Prenatal Allergen Exposure Perturbs Sexual Differentiation and Programs Lifelong Changes in Adult Social and Sexual Behavior.

Sexual differentiation is the early life process by which the brain is prepared for male or female typical behaviors, and is directed by sex chromosomes, hormones and early life experiences. We have recently found that innate immune cells residing in the brain, including microglia and mast cells, are more numerous in the male than female rat brain. Neuroimmune cells are also key participants in the sexual differentiation process, specifically organizing the synaptic development of the preoptic area and leading to male-typical sexual behavior in adulthood. Mast cells are known for their roles in allergic responses, thus in this study we sought to determine if exposure to an allergic response of the pregnant female in utero would alter the sexual differentiation of the preoptic area of offspring and resulting sociosexual behavior in later life. Pregnant rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally with OVA on gestational day 15, which produced robust allergic inflammation, as measured by elevated immunoglobulin E. Offspring of these challenged mother rats were assessed relative to control rats in the early neonatal period for mast cell and microglia activation within their brains, downstream dendritic spine patterning on POA neurons, or grown to adulthood to assess behavior and dendritic spines. In utero exposure to allergic inflammation increased mast cell and microglia activation in the neonatal brain, and led to masculinization of dendritic spine density in the female POA. In adulthood, OVA-exposed females showed an increase in male-typical mounting behavior relative to control females. In contrast, OVA-exposed males showed evidence of dysmasculinization, including reduced microglia activation, reduced neonatal dendritic spine density, decreased male-typical copulatory behavior, and decreased olfactory preference for female-typical cues. Together these studies show that early life allergic events may contribute to natural variations in both male and female sexual behavior, potentially via underlying effects on brain-resident mast cells.

Sex differences in neuroimmunity as an inherent risk factor.

Identifying and understanding the sources of inherent risk to neurodevelopmental disorders is a fundamental goal of neuroscience. Being male or being exposed to inflammation early in life are two known risk factors, but they are only infrequently associated with each other. Cellular and molecular mechanisms mediating the masculinization of the brain in animal models reveal a consistent role for inflammatory signaling molecules and immune cells in the healthy male brain. Why this is so remains in the realm of speculation but may have its origins in the maternal immune system. Masculinization of the brain occurs during a restricted critical period that begins in utero and overlaps with the sensitive period during which maternal immune activation negatively impacts the developing brain. The convergence of maleness and early life inflammation as risk factors for neuropsychiatric disorders compels us to consider whether sexual differentiation of the brain in males creates an inherent and greater risk than that experienced by females.

Alternative splicing of GnRH2 and GnRH2-associated peptide plays roles in gonadal differentiation of the rice field eel, Monopterus albus.

The rice field eel, Monopterus albus, is a protogynous hermaphrodite fish, in which the gonads are initially female ovaries which then transform into male testes. The exact mechanisms governing sex reversal in the rice field eel are unknown. In this study, a novel alternative splicing variant of GnRH2 (GnRH2-SV), retaining the second intron, was discovered in the gonad of the rice field eel. Compared to GnRH2, GnRH2-SV may give rise to a novel truncated GnRH2-associated peptide (New GAP2). The normal transcript of GnRH2 was primarily expressed in the brain, and could also be detected in the liver, spleen, ovary, and testis. However, GnRH2-SV was only expressed in the ovary and testis. During sex reversal, GnRH2 expression levels increased significantly at late stages; however, expression levels of GnRH2-SV were lower in ovary than in ovotestis and testis. We also examined the effect of three peptides (GnRHa, GAP2, and New GAP2) on gonadal sex differentiation during the third stage of ovarian development of the rice field eel. Compared to the control group, the expression of amh increased significantly following incubation with each of the three peptides. However, only New GAP2 stimulated the expression of sox9a1 mRNA in vitro. After intraperitoneal injection of GAP2, the expression of amh, foxl2, and cyp19a1a increased significantly after 12 h; the concentration of serum 11-KT was also significantly increased at the 12 h time point. Treatment with New GAP2 significantly increased the expression of amh, dmrt1a, and sox9a1, and also increased the concentration of serum 11-KT. After treated with GnRHa, the expression of amh, dmrt1a, sox9a1, cyp19a1a, and foxl2 increased significantly, as did the level of serum E2. These results indicated that both GAP2 and New GAP2 play a crucial role in inducing expression changes of sex-differentiation related genes, and may be involved in the gonadal development and sex reversal in the rice field eel.

Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system.

Neuroscientists are likely to discover new sex differences in the coming years, spurred by the National Institutes of Health initiative to include both sexes in preclinical studies. This review summarizes the current state of knowledge of the cellular and molecular mechanisms underlying sex differences in the mammalian nervous system, based primarily on work in rodents. Cellular mechanisms examined include neurogenesis, migration, the differentiation of neurochemical and morphological cell phenotype, and cell death. At the molecular level we discuss evolving roles for epigenetics, sex chromosome complement, the immune system, and newly identified cell signaling pathways. We review recent findings on the role of the environment, as well as genome-wide studies with some surprising results, causing us to re-think often-used models of sexual differentiation. We end by pointing to future directions, including an increased awareness of the important contributions of tissues outside of the nervous system to sexual differentiation of the brain.

Sexual orientation, fraternal birth order, and the maternal immune hypothesis: a review.

In 1996, psychologists Ray Blanchard and Anthony Bogaert found evidence that gay men have a greater number of older brothers than do heterosexual men. This "fraternal birth order" (FBO) effect has been replicated numerous times, including in non-Western samples. More recently, strong evidence has been found that the FBO effect is of prenatal origin. Although there is no direct support for the exact prenatal mechanism, the most plausible explanation may be immunological in origin, i.e., a mother develops an immune reaction against a substance important in male fetal development during pregnancy, and that this immune effect becomes increasingly likely with each male gestation. This immune effect is hypothesized to cause an alteration in (some) later born males' prenatal brain development. The target of the immune response may be molecules (i.e., Y-linked proteins) on the surface of male fetal brain cells, including in sites of the anterior hypothalamus, which has been linked to sexual orientation in other research. Antibodies might bind to these molecules and thus alter their role in typical sexual differentiation, leading some later born males to be attracted to men as opposed to women. Here we review evidence in favor of this hypothesis, including recent research showing that mothers of boys develop an immune response to one Y-linked protein (i.e., H-Y antigen; SMCY) important in male fetal development, and that this immune effect becomes increasingly likely with each additional boy to which a mother gives birth. We also discuss other Y-linked proteins that may be relevant if this hypothesis is correct. Finally, we discuss issues in testing the maternal immune hypothesis of FBO.

Two hypotheses on the causes of male homosexuality and paedophilia.

This note considers two hypotheses on the causes of homosexuality and paedophilia in men, viz. the hypotheses of maternal immunity and of postnatal learning. According to the maternal immune hypothesis, there is progressive immunization of some mothers to male-specific antigens by each succeeding male fetus, and there are concomitantly increasing effects of anti-male antibodies on the sexual differentiation of the brain in each succeeding male fetus. An attempt is made to assess the status of this hypothesis within immunology. Knowledge of the properties of anti-male antibodies is meagre and there has been little direct experimentation on them, let alone on their effects on the developing male fetal brain. Moreover until the relevant antigens are identified, it will not be possible to test mothers of male homosexuals or paedophiles for the presence of such antibodies. Yet until this experimentation has been done, it would seem premature to regard the hypothesis as more than a very provisional explanatory tool. The evidence in relation to the postnatal learning hypothesis is quite different. There is an abundance of data suggesting that male homosexuals and paedophiles report having experienced more sexual abuse (however defined) in childhood (CSA) than do heterosexual controls. The question revolves round the interpretation of these data. Many (though not all) of these studies are correlational and thus subject to the usual qualifications concerning such data. However, there are grounds for supposing that some of the reports are veridical, and there is support from a longitudinal study reporting a small but significant increase in paedophilia in adulthood following CSA. To summarize: most boys who experience CSA do not later develop into homosexuals or paedophiles. However, the available evidence suggests that a few do so as a result of the abuse.

The production of anti-H-Y monoclonal antibodies: their potential use in a sex test for bovine embryos.

In an attempt to improve the accuracy of sexing bovine embryos, new anti-H-Y monoclonal antibodies were produced and selected, using an extended screening procedure. In addition to the commonly used screening of soluble H-Y antigen sources, such as testis supernatant and Daudi supernatant, the binding specificity to cell surface H-Y antigen was tested also. A radioimmunoassay (RIA) employing male and, as a control, female bovine lymphocytes, and enzyme-linked immunosorbent assays (ELISAs) on solubilized membrane fractions resulted in the selection of a number of clones producing monoclonal antibody (mAb) with male-enhanced binding. Four of the anti-H-Y mAb were assessed for binding to Day 7 or 8 bovine embryos. The accuracy of sexing bovine embryos ranged from 58% to 71%. Two of the four antibodies did not react with presumed soluble H-Y antigen-containing sources in an ELISA. These results raise doubts about the suitability of the presumed soluble H-Y antigen sources, Daudi, TM4 and testis supernatant, to be used in screening tests for anti-H-Y antibodies.

Ambigüedad sexual

El sexo puede definirse con base en por lo menos seis características: genético, gonadal, genitales internos, genitales externos, hormonal y género. Los países que presentan síndrome de ambigüedad sexual pueden tener uan alteración cromosómica, o en el eje hipotálamo-pituitaria-gónadas, o en la producción de hormonas sexuales, o en la acción periférica de estas hormonas. En la niñez consultarán por la aparición anormal de sus genitales, criptorquidia no palpable, hipospadias, clitoromegalia o hernia inguinal. En la adolescencia y en la etapa adulta por pobre desarrollo de los caracteres sexuales secundarios, o ginecomastia en los varones, o virilización en las mujeres, infertilidad o tumores gonadales. La valoración será clínica, citogenética y hormonal para clasificarlos en tres grupos: disgenesia gonadal, pseudohermafroditismo msaculino, pseudohermafroditismo femenino con el fin de definir la asignación de sexo, el tratamiento hormonal y quirúrgico

Male antigen defined serologically does not identify a factor responsible for testicular development.

To test the proposal that the serologically detected male antigen (SDMA; which may or may not be the same as H-Y) was responsible for triggering the indifferent gonad to differentiate into the testis in mammals, H-Y negative sex-reversed XXSxr' male mice were investigated for the presence of SDMA. Serum from C57BL/6 female mice immunized against tissue from XXSxr' males did not contain SDMA specific antibody as detected by the complement-mediated sperm cytotoxicity assay. Thus, although SDMA is a male-specific factor and may play a role in male sex determination, it does not identify the testis-determining factor (TDF).