Exposure to 17β-trenbolone caused a skewed sex ratio in fish. However, the molecular initiating event and key molecular event(s) remain unknown. In this study, zebrafish were exposed to ...17β-trenbolone at nominal concentrations of 2 ng/L, 20 ng/L, 200 ng/L, and 2000 ng/L from fertilization to 60 days post fertilization (dpf). First, the sex ratio at 60 dpf was calculated to evaluate adverse outcomes on sexual differentiation. 17β-Trenbolone caused a skewed sex ratio toward males, with intersex individuals observed in the 20 ng/L group and all-male populations found in the 200 ng/L and 2000 ng/L groups. Then, the distribution and number of primordial germ cells, the expression of sex differentiation-related genes, and plasma vitellogenin concentrations were detected in wild-type zebrafish and the EGFP-nanos-3′UTR transgenic line using whole-mount in situ hybridization, real-time PCR, EGFP fluorescence quantification, and enzyme-linked immunosorbent assay. The results indicated that 17β-trenbolone exposure decreased the number of primordial germ cells at 1 dpf and 3 dpf, decreased expression of ovarian differentiation-related genes foxl2 and cyp19a1a at 60 dpf, increased expression of testis differentiation-related genes dmrt1, sox9a, and amh at 60 dpf, and decreased plasma vitellogenin levels at 60 dpf, revealing the key molecular events at different time points involved in affected sexual differentiation by 17β-trenbolone. Finally, molecular docking showed that 17β-trenbolone docked into ligand-binding domain of zebrafish androgen receptor with high binding energy (−3.72 kcal/mol), suggesting that binding to androgen receptor is the molecular initiating event affecting sexual differentiation by 17β-trenbolone. We found that 17β-trenbolone can bind to the zebrafish androgen receptor, decrease the number of primordial germ cells during the early embryonic stage, modulate the expression of genes related to sexual differentiation during gonadal differentiation, and eventually cause a skewed sex ratio toward males in adults.
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•17β-Trenbolone binds to zebrafish androgen receptor.•17β-Trenbolone decreases the number of primordial germ cells.•17β-Trenbolone modulates the expression of genes related to sexual differentiation.•17β-Trenbolone causes a skewed sex ratio toward males in zebrafish.
Sex has a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Neuroinflammation is involved in the onset and progression of several neurological ...diseases, and the fact that estrogens have anti-inflammatory activity suggests that these hormones may be a determinant in the sex-dependent manifestation of brain pathologies. We describe significant differences in the transcriptome of adult male and female microglia, possibly originating from perinatal exposure to sex steroids. Microglia isolated from adult brains maintain the sex-specific features when put in culture or transplanted in the brain of the opposite sex. Female microglia are neuroprotective because they restrict the damage caused by acute focal cerebral ischemia. This study therefore provides insight into a distinct perspective on the mechanisms underscoring a sexual bias in the susceptibility to brain diseases.
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•Transcriptome sequencing indicates sexual differentiation in adult murine microglia•Female microglia show a neuroprotective phenotype, independent from hormonal cues•Female microglia phenotype is retained after transfer into male brains•The presence of female microglia protects male brains from ischemic stroke
Villa et al. find significant differences in the transcriptomes of microglia isolated from the brains of healthy adult male and female mice. They find that microglia from female mice are neuroprotective and that they retain this functional ability when transferred into the brains of male mice.
Sexual differentiation of microglia Villa, Alessandro; Della Torre, Sara; Maggi, Adriana
Frontiers in neuroendocrinology,
January 2019, 2019-01-00, 20190101, Letnik:
52
Journal Article
Recenzirano
Odprti dostop
•Microglia exert immune and maintenance functions in the CNS.•Microglia play a role in the onset and progression of neurodegenerative diseases.•The peri-natal sexual differentiation of the brain ...includes microglia.•Microglia cells show a sex difference in development as well as in the adult brain.•This sex difference may underlie a sex bias in prevalence of neurological disorders.
Sex plays a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Despite sexual differentiation of the brain has been extensively investigated, the study of sex differences in microglia, the brain’s resident immune cells, has been largely neglected until recently. To fulfill this gap, our laboratory developed several tools, including cellular and animal models, which bolstered in-depth studies on sexual differentiation of microglia and its impact on brain physiology, as well as on the onset and progression of neurological disorders. Here, we summarize the current status of knowledge on the sex-dependent function of microglia, and report recent evidence linking these cells to the sexual bias in the susceptibility to neurological brain diseases.
Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this ...process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.
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•P. falciparum sexual differentiation is repressed by LysoPC found in human serum•LysoPC is a major building block of parasite phospholipid metabolism•LysoPC acts upstream of the earliest known events of sexual differentiation•Parasite metabolism alters host LysoPC levels during infection
The host-derived lipid lysophosphatidylcholine controls Plasmodium falciparum cell fate by repressing parasite sexual differentiation, a key step in malaria transmission.
Sex differences have been described regarding several aspects of human brain morphology; however, the exact biological mechanisms underlying these differences remain unclear in humans. Women with the ...complete androgen insensitivity syndrome (CAIS), who lack androgen action in the presence of a 46,XY karyotype, offer the unique opportunity to study isolated effects of sex hormones and sex chromosomes on human neural sexual differentiation. In the present study, we used diffusion tensor imaging to investigate white matter (WM) microstructure in 46,XY women with CAIS (n = 20), 46,XY comparison men (n = 30), and 46,XX comparison women (n = 30). Widespread sex differences in fractional anisotropy (FA), with higher FA in comparison men than in comparison women, were observed. Women with CAIS showed female-typical FA throughout extended WM regions, predominantly due to female-typical radial diffusivity. These findings indicate a predominant role of sex hormones in the sexual differentiation of WM microstructure, although sex chromosome genes and/or masculinizing androgen effects not mediated by the androgen receptor might also play a role.
To bring about sexual dimorphism in form, information from the sex determination pathway must trigger sex-specific modifications in developmental programs. DM-domain encoding genes have been found to ...be involved in sex determination in a multitude of animals, often at the level of male somatic gonad formation. Here we report our findings that the DM-domain transcription factors MAB-3 and DMD-3 function together in multiple steps during the late stages of C. elegans male somatic gonad development. Both mab-3 and dmd-3 are expressed in the linker cell and hindgut of L4 males and dmd-3 is also expressed in presumptive vas deferens cells. Furthermore, dmd-3, but not mab-3, expression in the linker cell is downstream of nhr-67, a nuclear hormone receptor that was previously shown to control late stages of linker cell migration. In mab-3; dmd-3 double mutant males, the last stage of linker cell migration is partially defective, resulting in aberrant linker cell shapes and often a failure of the linker cell to complete its migration to the hindgut. When mab-3; dmd-3 double mutant linker cells do complete their migration, they fail to be engulfed by the hindgut, indicating that dmd-3 and mab-3 activity are essential for this process. Furthermore, linker cell death and clearance are delayed in mab-3; dmd-3 double mutants, resulting in the linker cell persisting into adulthood. Finally, DMD-3 and MAB-3 function to activate expression of the bZIP transcription factor encoding gene zip-5 and downregulate the expression of the zinc metalloprotease ZMP-1 in the linker cell. Taken together, these results demonstrate a requirement for DM-domain transcription factors in controlling C. elegans male gonad formation, supporting the notion that the earliest DM-domain genes were involved in male somatic gonad development in the last common ancestor of the bilaterians.
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•Two C. elegans DM domain transcription factor encoding genes, mab-3 and dmd-3, are expressed in multiple tissues involved in male somatic gonad development.•mab-3; dmd-3 double mutants display defects in linker cell migration, resulting in aberrant linker cell morphology and premature arrest in many double mutant males.•mab-3; dmd-3 double mutants also display defects in linker cell engulfment by the hindgut and subsequent linker cell death and clearance.•MAB-3 and DMD-3 partially inhibit expression of the zinc matrix metalloproteinase encoding gene zmp-1 and activate expression of a basic leucine zipper containing transcription factor encoding gene zip-5 in the linker cell.•These results support the hypothesis that ancestral DM-domain genes were involved in male somatic gonad development.
A great deal of information is known regarding the process of sex differentiation in fish, and the mechanisms involved in primary sex determination are now beginning to be defined. A range of gonadal ...differentiation types have been described for fish, including gonochoristic species possessing purely ovarian or testicular tissues, as well as hermaphroditic species that can initially mature either as males (protandrous) or females (protogynous). Sex determination in fish is a very flexible process with respect to evolutionary patterns observed among genera and families, and within individuals is subject to modification by external factors. These influences can affect the fate of both somatic and germ cells within the primordial gonad, and include the action of genetic, environmental (e.g. temperature), behavioural, and physiological factors. Exogenous sex steroids administered at the time of sex determination can strongly influence the course of sex differentiation in fish, suggesting that they play a critical role in assignment of gonad determination as well as subsequent differentiation. Detailed information is available from fish systems describing the production of sex steroids, as well as the enzymes involved in steroid production. Both estradiol and the maturation hormone 17α, 20β-dihydroxy-4-pregnen-3-one (17α, 20β-DP) are produced by a two-step process involving different cell layers in the gonad, and have effects on the differentiation of gonadal and nongonadal tissues. Gonadal development and differentiation in some fish is also controlled by hormones from the pituitary gland (gonadotropins) that are regulated by release hormones (GnRH) and other neuroendocrine and gonadal factors. Genetic determination of sex in fish can involve monogenic or polygenic systems, with factors located on the autosomes or on sex chromosomes. In the latter case, both male (XY) and female (ZW) heterogametic systems have been described, as well as many subtle variations on these themes. Sex chromosomes are found in approximately 10% of fish species examined, and sex-linked phenotypic traits, and protein and molecular genetic markers have been identified in several fish systems. Some species of fish reproduce gynogenetically, producing all-female populations. Several gene families known to be involved in sex determination in other vertebrates have recently been shown to be similarly involved in fish, suggesting conservation of sex determination pathways. The lability of sex-determination systems in fish makes some species sensitive to environmental pollutants capable of mimicking or disrupting sex hormone actions. Such observations provide important insight into potential impacts from endocrine disruptors, and can provide useful monitoring tools for impacts on aquatic environments.
Abstract
Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the ...salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8–17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.
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