Sexual Development最新文献

The discovery in mammals that fetal testes are required in order to develop the male phenotype inspired research efforts to elucidate the mechanisms underlying gonadal sex determination and differentiation in vertebrates. A pioneer work in 1966 that demonstrated the influence of incubation temperature on sexual phenotype in some reptilian species triggered great interest in the environment's role as a modulator of plasticity in sex determination. Several chelonian species have been used as animal models to test hypotheses concerning the mechanisms involved in temperature-dependent sex determination (TSD). This brief review intends to outline the history of scientific efforts that corroborate our current understanding of the state-of-the-art in TSD using chelonian species as a reference.

This paper reviews the current knowledge on the environmental effects on penile development in humans. The specific focus is on endocrine-disrupting chemicals (EDCs), a heterogeneous group of natural or manmade substances that interfere with endocrine function, and whether they can induce hypospadias and micropenis in male neonates. Epidemiological data and animal observations first raised suspicions about environmental effects, leading to the testis dysgenesis syndrome (TDS) hypothesis. More recent research has provided stronger indications that TDS may indeed be the result of the direct or indirect effects of EDCs. Drawing on epidemiological and toxicological studies, we also report on the effects of maternal diet and substances like pesticides, phthalates, bisphenol A, and polychlorinated biphenyls. Proximity to contamination hazards and occupational exposure are also suspected to contribute to the occurrence of hypospadias and micropenis. Lastly, the cumulative effects of EDCs and the possibility of transgenerational effects, with the penile development of subsequent generations being affected, raise concerns for long-term public health.

At embryonic day (E) 10.5, prior to gonadal sex determination, XX and XY gonads are bipotential and able to differentiate into either a testis or an ovary. At this point, they are transcriptionally and morphologically indistinguishable. Sex determination begins around E11.5 in the mouse when the supporting cell lineage commits to either Sertoli or granulosa cell fate. Testis-specific factors such as SRY and SOX9 drive differentiation of bipotential-supporting cells into the Sertoli cell pathway, whereas ovary-specific factors like WNT4 and FOXL2 guide differentiation into granulosa cells. It is known that these 2 pathways are mutually antagonistic, and repression of the alternative fate is critical for maintenance of the testis or ovary programs. While we understand much about the transcription factor networks guiding the process of sex determination, it is only more recently that we have begun to understand how this process is epigenetically controlled. Studies in the past decade have demonstrated the importance of the chromatin state for gene expression and cell fate commitment, with histone modifications and DNA accessibility having a direct role in gene regulation. It is now clear that the chromatin state during sex determination is dynamic and likely critical for the establishment and/or maintenance of the transcriptional programs. Prior to sex determination, supporting cells have similar chromatin structure and histone modification profiles, reflecting the bipotential nature of these cells. After differentiation to Sertoli or granulosa cells, the chromatin state acquires sex-specific profiles. The proteins that regulate the deposition of histone modifications or the opening of compact chromatin likely play an important role in Sertoli and granulosa cell fate commitment and gonad development. Here, we describe studies profiling the chromatin state during gonadal sex determination and one example in which depletion of Cbx2, a member of the Polycomb Repressive Complex 1 (PRC1), causes male-to-female sex reversal due to a failure to repress the ovarian pathway.

Sex determination systems in vertebrates vary along a continuum from genetic (GSD) to environmental sex determination (ESD). Individuals that show a sexual phenotype opposite to their genotypic sex are called sex reversals. Aside from genetic elements, temperature, sex steroids, and exogenous chemicals are common factors triggering sex reversal, a phenomenon that may occur even in strict GSD species. In this paper, we review the literature on instances of sex reversal in fish, amphibians, reptiles, birds, and mammals. We focus on the offspring of sex-reversed parents in the instances that they can be produced, and show that in all cases studied the offspring of these sex-reversed parents exhibit a higher sensitivity to environmental perturbations than the offspring of non-sex-reversed parents. We suggest that the inheritance of this sensitivity, aside from possible genetic factors, is likely to be mediated by epigenetic mechanisms such as DNA methylation, since these mechanisms are responsive to environmental cues, and epigenetic modifications can be transmitted to the subsequent generations. Species with a chromosomal GSD system with environmental sensitivity and availability of genetic sex markers should be employed to further test whether offspring of sex-reversed parents have greater sensitivity to environmental perturbations. Future studies could also benefit from detailed whole-genome data in order to elucidate the underlying molecular mechanisms. Finally, we discuss the consequences of such higher sensitivity in the context of global climate change.

Sex reversal is the process by which an individual develops a phenotypic sex that is discordant with its chromosomal or genotypic sex. It occurs in many lineages of ectothermic vertebrates, such as fish, amphibians, and at least one agamid and one scincid reptile species. Sex reversal is usually triggered by an environmental cue that alters the genetically determined process of sexual differentiation, but it can also be caused by exposure to exogenous chemicals, hormones, or pollutants. Despite the occurrence of both temperature-dependent sex determination (TSD) and genetic sex determination (GSD) broadly among reptiles, only 2 species of squamates have thus far been demonstrated to possess sex reversal in nature (GSD with overriding thermal influence). The lack of species with unambiguously identified sex reversal is not necessarily a reflection of a low incidence of this trait among reptiles. Indeed, sex reversal may be relatively common in reptiles, but little is known of its prevalence, the mechanisms by which it occurs, or the consequences of sex reversal for species in the wild under a changing climate. In this review, we present a roadmap to the discovery of sex reversal in reptiles, outlining the various techniques that allow new occurrences of sex reversal to be identified, the molecular mechanisms that may be involved in sex reversal and how to identify them, and approaches for assessing the impacts of sex reversal in wild populations. We discuss the evolutionary implications of sex reversal and use the central bearded dragon (Pogona vitticeps) and the eastern three-lined skink (Bassiana duperreyi) as examples of how species with opposing patterns of sex reversal may be impacted differently by our rapidly changing climate. Ultimately, this review serves to highlight the importance of understanding sex reversal both in the laboratory and in wild populations and proposes practical solutions to foster future research.

It is unclear whether testosterone replacement therapy (TRT) in adolescent boys, affected by a range of endocrine diseases that may be associated with hypogonadism, is particularly common. The aim of this study was to assess the contemporary practice of TRT in boys included in the I-DSD Registry. All participating centres in the I-DSD Registry that had boys between 10 and 18 years of age and with a condition that could be associated with hypogonadism were invited to provide further information in 2019. Information on 162 boys was collected from 15 centres that had a median (range) number of 6 boys per centre (1.35). Of these, 30 (19%) from 9 centres were receiving TRT and the median (range) age at the start was 12.6 years (10.8-16.2), with 6 boys (20%) starting at <12 years. Median (range) age of boys not on TRT was 11.7 years (10.7-17.7), and 69 out of 132 (52%) were <12 years. TRT had been initiated in 20 of 71 (28%) boys with a disorder of gonadal development, 3 of 14 (21%) with a disorder of androgen synthesis, and all 7 (100%) boys with hypogonadotropic hypogonadism. The remainder who did not have TRT included 15 boys with partial androgen insensitivity, 52 with non-specific XY DSD, and 3 with persistent Müllerian duct syndrome. Before starting TRT, liver function and blood count were checked in 19 (68%) and 18 boys (64%), respectively, a bone age assessment was performed in 23 (82%) and bone mineral density assessment in 12 boys (43%). This snapshot of contemporary practice reveals that TRT in boys included in the I-DSD Registry is not very common, whilst the variation in starting and monitoring therapy is quite marked. Standardisation of practice may lead to more effective assessment of treatment outcomes.

The adaptive significance of temperature-dependent sex determination (TSD) remains elusive for many long-lived reptiles. Various hypotheses proposed potential ecological drivers of TSD. The Charnov-Bull'77 model remains the most robust and explains the maintenance of TSD in short-lived vertebrates, where sex ratios correlate with seasonal temperatures within years that confer sex-specific fitness (colder springs produce females who grow larger and gain in fecundity, whereas warmer summers produce males who mature at smaller size). Yet, evidence of fitness differentials correlated with incubation temperature is scarce for long-lived taxa. Here, it is proposed that the Charnov-Bull'77 model applies similarly to long-lived taxa, but at a longer temporal scale, by revisiting ecological and genetic data from the long-lived turtle Podocnemis expansa. After ruling out multiple alternatives, it is hypothesized that warmer-drier years overproduce females and correlate with optimal resource availability in the flood plains, benefitting daughters more than sons, whereas resources are scarcer (due to reduced flowering/fruiting) during colder-rainier years that overproduce males, whose fitness is less impacted by slower growth rates. New technical advances and collaborative interdisciplinary efforts are delineated that should facilitate testing this hypothesis directly, illuminating the understanding of TSD evolution in P. expansa and other long-lived TSD reptiles.

Atheriniform fishes have recently emerged as attractive models for evolutionary, ecological, and molecular/physiological studies on sex determination. Many species in this group have marked temperature-dependent sex determination (TSD) and yet many species also have a sex determinant gene that provides a strong drive for male differentiation. Thus, in these species the 2 forms of sex determination that were once considered to be mutually exclusive, environmental (ESD) and genotypic (GSD) sex determination, can coexist at environmentally relevant conditions. Here, we review the current knowledge on sex determination in atheriniform fishes with emphasis on the molecular and physiological mechanisms of ESD and GSD, the coexistence and cross-talk between these 2 mechanisms, the possibility of extragonadal transduction of environmental information and/or extragonadal onset of sex determination, and the results of field studies applying novel tools such as otolith increment analysis and molecular markers of genetic sex developed for selected New World and Old World atheriniform species. We also discuss the existence of molecular and histological mechanisms to prevent the discrepant differentiation in parts of the gonads because of ambiguous or conflicting environmental and genetic signals and particularly the possibility that the female is the default state in these species.