p = 0.011), compared with co-twin controls; this is consistent with MBP-induced inhibition of steroidogenesis followed by compensatory Leydig cell hyperplasia/hypertrophy.Conclusions: These findings suggest that MBP/DBP suppresses steroidogenesis by fetal-type Leydig cells in primates as in rodents, but this cannot be studied in vitro. [ABSTRACT FROM AUTHOR]

Terephthalic acid (TPA) is a worldwide aromatic compound widely used to manufacture resins and the raw material for the polymerization reaction with ethylene glycol to produce polyethylene terephthalate, known as PET. The use of TPA extends to the synthesis of phthalates, plasticizers used in various industrialized products such as toys and cosmetics. The present study aimed to evaluate the testicular toxicity of terephthalic acid on male mice exposed in utero and during lactation to TPA in different developmental windows. The animals were treated intragastric with TPA at stock dispersal dosages corresponding to 0.0014 g/ml and 0.56 g/ml of TPA in 0.5% v/v carboxymethylcellulose as well as the control dose, composed solely of dispersion of carboxymethylcellulose (0.5% v/v). Four experimental windows were established: group I—treatment in utero, in the fetal period (gestational day—GD 10.5–18.5), with euthanasia at GD 18.5; group II—treatment in utero, in the fetal period (GD 10.5–18.5) and the lactational period (postnatal day (PND-15)), with euthanasia at 15 days; group III—treatment in utero in the fetal period (DG 10.5–18.5) with euthanasia at 70 days (age of sexual maturity, PND 70); group IV—treatment in utero, in the fetal period (GD 10.5–18.5) and the lactational period (PND-15), with euthanasia at 70 days (PND70). The results indicate that TPA changes the reproductive parameters (testicular weight, GI, penis size, and anogenital index) only at the dose of 0.56 g/ml in the fetal period. Data on the volumetric ratio of the testis elements show that the dispersion with the highest concentration of TPA significantly altered the blood vessel/capillary, lymphatic vessel, and connective tissue percentages. Only at the dose of 0.56 g/ml TPA was it effective in decreasing the Leydig and Sertoli cell numbers of the euthanized animals at GD 18.5. In group II, TPA increased the diameter and lumen of seminiferous tubules, which indicates that TPA accelerated the maturation process of Sertoli cells without changing the number and the nuclear volume of these cells. The Sertoli and Leydig cell numbers of the 70-day animals exposed to TPA in the gestational and lactational period were similar to the control. Therefore, the present study is the first in the literature to show that TPA presents a testicular toxicity during fetal (DG18.5) and postnatal life (PND15), without repercussion in adulthood (70 days). [ABSTRACT FROM AUTHOR]

Background: Despite advances in screening and therapy, breast cancer (BC) remains the predominant cancer in women globally. Dysregulation of microRNAs (miRNAs) is pivotal in carcinogenesis across various cancers, including BC. Evidence indicates that miR‐1307‐3p is upregulated in BC tumors, yet its target genes are not fully elucidated. This study aimed to explore how miR‐1307‐3p regulates BC proliferation, migration, invasion, and angiogenesis and to identify potential target genes. Methods: Basal miR‐1307‐3p levels were quantified in BC cell lines MDA‐MB‐231 and MCF‐7, as well as MCF‐10A using quantitative real‐time reverse transcription‐PCR (RT‐qPCR). The impact of miR‐1307‐3p inhibition on BC cell proliferation, migration, invasion, and angiogenesis was assessed. Nine miRNA‐target prediction databases identified potential miR‐1307‐3p targets. Target expression was validated using RT‐qPCR, Western blot, and dual‐luciferase reporter assays. MiR‐1307‐3p was overexpressed in MDA‐MB‐231 and MCF‐7 compared to MCF‐10A. Results: Inhibiting miR‐1307‐3p significantly reduced BC cell proliferation, migration, invasion, and angiogenesis. Bioinformatics analysis identified 17 potential miR‐1307‐3p targets, with protamine 2 (PRM2) overexpression confirmed via Western blot and dual‐luciferase assays. Conclusion: MiR‐1307‐3p overexpression in BC promotes proliferation, migration, invasion, and angiogenesis. PRM2 emerges as a novel miR‐1307‐3p target in BC. [ABSTRACT FROM AUTHOR]

Spontaneous cerebral vasomotion, characterized by ∼0.1 Hz rhythmic contractility, is crucial for brain homeostasis. However, our understanding of vasomotion is limited due to a lack of high-precision analytical methods to determine single vasomotion events at basal levels. Here, we developed a novel strategy that integrates a baseline smoothing algorithm, allowing precise measurements of vasodynamics and concomitant Ca2+ dynamics in mouse cerebral vasculature imaged by two-photon microscopy. We identified several previously unrecognized vasomotion properties under different physiological and pathological conditions, especially in ischemic stroke, which is a highly harmful brain disease that results from vessel occlusion. First, the dynamic characteristics between SMCs Ca2+ and corresponding arteriolar vasomotion are correlated. Second, compared to previous diameter-based estimations, our radius-based measurements reveal anisotropic vascular movements, enabling a more precise determination of the latency between smooth muscle cell (SMC) Ca2+ activity and vasoconstriction. Third, we characterized single vasomotion event kinetics at scales of less than 4 seconds. Finally, following pathological vasoconstrictions induced by ischemic stroke, vasoactive arterioles entered an inert state and persisted despite recanalization. In summary, we developed a highly accurate technique for analyzing spontaneous vasomotion, and our data suggested a potential strategy to reduce stroke damage by promoting vasomotion recovery. [ABSTRACT FROM AUTHOR]

Introduction: The increasing prevalence of infertility in male dogs in clinical practice mirrors current trends seen in human medicine. Acquired infertility is notably more common in dogs compared to congenital causes, with conditions such as testicular degeneration leading to irreversible loss of fertility. Current diagnostic methods for testicular degeneration, such as histopathological and cytological examinations, rely on testicular biopsy or fine needle aspiration, making them less feasible for routine use. Anti-Müllerian hormone (AMH), produced by Sertoli cells, has emerged as a potential alternative biomarker for testicular health, which can be measured in serum. This study evaluates AMH as a potential marker for testicular degeneration, using cryptorchid dogs as models for impaired fertility and altered testicular histology. Methods: The relationship between serum AMH levels and AMH tissue expression with impaired spermatogenesis and altered histology was investigated. Serum AMH levels were determined in intact, cryptorchid, and castrated individuals using an immuno-enzymatic ELISA kit and compared between subgroups based on testicular location. Tissue AMH immuno-expression was differentially quantified in two regions of interest (ROIs), the interstitial space and the seminiferous tubule, in both descended and retained gonads. Furthermore, testicles were analyzed using histomorphometric analysis in seminiferous tubules, while spermatogenesis was evaluated using the Johnsen score. Results: Serum AMH levels were positively correlated with AMH expression assessed in both interstitial space (ρ = 0.494, p ≤ 0.01) and seminiferous tubules (ρ = 0.610, p ≤ 0.001). Conversely, serum AMH levels showed a negative correlation with the seminiferous tubule area (ρ = -0.435, p ≤ 0.05). Smaller seminiferous tubule areas were linked to increased AMH reactivity in both seminiferous tubules (ρ = -0.774, p ≤ 0.001) and interstitial space (ρ = -0.725, p ≤ 0.001). Additionally, lower Johnsen scores were associated with higher serum AMH levels (ρ = -0.537, p ≤ 0.01) and elevated AMH expression in both seminiferous tubules (ρ = -0.756, p ≤ 0.001) and interstitial space (ρ = -0.679, p ≤ 0.001). Discussion: Our results suggest that higher serum levels and tissue expression of AMH are linked to smaller seminiferous tubules and poorer Johnsen scores, reflecting degenerative changes and Sertoli cell dysfunction in retained testicles. Given the similarities in the mechanisms that increase AMH levels in both cryptorchid and non-cryptorchid testicles affected by testicular degeneration, this study recommends using AMH as a marker for diagnosing testicular degeneration in dogs. [ABSTRACT FROM AUTHOR]

Background: Androgens are essential hormones for testicular development and the maintenance of male fertility. Environmental factors, stress, aging, and psychological conditions can disrupt androgen production, impacting the androgen signaling pathway and consequently spermatogenesis. Within the testes, testosterone is produced by Leydig cells and acts on Sertoli cells by activating the androgen receptor (AR), which then translocates to the nucleus to function as a transcription factor. Despite clinical correlations between low testosterone levels and diminished sperm quality, the precise mechanism remains unclear. Methods: This study explores the hypothesis that reduced androgen levels impair Sertoli cell function by disrupting AR transcriptional regulation. Using an androgen blockade model with enzalutamide, we investigated the impact of low androgen levels on AR target genes in Sertoli cells through ChIP-seq and RNA-seq assays. Results: Our results reveal that androgen blockage increases AR enrichment on the promoter region of Wee1, promoting Wee1 expression, while decreasing binding to the promoter region of Lfng, inhibiting its expression. Increased WEE1 protein inhibits Sertoli cell proliferation, whereas reduced LFNG affects Notch modification, leading to decreased production of glial cell line-derived neurotrophic factor (GDNF), a key growth factor for spermatogonial stem cell self-renewal. Conclusions: These findings provide new insights into the molecular mechanisms by which low androgen levels interfere with Sertoli cell functions, offering novel perspectives for the clinical treatment of male reproductive disorders. [ABSTRACT FROM AUTHOR]

ARL13B is a small regulatory GTPase that controls ciliary membrane composition in both motile cilia and non-motile primary cilia. In this study, we investigated the role of ARL13B in the efferent ductules, tubules of the male reproductive tract essential to male fertility in which primary and motile cilia co-exist. We used a genetically engineered mouse model to delete Arl13b in efferent ductule epithelial cells, resulting in compromised primary and motile cilia architecture and functions. This deletion led to disturbances in reabsorptive/secretory processes and triggered an inflammatory response. The observed male reproductive phenotype showed significant variability linked to partial infertility, highlighting the importance of ARL13B in maintaining a proper physiological balance in these small ducts. These results emphasize the dual role of both motile and primary cilia functions in regulating efferent duct homeostasis, offering deeper insights into how cilia related diseases affect the male reproductive system. The deletion of ARL13B disrupts primary and motile cilia structure in the efferent ductules, leading to impaired homeostasis, inflammation, and subfertility. This highlights ARL13B's critical role in male reproductive physiology. [ABSTRACT FROM AUTHOR]

Background: Obesity poses a significant global health challenge, with profound implications for women's reproductive health. The relationship between ovarian reserve and body mass index (BMI) remains a subject of debate. While obesity is generally associated with poorer outcomes in assisted reproductive technology (ART), the evidence remains inconclusive. This study aimed to investigate the effect of pre-pregnancy BMI on ovarian reserve and ART outcomes in infertile patients. Methods: We conducted a retrospective cohort study involving women who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) procedures at Tongji Hospital between 2016 and 2023. The study included 30,746 initial fresh cycles and 5,721 singleton deliveries. Patients were stratified by age and further categorized into four BMI groups: lean (< 18.5 kg/m²), normal weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²), and obese (≥ 30.0 kg/m²). The primary endpoints of the study were pregnancy and perinatal outcomes. To explore the association between BMI and these outcomes, we adjusted for relevant confounding factors and utilized multivariate linear regression models, complemented by multifactorial logistic regression analyses. Results: Anti-Müllerian hormone (AMH) levels were significantly lower in the overweight and obese groups compared to the normal weight group. After adjusting for age, a negative correlation was found between AMH and BMI in the age subgroups of 20–30 and 30–35 years. Among women aged 20–35 years, those in the overweight and obese groups had significantly fewer retrieved oocytes, mature oocytes, and two-pronuclear (2PN) embryos than their normal weight counterparts. Despite these differences, pregnancy outcomes in the overweight and obese groups were comparable to those in the normal weight group across all age categories. Additionally, obesity was linked to an increased risk of gestational diabetes mellitus, hypertensive disorders of pregnancy, and macrosomia. Conclusions: An age-related decrease in AMH levels was evident with increasing BMI. Although being overweight or obese is associated with poorer embryo and perinatal outcomes, it does not seem to have a substantial impact on fertility. [ABSTRACT FROM AUTHOR]

Recent studies on male infertility reveal a growing worry: more infertile men are dealing with inflammation in the testis. Analyzing testicular biopsies from infertile men highlights a significant presence of inflammation. This connection, supported by clinical and pathological evidence, emphasizes that testicular inflammation hampers sperm production, leading to lasting declines in sperm count and quality. However, the exact reasons behind male infertility due to orchitis, a type of testicular inflammation, are still uncertain. Understanding these fundamental aspects of molecular signals and cellular mechanisms in testicular inflammation is crucial. Our review delves into recent literature with a dual objective: elucidating potential mechanisms involving immune cells, non-immune cells, and cytokines that link orchitis to male infertility, while also paving the way for precise interventions and solutions to address the challenges of male infertility. [ABSTRACT FROM AUTHOR]

Anti-Müllerian hormone (AMH) is a peptide belonging to the transforming growth factor beta superfamily and acts exclusively through its receptor type 2 (AMHR2). From the 8th week of pregnancy, AMH is produced by Sertoli cells, and from the 23rd week of gestation, it is produced by granulosa cells of the ovary. AMH plays a critical role in regulating gonadotropin secretion, ovarian tissue responsiveness to pituitary hormones, and the pathogenesis of polycystic ovarian syndrome. It inhibits the transition from primordial to primary follicles and is considered the best marker of ovarian reserve. Therefore, measuring AMH concentration of the hormone is valuable in managing assisted reproductive technologies. AMH was initially discovered through its role in the degeneration of Müllerian ducts in male fetuses. However, due to its ability to inhibit the cell cycle and induce apoptosis, it has also garnered interest in oncology. For example, antibodies targeting AMHR2 are being investigated for their potential in diagnosing and treating various cancers. Additionally, AMH is present in motor neurons and functions as a protective and growth factor. Consequently, it is involved in learning and memory processes and may support the treatment of Alzheimer's disease. This review aims to provide a comprehensive overview of the biology of AMH and its role in both endocrinology and oncology. [ABSTRACT FROM AUTHOR]

Spermatogonial stem cells (SSCs) play a crucial role in the male reproductive system, responsible for maintaining continuous spermatogenesis. The microenvironment or niche of SSCs is a key factor in regulating their self-renewal, differentiation and spermatogenesis. This microenvironment consists of multiple cell types, extracellular matrix, growth factors, hormones and other molecular signals that interact to form a complex regulatory network. This review aims to provide an overview of the main components of the SSCs microenvironment, explore how they regulate the fate decisions of SSCs, and discuss the potential impact of microenvironmental abnormalities on male reproductive health. [ABSTRACT FROM AUTHOR]

A significant consequence of climate change is the rising incidence of wildfires. When wildfires occur close to wine grape (Vitis vinifera) production areas, smoke-derived volatile phenolic compounds can be taken up by the grape berries, negatively affecting the flavor and aroma profile of the resulting wine and compromising the production value of entire vineyards. Evidence for the permeation of smoke-associated compounds into grape berries has been provided through metabolomics; however, the basis for grapevines' response to smoke at the gene expression level has not been investigated in detail. To address this knowledge gap, we employed time-course RNA sequencing to observe gene expression-level changes in grape berries in response to smoke exposure. Significant increases in gene expression (and enrichment of gene ontologies) associated with detoxification of reactive compounds, maintenance of redox homeostasis, and cell wall fortification were observed in response to smoke. These findings suggest that the accumulation of volatile phenols from smoke exposure activates mechanisms that render smoke-derived compounds less reactive while simultaneously fortifying intracellular defense mechanisms. The results of this work lend a better understanding of the molecular basis for grapevines' response to smoke and provide insight into the origins of smoke-taint-associated flavor and aroma attributes in wine produced from smoke-exposed grapes. [ABSTRACT FROM AUTHOR]

Introduction: Over the past few decades, there has been growing concern about the concurrent trends of increasing Autism Spectrum Disorder (ASD) prevalence and declining sperm quality. These trends represent significant public health challenges that warrant thorough investigation of their underlying causes and implications. Objectives: The primary objectives of this study are to analyze trends in ASD prevalence and sperm quality parameters from 2000 to 2024, assess the statistical significance and effect size of these trends, explore potential correlations between ASD prevalence and sperm quality parameters, and identify significant predictors among sperm quality parameters that influence ASD prevalence. Methods: This study employed a longitudinal approach using multiple regression, time series analysis, ANOVA, Principal Component Analysis (PCA), hierarchical clustering, logistic regression, and cross-correlation analysis. Data on ASD prevalence were sourced from the CDC Autism and Developmental Disabilities Monitoring Network, while sperm quality data were collected from various published studies. Results: The findings reveal significant negative associations between ASD prevalence and sperm quality parameters such as sperm concentration and motility, suggesting that better sperm quality is linked to lower ASD rates. Conversely, parameters like sperm DNA fragmentation (SDF), volume of ejaculate, pH level, and semen viscosity show positive associations with ASD prevalence, indicating higher values in these parameters correlate with higher ASD rates. Conclusion: The study highlights the importance of maintaining reproductive health to potentially mitigate ASD risk and calls for further research to elucidate the underlying mechanisms driving these trends. These findings support the hypothesis that reproductive health factors play a crucial role in ASD etiology and suggest potential biological markers for assessing ASD risk. [ABSTRACT FROM AUTHOR]

Background: Today, several bioinformatics tools are available for analyzing restriction fragment length data. RFLP-kenzy is a new bioinformatic tool for identifying restriction key enzyme that cut at least 1 sequence and a maximum of n-1 sequence. Results: This bioinformatic tool helps researchers to select appropriate enzymes that yield different RFLP patterns, especially from overly identical sequences with single nucleotide mutation or other small variations. By using RFLP-kenzy, multiple DNA sequences could be analyzed simultaneously and the key enzymes list is provided. The present paper also demonstrates the ability of RFLP-kenzy to identify the key enzymes through the analysis of 16S rRNA sequences and the complete genome of various genera of microorganisms. Conclusion: From the results, several key enzymes were provided indicating the importance of this new tool in the selection of appropriate restriction enzymes. [ABSTRACT FROM AUTHOR]

Introduction: Tamoxifen is the most frequently prescribed therapy for estrogen positive breast cancer. The duration of a therapeutic course might range between five to ten years. The purpose of this study is to examine histological reactions to Tamoxifen on retinas of adult female albino rats and the potential beneficial impact of melatonin versus lutein. Material and Methods: Sixty adult female albino rats were randomly divided into 6 groups. Control group (I), melatonin administered group (II) rats obtained daily doses of melatonin (10 mg/kg), Lutein administered group (III) rats obtained lutein daily (50 mg/kg), Tamoxifen administered group (IV) rats obtained daily Tamoxifen (5mg/kg), Tamoxifen and melatonin treated group (V), Tamoxifen and lutein treated group (VI) rats received the aforementioned doses. At termination of the study (4 weeks), the animals were anesthetized, sacrificed, and retinal samples were collected for histological, immunohistochemical, and electron microscopic examination. Results: Tamoxifen was found to be deleterious to retinal tissue. Both total retinal thickness and number of ganglion cells showed an extremely significant reduction. There was a significant rise in GFAP and Caspase-3 immunohistochemical reactivity. Ultrastructural alterations revealed degeneration of pigmented epithelium, distortion of photoreceptors, degeneration of outer and inner nuclear layer cells with small shrunken nuclei, intercellular gap expanding, and mitochondrial degeneration. Ganglion cells have notched, irregular nuclei and degraded mitochondria. Coadministration of Lutein exhibited significantly retinal tissue protection than melatonin. Conclusion: Lutein has a greater protective effect on retinal tissue than melatonin against the potentially harmful effects of Tamoxifen. Patients on long term or high dose tamoxifen therapy were recommended to have regular follow up for possible retinal changes. More studies were recommended on the protective effects of lutein on patients receiving tamoxifen therapy. Various antioxidants in the market should be taken after medical consultation to take benefit of them and avoid their hazardous effects. [ABSTRACT FROM AUTHOR]

Background & objectives: Notably, 17-hydroxy progesterone (17-OHP) (17-OHP) is a precursor for testosterone (T) synthesis, and intratesticular testosterone (ITT) is essential for spermatogenesis. Varicocele (Vx) has an estimated prevalence of 15% in the general population and 35% in those with primary infertility. We aimed to evaluate the correlation between changes of serum 17-OHP after sub-inguinal micro-varicocelectomy and improvement of semen parameters. Patients and methods: The current prospective study included 45 infertile men attending the andrology clinic form February 2021 to August 2021. Two semen analyses and hormonal profile were evaluated. Colored duplex ultasonography (CDUS) was done in standing and supine position for accurate measurements of testicular volumes and confirmation of Vx. Patients underwent sublinguinal micro-varicocelectomy using a surgical microscope HB Surgitech. We followed them prospectively up for three months following micro-varicocelectomy with serum TT and 17-OHP. Results: Sperm concentration improved significantly from 8.36 ± 5.04 million/ml to 12.52 ± 8.42 million/ml after 3 months following sub-inguinal micro-varicocelectomy (p = 0.001), with normalization of concentration in 15/45 (33%) patients. Total motility did not improve significantly but progressive motility improved significantly from 8.62 ± 8.74% to 16.24 ± 14.45% (p = 0.001). Abnormal forms significantly declined from 96.67 ± 2.03% to 95.75 ± 2.47% (p = 0.009). Serum 17 OHP and 17 OHP/total testosterone (TT) improved significantly from 1.21 ± 0.45 ng/ml and 0.26 ± 0.09 to 1.42 ± 0.76 ng/ml and 0.3 ± 0.16 (p = 0.013, p = 0.004), respectively, while serum TT did not improve significantly. A significant correlation was found between improvement in sperm concentration and both serum 17 OHP and 17 OHP/TT ratio (p = 0.001, p = 004). Furthermore, change in abnormal sperm forms showed significant correlations with changes in both 17-OHP and 17-OHP/TT. Conclusions: 17 OHP and 17OHP/ TT ratio can be used as biomarkers to detect improvement in semen parameters following sub-inguinal micro-varicocelectomy. [ABSTRACT FROM AUTHOR]

Concerns regarding man‐made organic chemicals pervading our ecosystem and having adverse and detrimental effects upon organisms, including man, have now been studied for several decades. Since the 1970s, some environmental pollutants were identified as having endocrine disrupting affects. These endocrine disrupting chemicals (EDC) were initially shown to have estrogenic or anti‐estrogenic properties and some were also shown to bind to a variety of hormone receptors. However, since the 1990s it has also been identified that many of these EDC additionally, have the ability of causing abnormal alterations in Ca2+ signalling pathways (also commonly involved in hormone signalling), leading to exaggerated elevations in cytosolic [Ca2+] levels, that is known to cause activation of a number of cell death pathways. The major emphasis of this review is to present a personal perspective of the evidence for some types of EDC, specifically alkylphenols and brominated flame retardants (BFRs), causing direct effects on Ca2+ transporters (mainly the SERCA Ca2+ ATPases), culminating in acute cytotoxicity and cell death. Evidence is also presented to indicate that this Ca2+ATPase inhibition, which leads to abnormally elevated cytosolic [Ca2+], as well as a decreased luminal ER [Ca2+], which triggers the ER stress response, are both involved in acute cytotoxicity. [ABSTRACT FROM AUTHOR]

Pratylenchus neglectus and P. thornei are among the most destructive root lesion nematodes of wheat in the Pacific Northwest, United States of America and throughout the world. The aim of this study was to determine whether both nematode species were similar in their ability to induce defense genes in roots of wheat genotype Scarlet, and whether a combination of both species induced a different pattern of gene induction than each species alone. The long-term aspect of the research was to identify nematode-inducible promoters for deploying defense genes in roots in breeding programs. The root transcriptomes of genotype Scarlet were obtained after a one-week infection period with each nematode species separately, or both species combined. Root defense gene expression was induced for all three treatments relative to the no-nematode control, but P. thornei affected expression to a greater extent compared to P. neglectus. The species combination induced the highest number of defense genes. This result was not predicted from nematode enumeration studies, in which P. thornei colonization was substantially lower than that of P. neglectus, and the nematode combination did not show a significant difference. Quantitative real time polymerase chain reaction (qRT-PCR) assays for Dehydrin2, Glucan endo-1,3-beta-glucosidase, 1-cys-Peroxiredoxin, Pathogenesis-related protein 1 and Late embryogenesis-abundant proteins 76 and group 3 authenticated the induction observed in the transcriptome data. In addition, a near-isogenic line of Scarlet harboring genetic resistance to fungal soilborne pathogens, called Scarlet-Rz1, showed similar or higher levels of defense gene expression compared to fungus-susceptible Scarlet in qRT-PCR assays. Finally, transcriptome expression patterns revealed nematode-inducible promoters that are responsive to both P. neglectus and P. thornei. [ABSTRACT FROM AUTHOR]

Across the globe, many species of insects are facing population decline. This is largely driven by anthropogenic changes to the environment, including the widespread exposure of invertebrates to endocrine disrupting chemicals (EDCs), which impair fertility. To test whether generations of Drosophila melanogaster born from parents exposed to a common dietary EDC, equol, could recover reproductive function, we quantified the reproductive capacity of the two subsequent generations. Using a novel suite of flow cytometry assays to assess sperm functionality in real time, we find that sperm function is compromised across three generations, even after non-exposed in individuals contribute to the breeding population. Though the sex ratio alters in response to EDC exposure, favouring the survival of female offspring, most lineages with ancestral EDC exposure exhibit persistent subfertility in both the male and female. Male offspring with ancestral EDC exposure present with reduced fertility and dysfunctional spermatozoa, whereby spermatozoa are metabolically stressed, lack DNA integrity and present with permanent epigenetic alterations. Across generations, male and female offspring demonstrate distinct patterns of reproductive characteristics, depending upon the specific lineage of EDC exposure. Our results illustrate how dietary EDCs present in agricultural plants could promote transgenerational subfertility and contribute to declining insect populations. [ABSTRACT FROM AUTHOR]

Key Clinical Message: A comprehensive diagnostic approach is crucial for patients with primary amenorrhea and short stature. Karyotyping and imaging studies help to detect hidden chromosomal abnormalities and anatomical differences, emphasizing their value in this context. A 16‐year‐old girl with absent menstruation and short stature. Further examination revealed constitutional stunting and primary amenorrhea. Karyotyping revealed a 46, XY chromosomal abnormality, whereas pelvic ultrasonography showed uterine hypoplasia and a unicornuate uterus with a rudimentary horn. After 11 months of therapy, she experienced menarche and improved secondary sexual characteristics. [ABSTRACT FROM AUTHOR]

Background: Increasing studies have reported a causal relationship between androgenetic alopecia (AGA) and lipid‐related metabolites. However, the relationships between HDL‐C, LDL‐C, Omega‐6, and Omega‐3 with AGA remain unclear. Some research findings are even contradictory. Therefore, we designed this study to explore this issue. Methods: In this study, we selected seven exposure factors, screened SNPs with significant associations, removed linkage disequilibrium and weak instrumental variables, and conducted bidirectional MR analysis. Results: The study found that omega‐6 and LDL‐C, especially total cholesterol in medium LDL and total cholesterol in small LDL, are risk factors for the occurrence of androgenetic alopecia. Conclusion: In summary, we found that various lipid‐related metabolites have a causal relationship with the occurrence of androgenetic alopecia, providing new insights into the pathogenesis of androgenetic alopecia and offering references for clinical treatment of androgenetic alopecia. [ABSTRACT FROM AUTHOR]

Spermatogenesis is a multi-step biological process where mitotically active diploid (2n) spermatogonia differentiate into haploid (n) spermatozoa via regulated meiotic programming. The alarming rise in male infertility has become a global concern during the past decade thereby demanding an extensive profiling of testicular gene expression. Advancements in Next- Generation Sequencing (NGS) technologies have revolutionized our empathy towards complex biological events including spermatogenesis. However, despite multiple attempts made in the past to reveal the testicular transcriptional signature(s) either with bulk tissues or at the single-cell, level, comprehensive reviews on testicular transcriptomics and associated disorders are limited. Notably, technologies explicating the genome-wide gene expression patterns during various stages of spermatogenic progression provide the dynamic molecular landscape of testicular transcription. Our review discusses the advantages of single-cell RNA-sequencing (Sc-RNA-seq) over bulk RNA-seq concerning testicular tissues. Additionally, we highlight the cellular heterogeneity, spatial transcriptomics, dynamic gene expression and cell-tocell interactions with distinct cell populations within the testes including germ cells (Gc), Sertoli cells (Sc), Peritubular cells (PTc), Leydig cells (Lc), etc. Furthermore, we provide a summary of key finding of single-cell transcriptomic studies that have shed light on developmental mechanisms implicated in testicular disorders and male infertility. These insights emphasize the pivotal roles of Sc-RNA-seq in advancing our knowledge regarding testicular transcriptional landscape and may serve as a potential resource to formulate future clinical interventions for male reproductive health. [ABSTRACT FROM AUTHOR]

Sterilization and castration have been synonyms for thousands of years. Making an animal sterile meant to render them incapable of producing offspring. Castration or the physical removal of the testes was discovered to be the most simple but reliable method for managing reproduction and sexual behavior in the male. Today, there continues to be global utilization of castration in domestic animals. More than six hundred million pigs are castrated every year, and surgical removal of testes in dogs and cats is a routine practice in veterinary medicine. However, modern biological research has extended the meaning of sterilization to include methods that spare testis removal and involve a variety of options, from chemical castration and immunocastration to various methods of vasectomy. This review begins with the history of sterilization, showing a direct link between its practice in man and animals. Then, it traces the evolution of concepts for inducing sterility, where research has overlapped with basic studies of reproductive hormones and the discovery of testicular toxicants, some of which serve as sterilizing agents in rodent pests. Finally, the most recent efforts to use the immune system and gene editing to block hormonal stimulation of testis function are discussed. As we respond to the crisis of animal overpopulation and strive for better animal welfare, these novel methods provide optimism for replacing surgical castration in some species. [ABSTRACT FROM AUTHOR]

Background: Brominated Flame Retardants (BFRs) have attracted widespread concern due to their environmental persistence and potential toxicity. This study aims to examine the association between BFRs exposure and hypertension. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005 to 2016 for the cross-sectional analysis. To evaluate the individual and combined impacts of BFRs exposure on hypertension, we utilized multivariate models, including generalized additive models, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models. Results: 9882 individuals (48% male) aged ≥ 20 were included in the final analysis, of whom 4114 had hypertension. After controlling for potential covariates, higher serum concentrations of PBDE100 (OR: 1.26; 95% CI: 1.01, 1.57) and PBDE153 (OR: 1.50; 95% CI: 1.18, 1.88) were significantly associated with hypertension. A nonlinear relationship between PBDE28 and hypertension was observed (P = 0.03). Moreover, BFRs mixture were positively associated with the prevalence of hypertension in both the WQS (β:1.09; 95% CI: 1.02, 1.17; P = 0.02) and BKMR models. Conclusion: Our study suggested that BFRs exposure is positively associated with hypertension in the general population. To confirm this association and elucidate the mechanisms, further research is required. [ABSTRACT FROM AUTHOR]

Male infertility is a major public health concern globally with unknown etiology in approximately half of cases. The decline in total sperm count over the past four decades and the parallel increase in childhood obesity may suggest an association between these two conditions. Here, we review the molecular mechanisms through which obesity during childhood and adolescence may impair future testicular function. Several mechanisms occurring in obesity can interfere with the delicate metabolic processes taking place at the testicular level during childhood and adolescence, providing the molecular substrate to hypothesize a causal relationship between childhood obesity and the risk of low sperm counts in adulthood. Pediatric obesity is increasing worldwide and its contribution to the decline is sperm count has been questioned. By comprehensively reviewing the literature, the authors herein report molecular mechanisms that may suggest the causality of this association. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does anogenital distance (AGD) – distance from the anus to the genitals – correlate from infancy (3 months) to the age of 9 years in boys and girls? SUMMARY ANSWER In boys, AGD correlated from infancy to 9 years of age, whereas in girls, correlations were weaker, especially between infancy and later childhood. WHAT IS KNOWN ALREADY AGD is considered a marker for prenatal androgen action. In males, reduced AGD is associated with testicular cancer, infertility, and lower sperm count. In females, AGD is associated with endometriosis and polycystic ovary syndrome. STUDY DESIGN, SIZE, DURATION In the Odense Child Cohort, a prospective population-based birth cohort, pregnant women were enrolled in early pregnancy. AGD and BMI were measured repeatedly in children at ages 3 and 18 months, as well as at 3, 5, 7, and 9 years. PARTICIPANTS/MATERIALS, SETTING, METHODS AGD was measured from the anus to the scrotum (AGDas) and to the penis (AGDap) in 1022 boys, and to the posterior fourchette and the clitoris in 887 girls repeatedly between the age of 3 months to 9 years. In total, 7706 assessments were made. AGD was adjusted for body weight, and SD scores (the difference between individual AGD and the mean of AGD in the population divided by SD of AGD) were calculated for each child. Pearson correlation coefficient (r) of each measurement was performed to investigate whether individual AGD was stable during childhood. Short predictive values at 3 months (20th percentile) to 9 years were investigated using the AUC produced by the receiver operating characteristic curve. MAIN RESULTS AND THE ROLE OF CHANCE In boys, AGD/body size-index SD score correlated significantly between infancy and 9 years, strongest for AGDas (r  = 0.540 P  > 0.001). In girls, weaker significant correlation coefficients were found between AGD at infancy and 9 years; higher correlation coefficients were found between AGD from 3 to 9 years (P  > 0.001). Short AGDas in infancy predicted short AGDas in boys aged 9 years (AUC: 0.767, sensitivity 0.71, specificity 0.71). The predictive values of short infant AGDap, penile width (in boys), and AGD (in girls) concerning short outcomes at 9 years were low. LIMITATIONS, REASONS FOR CAUTION The AGD measurements are less precisely measurable in girls compared to boys, especially in infancy, resulting in less reproducible measurements. Additionally, because AGD is shorter in girls, the same absolute measurement error is relatively more significant, potentially contributing to greater variability and lower reproducibility in girls. This may contribute to the weaker correlations in girls compared to boys. WIDER IMPLICATIONS OF THE FINDINGS In boys, AGDas, relative to body size, correlated from infancy to 9 years, suggesting that AGD in infancy can be considered a non-invasive marker of later reproductive health. Further follow-up studies are needed to evaluate long-term individual tracking of AGD as well as assessment of childhood AGD as early marker of adult reproductive health. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by Odense University Hospital, Denmark, the Region of Southern Denmark, the Municipality of Odense, Denmark, the University of Southern Denmark, Odense Patient data Exploratory Network (OPEN), Denmark, the Danish Research Council (4004-00352B_FSS), Novo Nordisk Foundation, Denmark (grant no. NNF19OC0058266 and NNF17OC0029404), Sygeforsikring Danmark (journalnr. 2021-0173), the Collaborative Foundation between Odense University Hospital and Rigshospitalet, and Helsefonden. There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

The present study sought to analyze the possible changes that might be caused by MSG and soybean on the secretion of both the male and female reproductive hormones in wistar rats. Two hundred and ten wistar rats (105 female and 105 male rats) were used for this study. The 105 female rats were equally divided into three groups representing the various experimental durations of 2, 4, and 6 months. Each of these groups consisting of 35 rats were further divided equally into 7 subgroups each containing 5 rats. 3 out of the 7 subgroups were orally administered MSG, another 3 out of the 7 subgroups were orally administered soybean according to the established LD50 as follows: 1000 mg/kg b.w (low dose, LD), 2000 mg/kg b.w (medium dose, MD), 3000 mg/kg b.w (High dose, HD) daily, while the 7th group served as the control group and was given only water and normal rat chow. The 105 male rats were also grouped in same manner and orally administered the MSG and soybean. The levels of LH, FSH, progesterone (PRG), oestrogen (E2) and testosterone were analyzed by ELISA technique. Long period administration of MSG significantly (p<0.05) decreased the levels of LH, PRG, E2 and FSH in the female rats when compared with the control group. Consumption of soybean for a long period of time significantly (p<0.05) decreased the level of E2 and FSH in the female rats, while short period administration significantly (p<0.05) increased the PRG level and long period administration significantly (p<0.05) decreased the PRG level in comparison with the control. Long and short period consumption of MSG as well as soybean significantly (p<0.05) decreased the levels of testosterone and LH in the male rats, while only long period administration of both significantly (p<0.05) decreased the level of FSH in the male rats when compared with the control group. The consumption of both small and large amounts of MSG and soybean elicit reproductive hormonal imbalance irrespective of the gender through the alteration of the levels of FSH, LH, E2, testesterone and PRG. [ABSTRACT FROM AUTHOR]

Adolescence is one of the critical periods of individual development, which is highly sensitive to changes caused by stress factors. Stress-related hormonal imbalances can negatively affect puberty and reproductive function. The aim of the study was to investigate the long-lasting reproductive effects of chronic pubertal stress in rats. Animals were subjected to immobilization stress daily from 30 to 45 postnatal day by placing them for 1 h in cylinders 4.5 cm in diameter and 10 cm in long, equipped with breathing holes. The timing of puberty in animals was studied and their somatic development was assessed. Further studies were conducted in 6-month-old sexually mature rats. The results were compared with the corresponding parameters in intact animals. Pubertal stress delayed sexual maturation in females and decreased weight gain in males. In adult animals of both sexes, pubertal stress did not change testosterone levels or the weight and morphology of the gonads significantly, except for minor vacuolation of the spermatogenic epithelium. The spermatogenesis index in the experimental group was significantly lower than in the control, due to a decrease in the number of late spermatids. Pubertal stress led to a 25.9% decrease in the number of spermatozoa in epididymal washes, an increase in the number of their pathological forms and a 2.4-fold slowdown in oxidative-reductive processes in spermatozoa. The content of malonic dialdehyde increased in the testes and ovaries, which indicates the activation of lipid peroxidation. Thus, chronic pubertal stress led to a decrease in the reproductive potential of male rats. Females are less susceptible to the negative effects of pubertal stress. [ABSTRACT FROM AUTHOR]

Capybaras (Hydrochoerus hydrochaeris) are the biggest rodents in the world and are of great importance in conservation. The species can be a rodent model in reproduction and have a massive role in the food chain in South America. Molecular studies of the reproduction of this animal are essential for all animal class conservation, mainly rodents. In this way, hormone signaling can help understand reproduction's external and internal mechanisms. In this work, estrogen receptors a and ß, aromatase cytochrome P450 enzyme, and androgens were detected by immunohistochemistry on Leydig cells, Sertoli cells, myoid cells, and seminiferous epithelium H. hydrochaeris testis. Nine animals were sacrificed and collected the testicles, and for each staining (hematoxylin and eosin, Mallory, and immunohistochemistry for four antibodies) it was made five slides per animal; after that, a qualitative analysis was performed. The presence of estrogen receptors a and ß in germinal epithelial cells, with more robust expression in spermatogonia and spermatocytes, may indicate the action of these hormones in the initial process of sperm cell development, needing more studies to investigate this first evidence. In other animals is believed that the aromatase cytochrome P450 enzyme can promote the transformation of androgens into estrogen, and in H. hydrochaeris is observed in those cells and androgen receptors. Sertoli cells exhibited moderate immunostaining for androgen and estrogen receptors a and ß in the cytoplasm, with poor labeling for the aromatase cytochrome P450 enzyme in the nucleus in H. hydrochaeris. It is suggested that Sertoli cells may be responsible for producing estrogen in adult animals. [ABSTRACT FROM AUTHOR]

Background: Reproductive health promotion can enable early mitigation of behavioral and environmental risk factors associated with adverse pregnancy outcomes, while optimizing health of women + (all genders that can gestate a fetus) and babies. Although the biological and social influences of partners on pregnancy are well established, it is unknown whether online Canadian government reproductive health promotion also targets men and partners throughout the reproductive lifespan. Methods: Reproductive health promotion, designed for the general public, was assessed in a multi-jurisdictional sample of Canadian government (federal, provincial/territorial, and municipal) and select non-governmental organization (NGO) websites. For each website, information related to environmental and behavioral influences on reproductive health (preconception, pregnancy, postpartum) was evaluated based on comprehensiveness, audience-specificity, and scientific quality. Results: Government and NGO websites provided sparse reproductive health promotion for partners which was generally limited to preconception behavior topics with little coverage of environmental hazard topics. For women + , environmental and behavioral influences on reproductive health were well promoted for pregnancy, with content gaps for preconception and postpartum stages. Conclusion: Although it is well established that partners influence pregnancy outcomes and fetal/infant health, Canadian government website promotion of partner-specific environmental and behavioral risks was limited. Most websites across jurisdictions promoted behavioral influences on pregnancy, however gaps were apparent in the provision of health information related to environmental hazards. As all reproductive stages, including preconception and postpartum, may be susceptible to environmental and behavioral influences, online health promotion should use a sex- and gender-lens to address biological contributions to embryo, fetal and infant development, as well as contributions of partners to the physical and social environments of the home. [ABSTRACT FROM AUTHOR]

Cystic spermatogenesis in the subadult, maturing and adult Greenland shark (Somniosus microcephalus) displays multiple novel features, characterized early on by an unorganized internal cellular environment of the spermatocysts (anatomically discrete follicle-like units containing a single germ cell stage and its complement of co-developing Sertoli cells). These typically show polar asymmetries due to asymmetrically distributed germ and Sertoli cells. These arise from several novel cellular rearrangements at the immature pole, including fusion of a cluster of somatic cells with newly formed cysts containing only one to three spermatogonia and that already display an excess of Sertoli cells. The subadult's germinative zone revealed an additional novelty, namely numerous previously formed somatic cell-lined rings into which spermatogonia were incorporated. A striking finding was the conspicuous rarity of the routinely discernible Sertoli mitotic figures in the hallmark cyst stage of diametric elasmobranch spermatogenesis that is known for the peak display of the latter. Scrutiny of sequentially unfolding phenomena in the linearly arranged spermatogonial generations revealed that the cellular developments at the most common type of cyst–duct transition area (comprising slender to spindle-like basophilic cells with pointed ends) were concurrent with the discreet appearance of a second dark Sertoli nucleus, a development that persisted in spermiated cysts. Spermatogenically active mature males displayed vigorous meiotic divisions. However, a scattering of their spermatid cysts also displayed shark-atypical asynchronous passage through spermiogenesis, phenomena which were exacerbated as arrested spermiogenesis in an archival collection of tissues from 13 maturing specimens. Subadult specimens revealed meiotic arrest, and foci of infiltration of leukocytes that originate from a mass of eosinophilic, granule-laden immune cells dorsally under the testis capsule. This tissue was identical to the testis-affixed bone marrow equivalent in other shark species. This tissue is likely developmentally regulated in the Greenland shark as it is absent in adults. [ABSTRACT FROM AUTHOR]

This work describes the relevance of toxicology studies of environmental chemicals, with a focus on phthalates, for a hypothesis that certain human male reproductive disorders and diseases have a common etiology of disturbance of normal development in utero. The "Testicular Dysgenesis Syndrome" hypothesis in humans has parallels in male reproductive tract abnormalities and microscopic lesions reported for phthalate toxicity in rats. Additionally, this work describes the histological findings of abnormal testicular development (testicular dysgenesis) in rats as compared to those in humans, as well as potential findings in rats at different ages, from the embryo to the adult. [ABSTRACT FROM AUTHOR]

An intense period of human population expansion over the past 250 years is about to cease. Total fertility rates are falling dramatically all over the world such that highly industrialized nations, including China and the tiger economies of SE Asia, will see their populations decline significantly in the coming decades. The socioeconomic, geopolitical and environmental ramifications of this change are considerable and invite a multidisciplinary consideration of the underlying mechanisms. In the short-term, socioeconomic factors, particularly urbanization and delayed childbearing are powerful drivers of reduced fertility. In parallel, lifestyle factors such as obesity and the presence of numerous reproductive toxicants in the environment, including air-borne pollutants, nanoplastics and electromagnetic radiation, are seriously compromising reproductive health. In the longer term, it is hypothesized that the reduction in family size that accompanies the demographic transition will decrease selection pressure on high fertility genes leading to a progressive loss of human fecundity. Paradoxically, the uptake of assisted reproductive technologies at scale, may also contribute to such fecundity loss by encouraging the retention of poor fertility genotypes within the population. Since the decline in fertility rate that accompanies the demographic transition appears to be ubiquitous, the public health implications for our species are potentially devastating. [ABSTRACT FROM AUTHOR]

In mammals, gonadal somatic cell lineage differentiation determines the development of the bipotential gonad into either the ovary or testis. Sertoli cells, the only somatic cells in the spermatogenic tubules, support spermatogenesis during gonadal development. During embryonic Sertoli cell lineage differentiation, relevant genes, including WT1, GATA4, SRY, SOX9, AMH, PTGDS, SF1, and DMRT1, are expressed at specific times and in specific locations to ensure the correct differentiation of the embryo toward the male phenotype. The dysregulated development of Sertoli cells leads to gonadal malformations and male fertility disorders. Nevertheless, the molecular pathways underlying the embryonic origin of Sertoli cells remain elusive. By reviewing recent advances in research on embryonic Sertoli cell genesis and its key regulators, this review provides novel insights into sex determination in male mammals as well as the molecular mechanisms underlying the genealogical differentiation of Sertoli cells in the male reproductive ridge. [ABSTRACT FROM AUTHOR]

Vitamin D is a fat-soluble steroid hormone that was initially known only for regulating calcium and phosphorus levels and maintaining bone health. However, it was later discovered that many organs express vitamin D metabolizing enzymes and have a ligand for vitamin D, which regulates the expression of an extensive assortment of genes. As a result, vitamin D is indispensable for the proper function of organs, and its deficiency is believed to be a critical factor in symptoms and disorders such as cardiovascular diseases, autoimmune diseases, and cancers. The significance of vitamin D in reproductive tissues was recognized later, and studies have revealed its crucial role in male and female fertility, as well as proper reproductive function during pregnancy. Vitamin D deficiency has been identified as a risk factor for infertility, gonadal cancers, pregnancy complications, polycystic ovary syndrome, and endometriosis. However, data investigating the association between vitamin D levels and reproductive disorders, including endometriosis, have encountered inconsistencies. Therefore, the present study aims to review existing research on the effect of vitamin D on proper reproductive function, and the role of deficiency in reproductive diseases and specifically focuses on endometriosis. [ABSTRACT FROM AUTHOR]

Environmental variation in the Anthropocene involves several factors that interfere with endocrine systems of wildlife and humans, presenting a planetary boundary of still unknown dimensions. Here, we focus on chemical compounds and other impacts of anthropogenic and natural origins that are adversely affecting reproduction and development. The main sink of these endocrine disruptors (EDs) is surface waters, where they mostly endanger aquatic vertebrates, like teleost fish and amphibians. For regulatory purposes, EDs are categorized into EATS modalities (oestrogenic, androgenic, thyroidal, steroidogenesis), only addressing endocrine systems being assessable by validated tests. However, there is evidence that non-EATS modalities—and even natural sources, such as decomposition products of plants or parasitic infections—can affect vertebrate endocrine systems. Recently, the disturbance of natural circadian light rhythms by artificial light at night (ALAN) has been identified as another ED. Reviewing the knowledge about EDs affecting teleosts and amphibians leads to implications for risk assessment. The generally accepted WHO-definition for EDs, which focuses exclusively on 'exogenous substances' and neglects parasitic infections or ALAN, seems to require some adaptation. Natural EDs have been involved in coevolutionary processes for ages without resulting in a general loss of biodiversity. Therefore, to address the 'One Health'-principle, future research and regulatory efforts should focus on minimizing anthropogenic factors for endocrine disruption. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'. [ABSTRACT FROM AUTHOR]

Background: Disorders/differences of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. With overlapping phenotypes and multiple genes involved, poor diagnostic yields are achieved for many of these conditions. The current DSD diagnostic regimen can be augmented by investigating transcriptome/proteome in vivo, but it is hampered by the unavailability of affected gonadal tissue at the relevant developmental stage. We try to mitigate this limitation by reprogramming readily available skin tissue-derived dermal fibroblasts into Sertoli cells (SC), which could then be deployed for different diagnostic strategies. SCs form the target cell type of choice because they act like an organizing center of embryonic gonadal development and many DSD arise when these developmental processes go awry. Methods: We employed a computational predictive algorithm for cell conversions called Mogrify to predict the transcription factors (TFs) required for direct reprogramming of human dermal fibroblasts into SCs. We established trans-differentiation culture conditions where stable transgenic expression of these TFs was achieved in 46, XY adult dermal fibroblasts using lentiviral vectors. The resulting Sertoli like cells (SLCs) were validated for SC phenotype using several approaches. Results: SLCs exhibited Sertoli-like morphological and cellular properties as revealed by morphometry and xCelligence cell behavior assays. They also showed Sertoli-specific expression of molecular markers such as SOX9, PTGDS, BMP4, or DMRT1 as revealed by IF imaging, RNAseq and qPCR. The SLC transcriptome shared about two thirds of its differentially expressed genes with a human adult SC transcriptome and expressed markers typical of embryonic SCs. Notably, SLCs lacked expression of most markers of other gonadal cell types such as Leydig, germ, peritubular myoid or granulosa cells. Conclusions: The trans-differentiation method was applied to a variety of commercially available 46, XY fibroblasts derived from patients with DSD and to a 46, XX cell line. The DSD SLCs displayed altered levels of trans-differentiation in comparison to normal 46, XY-derived SLCs, thus showcasing the robustness of this new trans-differentiation model. Future applications could include using the SLCs to improve definitive diagnosis of DSD in patients with variants of unknown significance. Highlights: Disorders/differences of sex development (DSD) have low diagnostic rates. Validation of variants of unknown significance and discovery of developmental pathways can be improved by utilizing gonadal tissue/cell for genomic and transcriptomic analysis. As these cells are not readily accessible, we have developed a novel method for trans-differentiating 46, XY dermal fibroblasts into Sertoli-like cells (SLC). Our trans-differentiation method can produce SLCs from dermal fibroblasts belonging to a variety of 46,XY DSDs, thus showing its robustness. This method can aid as a tool for precision medicine towards diagnosing DSD. Plain language summary: Individuals with disorders/differences of sex development (DSD) frequently do not get a specific genetic diagnostic. A limitation in the field is that the relevant cell types that would be needed to study the molecular events occurring at the time of onset of many DSD are found in the embryonic gonad. This, of course, is not accessible for research or diagnostic purposes. We set out to develop a method for directly transforming more accessible cells, from adult skin, into the cells known to organize the male gonad in the embryo, Sertoli cells. A combination of unique transcription factors was stably integrated into skin fibroblasts, and culture under appropriate conditions allowed differentiation into Sertoli-like cells (SLC), but not other gonadal cell types. The SLCs recapitulated known patterns of gene expression, shape, and behavior of Sertoli cells. The method was also tested on commercially available fibroblasts from a variety of DSD genetic backgrounds. The resulting cells exhibited condition-specific behavior (gene expression, adhesion to substrate, division rate...). This method provides a new tool to study molecular events occurring at the time of onset of DSD in the embryonic gonad, and the impact of patient-specific mutations on those. It could allow identification of new developmental pathways (and, thus, new candidate genes for DSD), as well as a provide models to validate the impact of variants of unknown significance, or to test approaches to correct the genetic anomaly in patient cells. [ABSTRACT FROM AUTHOR]

Background: Aphanomyces euteiches is a soil-borne oomycete that causes root rot in pea and other legume species. Symptoms of Aphanomyces root rot (ARR) include root discoloration and wilting, leading to significant yield losses in pea production. Resistance to ARR is known to be polygenic but the roles of single genes in the pea immune response are still poorly understood. This study uses transcriptomics to elucidate the immune response of two pea genotypes varying in their levels of resistance to A. euteiches. Results: In this study, we inoculated roots of the pea (P. sativum L.) genotypes 'Linnea' (susceptible) and 'PI180693' (resistant) with two different A. euteiches strains varying in levels of virulence. The roots were harvested at 6 h post-inoculation (hpi), 20 hpi and 48 hpi, followed by differential gene expression analysis. Our results showed a time- and genotype-dependent immune response towards A. euteiches infection, involving several WRKY and MYB-like transcription factors, along with genes associated with jasmonic acid (JA) and abscisic acid (ABA) signaling. By cross-referencing with genes segregating with partial resistance to ARR, we identified 39 candidate disease resistance genes at the later stage of infection. Among the genes solely upregulated in the resistant genotype 'PI180693', Psat7g091800.1 was polymorphic between the pea genotypes and encoded a Leucine-rich repeat receptor-like kinase reminiscent of the Arabidopsis thaliana FLAGELLIN-SENSITIVE 2 receptor. Conclusions: This study provides new insights into the gene expression dynamics controlling the immune response of resistant and susceptible pea genotypes to A. euteiches infection. We present a set of 39 candidate disease resistance genes for ARR in pea, including the putative immune receptor Psat7g091800.1, for future functional validation. [ABSTRACT FROM AUTHOR]

Cancer is a major socioeconomic burden that seriously affects the life and spirit of patients. However, little is known about the role of environmental toxicant exposure in diseases, especially ubiquitous di-(2-ethylhexyl) phthalate (DEHP) which is one of the most widely used plasticizers. Hence, the objective of this study was to assess the potential association between cancer and DEHP. The data were collected using the 2011–2018 National Health and Nutrition Examination Survey (NHANES) data (n = 6147), and multiple logistic regression was conducted to evaluate the association. The concentrations of DEHP were calculated by each metabolite and split into quartiles for analysis. After adjusting for confounding factors, DEHP was significantly associated with an increased risk of cancer prevalence, and the metabolites of DEHP showed similar results (OR > 1.0, p < 0.05). Simultaneously, the association remained when the analyses were stratified by age and sex, and the risk of cancer appeared to be higher in male patients. In addition, further analysis suggested that DEHP exposure obviously increased the risk of female reproductive system cancer, male reproductive system cancer, and other cancers (OR > 1.0, p < 0.05) but not skin and soft tissue cancer. DEHP exposure is associated with the risk of cancer, especially female reproductive system cancer, male reproductive system cancer and other cancers. [ABSTRACT FROM AUTHOR]

Context: Resumption of testicular function after gonadotrophin-releasing hormone (GnRH) immunisation varies among individual animals and some stallions regain fertility only after a prolonged time. Aims: This study evaluated endocrine effects of GnRH immunisation and early subsequent re-stimulation with a GnRH agonist. We hypothesised that GnRH agonist treatment advances resumption of normal endocrine function in GnRH-vaccinated stallions. Methods: Shetland stallions were assigned to an experimental and a control group (n = 6 each). Experimental stallions were GnRH-immunised twice, 4 weeks apart. Each experimental stallion was hemicastrated together with an age-matched control animal when testosterone concentration decreased below 0.3 ng/mL. Three weeks later, daily treatment with the GnRH agonist buserelin was initiated (4 μg/day for 4 weeks followed by 8 μg/day). The remaining testicle was removed when testosterone concentration exceeded 0.5 ng/mL in vaccinated stallions. Blood was collected for LH, FSH, oestradiol and anti-müllerian hormone (AMH) analyses, and testicular and epididymal tissue were conserved for real-time qPCR and histology. Key results: GnRH vaccination reduced blood concentrations of LH and FSH, with a structural deterioration of testicular tissue and disruption of spermatogenesis. Daily buserelin treatment for approximately 60 days partially restored gonadotropin secretion and induced a recovery of the functional organisation of the testicular tissue with effective spermatogenesis. Conclusions: Endocrine testicular function can be restored in GnRH-vaccinated stallions by daily low-dose buserelin treatment. The buserelin treatment protocol may potentially be improved regarding the dose, interval and duration. Implications: Daily buserelin treatment can be recommended for treatment of GnRH-vaccinated stallions with prolonged inhibition of testicular function. GnRH vaccination is used in male horses to reduce sexual behaviour and gonadal function, but the time to regain fertility varies considerably among individual animals. Daily GnRH agonist treatment for approximately 60 days in stallions vaccinated against GnRH successfully stimulated the production of sex steroid hormones and spermatogenesis. This treatment may be recommended for GnRH-vaccinated stallions with persistent inhibition of testicular function and fertility. Image by Camille Gautier. This article belongs to the Collection Dedication to Jim Cummins. [ABSTRACT FROM AUTHOR]

Studies have implicated oxidative stress-sensitive signaling in the pathogenesis of stress-induced male infertility. However, apart from oxidative stress, gonadotropin inhibitory hormone (GnIH) plays a major role. The present study provides a detailed review of the role of GnIH in stress-induced male infertility. Available evidence-based data revealed that GnIH enhances the release of corticosteroids by activating the hypothalamic-pituitary-adrenal axis. GnIH also mediates the inhibition of the conversion of thyroxine (T4) to triiodothyronine (T3) by suppressing the hypothalamic-pituitary-thyroidal axis. In addition, GnIH inhibits gonadotropin-releasing hormone (GnRH), thus suppressing the hypothalamic-pituitary-testicular axis, and by extension testosterone biosynthesis. More so, GnIH inhibits kisspeptin release. These events distort testicular histoarchitecture, impair testicular and adrenal steroidogenesis, lower spermatogenesis, and deteriorate sperm quality and function. In conclusion, GnIH, via multiple mechanisms, plays a key role in stress-induced male infertility. Suppression of GnIH under stressful conditions may thus be a beneficial prophylactic and/or therapeutic strategy. [ABSTRACT FROM AUTHOR]

Mitochondrial function plays an important role in the maintenance of male fertility. However, the mechanisms underlying mitochondrial defect-related infertility remain mostly unclear. Here we show that a deficiency of PARL (Parl−/−), a mitochondrial protease, causes complete arrest of spermatogenesis during meiosis I. PARL deficiency led to severe downregulation of proteins of respiratory chain complex IV in testes that did not occur in other tested organs, causing a deficit in complex IV activity and ATP production. Furthermore, Parl−/− testes showed an almost complete loss of HSD17B3, a protein of the sER responsible for the last step in testosterone synthesis. While testosterone production appeared to be restored by overexpression of HSD17B12, loss of the canonical testosterone synthesis led to an upregulation of luteinizing hormone (LH) and of LH-regulated responses. These results suggest an important impact of the downstream regulation of mitochondrial defects that manifest in a cell-type-specific manner and extend beyond mitochondria. The mitochondrial protease PARL is essential for male fertility in mice, and knockout of PARL leads to an arrest in spermatogenesis due to downregulation of respiratory chain complex IV proteins in the testes and a deficit in ATP production there. [ABSTRACT FROM AUTHOR]

The need to determine the sex of the fetus in early pregnancy is usually based on medical indications for early implementation of appropriate therapeutic procedures, and is sometimes driven by parental curiosity. Medicine has made tremendous progress in early diagnosis of fetal sex in the last decades. The diagnostic methods described in the literature are characterized by varying degrees of accuracy, cost, and potential risk to the fetus. For these reasons, there is an ongoing debate about when and in which cases a particular method should be used. This paper presents an overview of the current methods of fetal sex determination. [ABSTRACT FROM AUTHOR]

Incorporation of bovine serum-derived albumin formulation (AlbuMAX) into a basic culture medium, MEMa, enables the completion of in vitro spermatogenesis through testicular tissue culture in mice. However, this medium was not effective in other animals. Therefore, we sought an alternative approach for in vitro spermatogenesis using a synthetic medium without AlbuMAX and aimed to identify its essential components. In addition to factors known to be important for spermatogenesis, such as retinoic acid and reproductive hormones, we found that antioxidants (vitamin E, vitamin C, and glutathione) and lysophospholipids are vital for in vitro spermatogenesis. Moreover, based on our experience with microfluidic devices (MFD), we developed an alternative approach, the PDMS-ceiling method (PC method), which involves simply covering the tissue with a flat chip made of PDMS, a silicone resin material used in MFD. The PC method, while straightforward, integrates the advantages of MFD, enabling improved and uniform oxygen and nutrient supply via tissue flattening. Furthermore, our studies underscored the significance of lowering the oxygen concentration to 10-15%. Using an integrated cultivation method based on these findings, we successfully achieved in vitro spermatogenesis in rats, which has been a long-standing challenge. Further improvements in culture conditions would pave the way for spermatogenesis completion in diverse animal species. [ABSTRACT FROM AUTHOR]