Sexual Differentiation Of Brain Research Articles

Cinsel Kimlik Gelişiminin Nörobiyolojik Yapıtaşları ve Çevresel Stresörlerin Epigenetik Etkileri

In this review, we explore the intricate development of sexual identity, drawing insights from genetic, endocrinological, neuroanatomical, and neurophysiological studies. Gender identity, encapsulating an individual's internal perception as male or female, undergoes a nuanced and gradual formation, commencing early in life and progressing through distinct stages. Gender nonconformity delineates behaviors that diverge from culturally prescribed norms, while gender dysphoria encompasses the emotional distress experienced by some individuals due to a mismatch between their gender identity and assigned sex at birth. The genesis of sexual identity involves multifaceted processes spanning numerous years. Human sex differentiation involves the suppression or inactivation of specific genes, a phenomenon illuminated by genetic investigations into gender dysphoria, which have shown comparable rates of genetic variations to the general population. Nevertheless, twin studies suggest an augmented likelihood of transsexuality among family members, hinting at potential environmental influences. Brain sexual differentiation occurs during mid-to-late pregnancy due to the impact of gonadal hormones. The mechanisms underpinning the loss of feminine brain characteristics and subsequent masculinization likely involve a combination of factors, indicating a complex interplay rather than a singular cause. Studies propose that human sexual behavior is not governed by a solitary gene but rather by a network of genes dispersed across the genome. Notably, disparities in brain structures, functionalities between genders, as well as variations in endocrine and serotonin-dopamine levels, are implicated in the etiology of gender dysphoria, contributing to the understanding of this complex phenomenon situated between genders.

Comparative neuroimaging of sex differences in human and mouse brain anatomy

In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions (r=0.30). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.

Comparative neuroimaging of sex differences in human and mouse brain anatomy.

In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions (r=0.30). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.

Oxytocin-induced birth causes sex-specific behavioral and brain connectivity changes in developing rat offspring

Despite six decades of the use of exogenous oxytocin for management of labor, little is known about its effects on the developing brain. Motivated by controversial reports suggesting a link between oxytocin use during labor and autism spectrum disorders (ASDs), we employed our recently validated rat model for labor induction with oxytocin to address this important concern. Using a combination of molecular biological, behavioral, and neuroimaging assays, we show that induced birth with oxytocin leads to sex-specific disruption of oxytocinergic signaling in the developing brain, decreased communicative ability of pups, reduced empathy-like behaviors especially in male offspring, and widespread sex-dependent changes in functional cortical connectivity. Contrary to our hypothesis, social behavior, typically impaired in ASDs, was largely preserved. Collectively, our foundational studies provide nuanced insights into the neurodevelopmental impact of birth induction with oxytocin and set the stage for mechanistic investigations in animal models and prospective longitudinal clinical studies.

Effect of Fetal Pituitary-Testes Suppression on Brain Sexual Differentiation and Reproductive Function in Male Sheep.

We previously demonstrated that treating fetal lambs on gestational day 62 with the long-acting gonadotrophin-releasing hormone (GnRH) antagonist degarelix (DG) suppresses pituitary-testicular function during midgestation. The objective of this study was to investigate whether impaired gonadotrophic drive during this fetal period has enduring effects on sexual differentiation and reproductive function in adult male sheep. We assessed the effects of prenatal administration of DG, with or without testosterone (T) replacement, on various sexually dimorphic behavioral traits in adult rams, including sexual partner preferences, as well as neuroendocrine responsiveness and testicular function. Our findings revealed that DG treatment had no effect on genital differentiation or somatic growth. There were some indications that DG treatment suppressed juvenile play behavior and adult sexual motivation; however, male-typical sexual differentiation of reproductive behavior, sexual partner preference, and gonadotropin feedback remained unaffected and appeared to be fully masculinized and defeminized. DG-treated rams showed an increased LH response to GnRH stimulation and a decreased T response to human chorionic gonadotropin stimulation, suggesting impaired Leydig cell function and reduced T feedback. Both effects were reversed by cotreatment with T propionate. DG treatment also suppressed the expression of CYP17 messenger RNA, a key enzyme for T biosynthesis. Despite the mild hypogonadism induced by DG treatment, ejaculate volume, sperm motility, and sperm morphology were not affected. In summary, these results suggest that blocking GnRH during midgestation does not have enduring effects on brain sexual differentiation but does negatively affect the testes' capacity to synthesize T.

Contribution of birds to the study of sexual differentiation of brain and behavior

Behavioral neuroendocrinology has largely relied on mammalian models to understand the relationship between hormones and behavior, even if this discipline has historically used a larger diversity of species than other fields. Recent advances revealed the potential of avian models in elucidating the neuroendocrine bases of behavior. This paper provides a review focused mainly on the contributions of our laboratory to the study of sexual differentiation in Japanese quail and songbirds. Quail studies have firmly established the role of embryonic estrogens in the sexual differentiation of male copulatory behavior. While most sexually differentiated features identified in brain structure and physiology result from the different endocrine milieu of adults, a few characteristics are organized by embryonic estrogens. Among them, a sex difference was identified in the number and morphology of microglia which is not associated with sex differences in the concentration/expression of neuroinflammatory molecules. The behavioral role of microglia and neuroinflammatory processes requires further investigations. Sexual differentiation of singing in zebra finches is not mediated by the same endocrine mechanisms as male copulatory behavior and “direct” genetic effect, i.e., not mediated by gonadal steroids have been identified. Epigenetic contributions have also been considered. Finally sex differences in specific aspects of singing behavior have been identified in canaries after treatment of adults with exogenous testosterone suggesting that these aspects of song are differentiated during ontogeny. Integration of quail and songbirds as alternative models has thus expanded understanding of the interplay between hormones and behavior in the control of sexual differentiation.

Sex Differences in Mouse Models of Autism Spectrum Disorders: Their Potential to Uncover the Impact of Brain Sexual Differentiation on Gender Bias

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a prevalence rate of 2.78%, and it is characterized by deficits in sociability and communication and restricted patterns of interests and activities. Remarkably, this psychiatric disorder exhibits a pronounced gender bias, with 80% of children diagnosed with ASD being boys. In this review, we will present advancements in mouse models of ASD and their potential contributions to our understanding of the disorder. We will highlight how initial pre-clinical investigations focused solely on male mice due to the gender bias in ASD and explain why we believe that this approach might have had detrimental consequences regarding our understanding of ASD etiology and pathophysiology. We will highlight the evidence of two sensitive periods during brain development when differential exposure to gonadal hormones may result in sex differences in brain function and behavior: the perinatal period and the pre-pubertal period. Finally, we will suggest neuroinflammation as a feasible biological mechanism that may converge different ASD etiological factors and cellular mechanisms into a brain sexual differentiation context, thus accounting for the gender disparities observed in the disorder.

Antibiotic-induced socio-sexual behavioral deficits are reversed via cecal microbiota transplantation but not androgen treatment

Recent evidence has demonstrated a sex-specific role of the gut microbiome on social behavior such as anxiety, possibly driven by a reciprocal relationship between the gut microbiome and gonadal hormones. For instance, gonadal hormones drive sex differences in gut microbiota composition, and certain gut bacteria can produce androgens from glucocorticoids. We thus asked whether the gut microbiome can influence androgen-dependent socio-sexual behaviors. We first treated C57BL/6 mice with broad-spectrum antibiotics (ABX) in drinking water to deplete the gut microbiota either transiently during early development (embryonic day 16-postnatal day [PND] 21) or in adulthood (PND 60–85). We hypothesized that if ABX interferes with androgens, then early ABX would interfere with critical periods for sexual differentiation of brain and thus lead to long-term decreases in males' socio-sexual behavior, while adult ABX would interfere with androgens’ activational effects on behavior. We found that in males but not females, early and adult ABX treatment decreased territorial aggression, and adult ABX also decreased sexual odor preference. We then assessed whether testosterone and/or cecal microbiota transplantation (CMT) via oral gavage could prevent ABX-induced socio-sexual behavioral deficits in adult ABX-treated males. Mice were treated with same- or other-sex control cecum contents or with testosterone for two weeks. While testosterone was not effective in rescuing any behavior, we found that male CMT restored both olfactory preference and aggression in adult ABX male mice, while female CMT restored olfactory preference but not aggression. These results suggest sex-specific effects of the gut microbiome on socio-sexual behaviors, independent of androgens.

Acute Ozone-Induced Transcriptional Changes in Markers of Oxidative Stress and Glucocorticoid Signaling in the Rat Hippocampus and Hypothalamus Are Sex-Specific.

Exposure to a prototypic air pollutant ozone (O3) has been associated with the activation of neuroendocrine stress response along with neural changes in oxidative stress (OS), inflammation, and Alzheimer's disease-like pathologies in susceptible animal models. We hypothesized that neural oxidative and transcriptional changes induced by O3 in stress responsive regions are sex-dependent. Male and female adult Long-Evans rats were exposed to filtered air or O3 for two consecutive days (0.8 ppm, 4 h/day) and brain regions were flash-frozen. Activities of cerebellar OS parameters and mitochondrial complex I, II, and IV enzymes were assessed to confirm prior findings. We assessed transcriptional changes in hypothalamus (HYP) and hippocampus (HIP) for markers of OS, microglial activity and glucocorticoid signaling using qPCR. Although there were no O3 or sex-related differences in the cerebellar activities of OS and mitochondrial enzymes, the levels of protein carbonyls and complex II activities were higher in females regardless of O3. There were no statistical differences in baseline expression of genes related to OS (Cat, Dhcr24, Foxm1, Gpx1, Gss, Nfe2l2, Sod1) except for lower HYP Sod1 expression in air-exposed females than males, and higher HIP Gss expression in O3-exposed females relative to matched males. Microglial marker Aif1 expression was higher in O3-exposed females relative to males; O3 inhibited Itgam only in males. The expression of Bdnf in HIP and HYP was inhibited by O3 in both sexes. Genes related to glucocorticoid signaling (Fkbp4, Fkbp5, Hsp90aa1, Hspa4, nr3c1, nr3c2) showed sex-specific effects due to O3 exposure. Baseline expression of HIP Fkbp4 was higher in females relative to males. O3 inhibited Nr3c1 in female HIP and male HYP, but Nr3c2 was inhibited in male HYP. Fkbp4 expression was higher in O3-exposed females when compared to matched males, whereas Fkbp5 was expressed at higher levels in both brain regions of males and females. These results indicate that sex-specific brain region responses to O3 might, in part, be caused by OS and regulation of glucocorticoid signaling.

Integrated multi-modal brain signatures predict sex-specific obesity status.

Investigating sex as a biological variable is key to determine obesity manifestation and treatment response. Individual neuroimaging modalities have uncovered mechanisms related to obesity and altered ingestive behaviours. However, few, if any, studies have integrated data from multi-modal brain imaging to predict sex-specific brain signatures related to obesity. We used a data-driven approach to investigate how multi-modal MRI and clinical features predict a sex-specific signature of participants with high body mass index (overweight/obese) compared to non-obese body mass index in a sex-specific manner. A total of 78 high body mass index (55 female) and 105 non-obese body mass index (63 female) participants were enrolled in a cross-sectional study. All participants classified as high body mass index had a body mass index greater than 25 kg/m2 and non-obese body mass index had a body mass index between 19 and 20 kg/m2. Multi-modal neuroimaging (morphometry, functional resting-state MRI and diffusion-weighted scan), along with a battery of behavioural and clinical questionnaires were acquired, including measures of mood, early life adversity and altered ingestive behaviours. A Data Integration Analysis for Biomarker discovery using Latent Components was conducted to determine whether clinical features, brain morphometry, functional connectivity and anatomical connectivity could accurately differentiate participants stratified by obesity and sex. The derived models differentiated high body mass index against non-obese body mass index participants, and males with high body mass index against females with high body mass index obtaining balanced accuracies of 77 and 75%, respectively. Sex-specific differences within the cortico-basal-ganglia-thalamic-cortico loop, the choroid plexus-CSF system, salience, sensorimotor and default-mode networks were identified, and were associated with early life adversity, mental health quality and greater somatosensation. Results showed multi-modal brain signatures suggesting sex-specific cortical mechanisms underlying obesity, which fosters clinical implications for tailored obesity interventions based on sex.

Retraction for Keshavarz et al., The imprinted lncRNA Peg13 regulates sexual preference and the sex-specific brain transcriptome in mice

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.

Comprehensive study of sex-based anatomical variations of human brain and development of sex-specific brain templates

The sex-based human brain structural variations alongside the necessity and development process for sex-specific brain templates were investigated in this study. Comparing magnetic resonance images of 500 female and 500 male subjects, no significant sex-based difference was observed for average cortical thickness, however, all the volumetric values, including the total brain volume (TBV) and major 19 brain regions, were found to be significantly different between females and males. Moreover, analyzing the fractional volume of the regions showed that these sex variations were not proportional to TBV for all regions. These findings underscore the importance of distinguishing the sex-based differences in human brain studies. While brain templates have been developed for general population and cohorts with the same characteristics such as race or age, there is a lack of sex-specific brain templates. To fill this gap and find a representative reference brain image for each sex, nonlinear templates were developed for female, male, and mixed population subjects. Next, a separate set of 109 female and 109 male brain images were used to evaluate the sex-specificity of the brain templates. It was observed that the female and male test subjects were registered to their sex-specific templates with the lowest amount of deformation/warping confirming better representativeness of the sex-specific templates for their target population. The findings of this study including the templates and the reported variations can be used in research involving sex dimorphic brain disorders, diseases, and/or injuries such as traumatic brain injury that is affected by the sex-based brain anatomical differences. Statement of significanceHuman brain exhibits sex-based variation both in size and volumetric composition of different regions. Despite these differences, there is a paucity of sex-specific brain templates. Addressing this gap marks the significance of our study as briefly explained here. We have shown that differences in male and female brain go beyond simple scaling and the observation of regional differences that are not proportional to the sex-based total brain volume variations has motivated us to develop sex-specific templates. The representativeness and difference of these sex-specific templates were assessed by measuring the amount of required warping in nonlinear registration of test subjects to them. It was shown that registration of female and male subjects to their corresponding sex-specific template involved lower level of warping compared to their registration to their opposite sex or mixed population brain template.

Sex-Specific Brain Activations during Single-Leg Exercise.

Females have an increased incidence of musculoskeletal injuries compared to males. Sex differences in neuromuscular control has been widely studied regarding the dynamics and muscle activity during preplanned movements. While muscle activation patterns and movement biomechanics are understood to differ between sexes, it is not well understood how sex influences brain activity for lower extremity movement. Since the brain plays a vital role for voluntary movement and joint stability, it is important to understand the sex differences in brain function in order to better understand neuromuscular control associated with increased musculoskeletal injury risk in female. The purpose of this study is to understand the differences in brain activation patterns between sexes during a simple active knee extension-flexion movement. It was hypothesized that females would demonstrate higher cortical activation in the somatosensory areas compared to males as a compensatory strategy. Cross-Sectional Study. Thirteen males and seventeen females who were healthy and physically active participated in this study (Male: 23.7±3.8 years, 74.5±13.5 kg, 172.3±6.4 cm; Female: 20.6±1.6 years, 65.4±12.8 kg, 163±6.1 cm). Functional magnetic resonance imaging data were obtained during a simple left knee extension-flexion exercise with their own leg weight while lying on the MRI table. The blood oxygen level dependent (BOLD) signals were compared between sexes. There was significantly greater activation in the visual cortices and premotor cortex in females compared to males during the studied movement. Males demonstrated significantly greater activation in the right cerebellum. The results revealed sex differences in BOLD signal during simple knee extension-flexion movement. The results suggest that sex may be a biological factor in understanding brain activity associated with knee motor control. Level 3.

Lactational exposure to venlafaxine provokes late repercussions on reproductive parameters in male rat offspring.

Exposure to selective serotonin reuptake inhibitors can affect hormone-dependent processes, such as the brain sexual differentiation. Because the use of these antidepressants cause concern during lactation, we evaluated the possible effects of venlafaxine on lactational exposure and its late repercussions on reproductive parameters in male rats. Lactating rats were exposed to venlafaxine (3.85, 7.7, or 15.4mg/kg/body weight; gavage), from lactational day 1 to 20. Venlafaxine and O-desmethylvenlafaxine residues were found in all milk samples of dams treated, demonstrating the lactational transfer of this antidepressant to the offspring. Although the maternal behavior was normal, the dams presented an increase in urea and uric acid levels in the groups treated with 7.7 and 15.4, respectively, as well as a spleen weight increased in the 3.85 and 15.4 groups. The male offspring showed a decrease in play behavior parameters in the intermediate dose group. Sperm analysis indicated a reduction in sperm motility in all treated groups. The androgen receptor expression in the hypothalamus was decreased in the highest dose group, although the sexual behavior had not been affected. In conclusion, venlafaxine was transferred through breast milk and promoted changes in play behavior, sperm quality, and hypothalamic androgen receptor (AR) content, which may indicate an incomplete masculinization of the brain of male offspring.

Sex-specific Effects of Endocrine-disrupting Chemicals on Brain Monoamines and Cognitive Behavior.

The period of brain sexual differentiation is characterized by the development of hormone-sensitive neural circuits that govern the subsequent presentation of sexually dimorphic behavior in adulthood. Perturbations of hormones by endocrine-disrupting chemicals (EDCs) during this developmental period interfere with an organism's endocrine function and can disrupt the normative organization of male- or female-typical neural circuitry. This is well characterized for reproductive and social behaviors and their underlying circuitry in the hypothalamus and other limbic regions of the brain; however, cognitive behaviors are also sexually dimorphic, with their underlying neural circuitry potentially vulnerable to EDC exposure during critical periods of brain development. This review provides recent evidence for sex-specific changes to the brain's monoaminergic systems (dopamine, serotonin, norepinephrine) after developmental EDC exposure and relates these outcomes to sex differences in cognition such as affective, attentional, and learning/memory behaviors.

Epigenetic Mechanisms of Brain Sexual Differentiation.

Across vertebrate species, gonadal hormones coordinate physiology with behavior to facilitate social interactions essential for reproduction and survival. In adulthood, these hormones activate neural circuits that regulate behaviors presenting differently in females and males, such as parenting and territorial aggression. Yet long before sex-typical behaviors emerge at puberty, transient hormone production during sensitive periods of neurodevelopment establish the circuits upon which adult hormones act. How transitory waves of early-life hormone signaling exert lasting effects on the brain remains a central question. Here we discuss how perinatal estradiol signaling organizes cellular and molecular sex differences in the rodent brain. We review classic anatomic studies revealing sex differences in cell number, volume, and neuronal projections, and consider how single-cell sequencing methods enable distinction between sex-biased cell-type abundance and gene expression. Finally, we highlight the recent discovery of a gene regulatory program activated by estrogen receptor α (ERα) following the perinatal hormone surge. A subset of this program displays sustained sex-biased gene expression and chromatin accessibility throughout the postnatal sensitive period, demonstrating a bona fide epigenetic mechanism. We propose that ERα-expressing neurons throughout the social behavior network use similar gene regulatory programs to coordinate brain sexual differentiation.

성분화질환을 둘러싼 법적 문제

Sexual differentiation disease is the abnormal condition in development situation of sexual differentiation which is the basis of gender determination.
 This thesis reviewed for the person born with this disease to enable normal growth without emotional disorders and inferiority complex under the system of male or female choice.
 The points are summarized as follows. First, it is about the malpractice of medical operation for gender confirmation. Malpractice cannot be admitted because the medical operation for gender confirmation of the son was suitable medical level at that time.
 Second, it is about the relation with the guarantee of gender determination of the son. About this, all unnecessary surgical operations should be postponed until the time when the son becomes mature and decides for himself.
 In addition, the doctor has the obligation to provide all information to the person with parental rights when the doctor is going to perform the gender confirmation operation on the patient with sexual differentiation disease. Especially, if the gender confirmation operation is not an emergency, the doctor should explain to the person with parental rights, thus the person with parental rights should not be misunderstood as emergency situation and not to perform early gender confirmation operation.
 Furthermore, the doctor should explain the side effect that the newborn baby can lose fertility through the gender confirmation operation. That is an important matter about basic human right to body, so if these information were not provided, it is against informed consent. Even in case the patient with sexual differentiation disease can live as male or female either, the son should be able to decide his gender as best interest not facing identity problem when he grow up.
 Third, it is about the birth registration of the person with sexual differentiation disease. About this, like family registration practice in Japan, birth registration should be reported in an undetermined state for happiness of the son, and the irreversible treatment like genital organ removal should be prohibited until the son can decide for himself. In addition, it is appropriate for the son to decide his gender and complete family relation register subsequently after adolescence appearing second sexual characteristics through sexual differentiation of brain.
 Fourth, it is about the decision criteria of gender correction to sexual differentiation disease. Recently, as the decision criteria, not only sex chromosome as the sole absolute criteria but also cause of abnormality, condition of internal and external genital organs, composition of sex chromosome, surgical operation possibility of external genital organs and prediction of future sexual function should be considered, and simultaneously, it also should be considered which gender would secure for his happy life, and then the doctor shall select the gender to perform operational treatment.

성분화질환자의 성별 자기결정권 확보방안

The gender of the son, according to the purpose of United Nations Convention on the Rights of the Child, Article 12, should be determined after considering his opinion in accordance with age and maturity, and then, the son should determine the gender with accurate and enough information to form his opinion about the gender.
 The son has the right to acquire his gender from the birth, and the parents have the right and obligation to determine the gender of their son, and government should not interrupt the gender determination by parents and their son. Therefore, the son whose gender is undecided when he was born also has the right not to be compelled to determine the gender.
 Under current law, male and female dichotomous system, recognition of third sex, and also the relation of birth registration should be considered to guarantee the right to gender determination of the son who was born sexually undifferentiated, and they are summarized as follows.
 First, Under current law, male and female dichotomous system of gender shall maintain in principle, and permanent lifetime third sex shall not be recognized. In addition, the establishment of permanent third sex is also not recognized, but maintenance of legal status as gender undetermination should be recognized until when the final decision is made by himself.
 Second, Under Act on the Registration, etc. of Family Relationship or its practice, the device of birth registration in gender undetermination condition should be prepared, that is to say, not only “male” or “female” but also “gender undetermination” should be prepared for selection option in birth registration form. These writing method is not to recognize permanent third sex but to recognize temporary until when the son grows up and performs his right to gender determination, and completes the gender subsequently in birth registration form.
 Third, in terms of law, gender determination of the son is the matter how to harmonize the right of the son who lives on and the right and obligation of the parents who bring up.
 The basic structure is that the right of the parents decreases gradually according to maturity of understanding and judgement of the son, and the right of the parents terminates when the judgement of the son matures enough. In other words, the step theory of gender, which gender is determined by maturity of the son, is that the decision right of the parents terminates and the son has the right to decide when the son has the judgement enough to decide the solution to the problem. However, the gender determination, even if the son can make a final decision applying the principle of mature minor, would influence all over his lifetime and simultaneously his mind and body for a long time unlike consent or refusal of one-time surgical operation.
 The sexual differentiation of brain of people shall confirm at the age of 2 or 3, so if sexual signs appeared at this time, the parents could determine ‘the sex of nurturing’ and complete the birth registration form subsequently.
 However, although the gender in birth registration form was completed subsequently at that time, the application of gender change should be recognized in case the son selects the opposite sex. For this, except inevitable reasons, the parents should not perform irreversible surgical operation like gonad removal which would interrupt the final gender determination of the son.

THE REPRODUCTIVE PATHOLOGIES OF MALE OFFSPRING BORN TO MOTHERS WITH FETOPLACENTAL INSUFFICIENCY: HORMONE DEPENDENT MECHANISMS OF DEVELOPING AND PROFYLAXIS

Introduction. Fetoplacental insufficiency (FPI) is the symptom complex that substantially results not only in pregnancy development and childbirth, but in the health condition of offspring at different times. It has been shown that offspring born to mothers with FPI have morphological and functional disturbances of different systems of organs. The aims of this research were to determine hormone depended mechanisms of reproductive pathologies developing in the ontogenesis of male offspring born to different aged mothers with FPI and experimental grounding of potential preventive activity of developed pharmaceutical composition suitable for animals of this phenotype. Materials and methods. Mature Wistar rat females of young (3-4 months) and mature (8-10 months) reproductive age have been used in the experiment. Eights groups for 7 pregnant females in each group have been formed. Modeling of FPI has been carried out by daily subcutaneous administration of the 50 % tetrachloromethane oil solution at dose of 2 ml/kg of body weight from 12th to 18th day of pregnancy. The reproductive system of male offspring has been estimated. Results. FPI influences the sex differentiation of brain in male offspring that reflects in delaying of sexual maturity in the form of postponed testicles moving to the scrotum. FPI leads to relative estrogenization, inhibition of sperm cells differentiation and causes significant changes in antioxidant defense system in male offspring at puberty. FPI causes changes of testosterone, estradiol levels and shifts sex hormones ratio to the hyperestrogenemia in the all of mature male offspring that influence the activity of male sexual behavior, worsens spermogram and fertility. Conclusion. Fetoplacental insufficiency in females in third trimester of pregnancy leads to marked changes in reproductive system of their male offspring born to mothers of reproductively young and reproductively mature age. Data obtained indicate the opportunity and ways to develop the medicines for prophylaxis of reproductive pathologies in children born to mothers with fetoplacental insufficiency.

Dmrt5 beyond the cortex: early role in the sexual differentiation of the mouse limbic system.

The mammalian limbic system is sexually dimorphic and underlies sex-specific innate behaviors such as mating, maternal care, and aggression. However, the genetic programs involved in the sexual differentiation of the limbic system are poorly understood. Dmrt transcription factors have emerged as conserved regulators of sex-specific traits across animal kingdom. They have been studied mostly in invertebrates, where they play an important role in nervous system sexual differentiation. In mammals, Dmrt genes have been predominantly studied in the gonads, however, Dmrt5, controls cortex development in humans and mice. In fact, mutations in DMRTA2 (Dmrt5) lead to a recessive human condition characterized by microcephaly and lissencephaly. Surprisingly, there are no studies beyond the cortex nor comparing males and females. In this work we use Dmrt5 null mutant mice, RNAseq and histological techniques to study Dmrt5 function in the developing mammalian nervous system beyond the cortex and comparing males and females. It is plausible that genetic factors involved in brain sexual differentiation, like Dmrt, may represent also etiologic causes for mental disorders, explaining the observed male-female sexual bias. In this study we showed that Dmrt5 is broadly expressed in the mouse nervous system, including the vomeronasal organ, olfactory tubercle, or ventral tegmental area (all key nodes in the control of innate behaviors). Furthermore, we showed that Dmrt5 is necessary for the correct specification of the main olfactory epithelium, the olfactory bulb, and several hypothalamic nuclei. Additionally, we found a novel function for Dmrt5 as a suppressor of sex differences in gene expression in the posterior hypothalamic area and midbrain. In this region, Dmrt5 could be specifying and maintaining a neuronal subpopulation or a group of neurons only in males. Taken together, Dmrt5 comes out as a crucial transcription factor for the accurate differentiation of limbic regions, integrating sex information. By studying the genetic factors involved in sexual differentiation of the nervous system, we might find potential factors to either afford protection or generate vulnerability in one sex versus the other for sex-biased mental disorders.