Brain Sex Research Articles

Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging

BackgroundThe necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females.MethodsWhole genome gene expression of young (3 months), adult (12 months), and old (24 months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed.ResultsMales and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females.ConclusionsThese findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimer’s, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations.

Perinatal programming of the orexinergic (hypocretinergic) system in hypothalamus and anterior pituitary by testosterone

Orexins A/B derived from hypothalamic prepro-orexin (PPO) are agonists for orexin receptors 1 (OX1) and 2 (OX2). Previously, we showed clear sex differences in the hypothalamic-pituitary-gonadal orexinergic system in adult rodents. Here, we studied the effect of sexual brain differentiation on the orexinergic system in neuroendocrine structures regulating reproduction. We evaluated: a: proestrous and neonatally androgenized female rats; b: adult males, untreated or gonadectomized in adulthood and injected with oil or estradiol and progesterone (E2/P4); c: control and demasculinized males (perinatally treated with flutamide and later castration) injected either with oil or E2/P4 in adulthood. Rats were sacrificed at 12:00 and 18:00h; blood samples and brains were collected. Hormones were measured using radioimmunoassay. PPO, OX1 and OX2 mRNAs were quantified by qPCR in medial basal hypothalamus, anterior hypothalamus, adenohypophysis, and cortex. Western blots for OX1 were done in the same structures. In normal females, gonadotropins surged at 18:00h coinciding with significant elevations of PPO, OX1 and OX2 mRNAs and OX1 protein in hypothalamus and pituitary; no increases were observed at noon. Afternoon changes were absent in masculinized females. Demasculinized males when treated with E2/P4 showed high PPO, OX1 and OX2 mRNAs and OX1 protein expression in hypothalamus and pituitary at 12:00 and 18:00h compared vehicle-treated controls. The same steroid treatment was ineffective in males with normal brain masculinization. Here we show that neonatal testosterone shapes the sexual differences in the hypothalamic-pituitary orexinergic system in synchronicity to establishing the brain sex differences of the reproductive axis. The female brain controls gonadotropin surges and concurrent elevations of all studied components of the orexinergic system, suggesting its participation as a possible link between food intake, behavior and hormonal control of reproduction.

Sex-Specific Effects of Testosterone on the Sexually Dimorphic Transcriptome and Epigenome of Embryonic Neural Stem/Progenitor Cells

The mechanisms by which sex differences in the mammalian brain arise are poorly understood, but are influenced by a combination of underlying genetic differences and gonadal hormone exposure. Using a mouse embryonic neural stem cell (eNSC) model to understand early events contributing to sexually dimorphic brain development, we identified novel interactions between chromosomal sex and hormonal exposure that are instrumental to early brain sex differences. RNA-sequencing identified 103 transcripts that were differentially expressed between XX and XY eNSCs at baseline (FDR = 0.10). Treatment with testosterone-propionate (TP) reveals sex-specific gene expression changes, causing 2854 and 792 transcripts to become differentially expressed on XX and XY genetic backgrounds respectively. Within the TP responsive transcripts, there was enrichment for genes which function as epigenetic regulators that affect both histone modifications and DNA methylation patterning. We observed that TP caused a global decrease in 5-methylcytosine abundance in both sexes, a transmissible effect that was maintained in cellular progeny. Additionally, we determined that TP was associated with residue-specific alterations in acetylation of histone tails. These findings highlight an unknown component of androgen action on cells within the developmental CNS, and contribute to a novel mechanism of action by which early hormonal organization is initiated and maintained.

Two cases of sodomy in USA and their bases of jurisprudence and science

The US Supreme Court issued contradicting verdicts for two similar cases of sodomy that came up in an interval of 17 years: Bowers v. Hardwick, 478 U.S. 186 (1986) and Lawrence v. Texas, 539 U. S. 558 (2003). The former petitioners were rejected while the latter was held up stating that the “Texas statute making it a crime for two persons of the same sex to engage in certain intimate sexual conduct violates the Due Process Clause”. The author compared the court documents of both the cases and found that the verdicts of the two courts had legal jurisprudence according to interpretivism or non-interpretivism in theories of judicial review. The latter verdict is also consistent with the claim of European Court of Human Rights that any citizen has the right to choose sodomy as a lifestyle. However, the National Institute of Medicine USA suggested a theoretical framework in 2011, claiming that homosexual behavior is social behavior instead of an individual action, and that this behavior originates from society and bounces back as a reverse action into society. It brings forth the minorities with socio-psychological issues, including alcohol abuse, substance abuse, violence, depression, suicide, and high incidence of disease. Interdisciplinary research has demonstrated that sodomy poses a disadvantage to the ecological environment for both animals and human beings; it is an apoptosis, harmful, and brings about inequities. Many factors responsible for sexual segregation, including competition among species, long-term war, work on faraway project fields, in prisons and refugee camps, provide the prerequisite or breeding ground for the spread of incidences of sodomy. Besides this, the huge gap between the rich and the poor, unsatisfactory heterosexual life, and painful sex experiences might be personal reasons for people to indulge in sodomy. Biological factors, including genes, hormones, brain sex differentiation, and fraternal order effect, as well as sex reversals, have hardly any effect, and show only one thousandth of the sex minority effect. Almost all persons who practice sodomy are devoid of inclinations to undergo sex reversal because there is a consistency between the gene type and phenotype of their sex organ. The capital involved in the sex industry and cultural influences are also factors that promote the practice of sodomy among youngsters. The sex industry spares no efforts to increase its capital to suit the lifestyles of people who indulge in availing the services that it offers. A booming sex service, sex medical services, sex cultural activities, and all of the conspicuous consumption are an essential component of the economic development of the West. A revolution in the sexual culture of societies that now propagates anti-monogamy and heterosexuality excites young men to indulge in strange practices of sodomy leading to acquiring sexually transmitted diseases. In earlier times, the great country of Greece announced rewards to their soldiers to fight bravely; a couple of ho-mosexuals rushed forward together. Although the army won a series of wars, the military strength went down quickly. Greece was defeated by Rome, and Greek civilization did not reach its brilliant peak. This paper suggests that male homosexuals need to be made aware of the nature of sodomy at the cognitive level and they need to practice self-discipline to overcome the behavior. Therefore, modern society has to pay more attention to explore the origin, nature, and solution to rid itself of sodomy. Four projects to be examined are suggested at the end of the paper.

Sex and gender affect the social brain: Beyond simplicity.

As the most fascinating, complex, and dynamic part of our organism, the human brain is shaped by many interacting factors that not only are of neurobiological (including sex hormones) and environmental origin but are also sociocultural in their very nature (such as social roles). Gender is one of these factors. Most neurological, neurodevelopmental, neuropsychiatric, and psychosomatic disorders are characterized by impairments in visual social cognition (primarily body language reading and face perception) and a skewed sex ratio: females and males are affected differently in terms of clinical picture, prevalence, and severity. Is the social brain sex specific? This is still an open question. For a long time and for many reasons, sex differences have been overlooked or entirely ignored in neuroscience and biomedical research: there is a paucity of neuroimaging work examining sex differences in the social brain. However, the pattern of experimental behavioral data in both healthy, typically developing individuals and patients with deficient social cognition is beyond simple interpretation: contrary to popular wisdom, females are not always more proficient in understanding social signals, and their social abilities may be particularly affected by disease. Clarification of how neurobiological sex and sociocultural gender affect the social brain would provide novel insights into understanding gender-specific vulnerability to neuropsychiatric disorders. This interaction is far beyond simplicity. Although sex differences represent a rather delicate topic, underestimation or exaggeration of possible effects retards progress in the field. © 2016 Wiley Periodicals, Inc.

Clinical dimensions of a ‘biological concept’: transsexualism and the interplay between etiological theory and clinical therapy

In 1966, the Johns Hopkins University School of Medicine became the first American medical institution to perform sex reassignment surgeries. This article interrogates the relationship between the emergence of this clinical therapy in the United States and the changing medical understandings of the contemporaneous condition it was intended to address - 'transsexualism.' I argue that, during the mid-to-late twentieth century, therapeutic practices and theories about the etiology of transsexualism were mutually constitutive. On one hand, the clinical development of sex reassignment surgery precipitated a newfound interest in the possible biological, as opposed to psychopathological, underpinnings of transsexualism. At the same time, different theories about etiology were marshaled by both advocates and critics of sex reassignment in their efforts to secure or undercut the medical legitimacy and clinical presence of competing therapeutic practices. Debates surrounding transsexualism's etiology were therefore about much more than the causes of this condition: these etiological conversations also intervened in fundamental debates about the ethics of medical care and the therapeutic identity of different clinical practices (that is, whether sex reassignment and psychotherapy were to be considered primarily symptomatic or curative).

Sexual dimorphisms in swimming behavior, cerebral metabolic activity and adrenoceptors in adult zebrafish (Danio rerio)

Sexually dimorphic behaviors and brain sex differences, not only restricted to reproduction, are considered to be evolutionary preserved. Specifically, anxiety related behavioral repertoire is suggested to exhibit sex-specific characteristics in rodents and primates. The present study investigated whether behavioral responses to novelty, have sex-specific characteristics in the neurogenetic model organism zebrafish (Danio rerio), lacking chromosomal sex determination. For this, aspects of anxiety-like behavior (including reduced exploration, increased freezing behavior and erratic movement) of male and female adult zebrafish were tested in a novel tank paradigm and after habituation. Male and female zebrafish showed significant differences in their swimming activity in response to novelty, with females showing less anxiety spending more time in the upper tank level. When fish have habituated, regional cerebral glucose uptake, an index of neuronal activity, and brain adrenoceptors’ (ARs) expression (α2-ARs and β-ARs) were determined using in vivo 2-[14C]-deoxyglucose methodology and in vitro neurotransmitter receptors quantitative autoradiography, respectively. Intriguingly, females exhibited higher glucose utilization than males in hypothalamic brain areas. Adrenoceptor’s expression pattern was dimorphic in zebrafish telencephalic, preoptic, hypothalamic nuclei, central gray, and cerebellum, similarly to birds and mammals. Specifically, the lateral zone of dorsal telencephalon (Dl), an area related to spatial cognition, homologous to the mammalian hippocampus, showed higher α2-AR densities in females. In contrast, male cerebellum included higher densities of β-ARs in comparison to female. Taken together, our data demonstrate a well-defined sex discriminant cerebral metabolic activity and ARs’ pattern in zebrafish, possibly contributing to male-female differences in the swimming behavior.

English

Brain sex does not always match the body sex, which is biologically acquired during intrauterine life and is affected by environmental factors that affect brain wiring developments of life events. The aim of present study was to investigate the neurocognitive functioning which is dependent on brain sex matters rather than the biological sex in normal healthy volunteers. A total of 126 participants were selected who filled and signed a special brain sex matter questionnaire as yes or no, which included a set of some special/specific and general questions. After, completing this questionnaire the participants were divided into four groups, group І: as very male brain sex, group ІІ: as very female brain sex, group ІІІ: as intermediate male brain sex and group ІV: as intermediate female brain sex respectively and then each group was subjected to a neurocognitive test by Leeds psychomotor battery tester. The psychomotor performance task and cortical arousal activity differences between very male brain sex and very female brain sex were found to be significant in total reaction time (TRT) p 0.05, While as, psychomotor performance task and cortical arousal activity differences between very female brain sex and intermediate female brain sex, significant differences were found only in movement reaction time (MRT) between the two groups p=0.005. Based on the finding it can be assumed that biological sex with very male brain sex matter has a superior neurocognitive function.

Neurological damage disrupts normal sex differences in psychophysiological responsiveness to music.

Men and women often display different physiological responses to emotional stimuli, and these responses can be affected by brain damage. Here, we investigated how brain damage differentially affects electrodermal responses based on sex. We studied neurologically normal, healthy adults and a sample of neurological patients. Participants listened to music, an emotional stimulus that reliably elicits skin conductance responses (SCRs). Electrodermal activity was recorded while participants listened to musical clips. When analyzing the data without regard to sex, there were no differences between healthy and brain-damaged participants in their SCRs. However, we found a significant interaction between brain injury status and sex. For men, brain damage significantly reduced SCRs. For women, there were no differences between brain-damaged participants and neurologically healthy participants. These findings illustrate the importance of including demographic variables, such as sex, when investigating brain-behavior relationships with a psychophysiological dependent variable.

Hormone modulation improves cognition in schizophrenia

Sex and stress hormones are reciprocally regulated and have opposing neurobiological effects (Sinclair et al, 2014). Molecular changes in brain sex and stress hormone receptors indicate that these systems are out of balance in people with schizophrenia. Furthermore, increased stress can precipitate the onset or trigger the relapse of psychosis, while low levels of estrogen can exacerbate symptoms in females with schizophrenia (Heringa et al, 2015). Also, the sex and stress hormone signaling systems are both activated at a time of increased risk for first developing schizophrenia, during human adolescence, when the prefrontal cortex appears primed to respond to cortisol (Sinclair et al, 2011) and when sex steroids are flooding the brain. While we often study these major hormonal systems individually, there is greater awareness that they work in concert and should be considered together.

At the frontier of epigenetics of brain sex differences.

The notion that epigenetics may play an important role in the establishment and maintenance of sex differences in the brain has garnered great enthusiasm but the reality in terms of actual advances has been slow. Two general approaches include the comparison of a particular epigenetic mark in males vs. females and the inhibition of key epigenetic enzymes or co-factors to determine if this eliminates a particular sex difference in brain or behavior. The majority of emphasis has been on candidate genes such as steroid receptors. Only recently have more generalized survey type approaches been achieved and these promise to open new vistas and accelerate discovery of important roles for DNA methylation, histone modification, genomic imprinting and microRNAs (miRs). Technical challenges abound and, while not unique to this field, will require novel thinking and new approaches by behavioral neuroendocrinologists.

Sex differences in the brain: a whole body perspective.

Most writing on sexual differentiation of the mammalian brain (including our own) considers just two organs: the gonads and the brain. This perspective, which leaves out all other body parts, misleads us in several ways. First, there is accumulating evidence that all organs are sexually differentiated, and that sex differences in peripheral organs affect the brain. We demonstrate this by reviewing examples involving sex differences in muscles, adipose tissue, the liver, immune system, gut, kidneys, bladder, and placenta that affect the nervous system and behavior. The second consequence of ignoring other organs when considering neural sex differences is that we are likely to miss the fact that some brain sex differences develop to compensate for differences in the internal environment (i.e., because male and female brains operate in different bodies, sex differences are required to make output/function more similar in the two sexes). We also consider evidence that sex differences in sensory systems cause male and female brains to perceive different information about the world; the two sexes are also perceived by the world differently and therefore exposed to differences in experience via treatment by others. Although the topic of sex differences in the brain is often seen as much more emotionally charged than studies of sex differences in other organs, the dichotomy is largely false. By putting the brain firmly back in the body, sex differences in the brain are predictable and can be more completely understood.

Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain

Aromatase, which converts testosterone in estradiol, is involved in the generation of brain sex dimorphisms. Here we used the “four core genotypes” mouse model, in which the effect of gonadal sex and sex chromosome complement is dissociated, to determine if sex chromosomes influence the expression of brain aromatase. The brain of 16 days old XY mouse embryos showed higher aromatase expression in the stria terminalis and the anterior amygdaloid area than the brain of XX embryos, independent of gonadal sex. Furthermore, estradiol or dihydrotestosterone increased aromatase expression in cultures of anterior amygdala neurons derived from XX embryos, but not in those derived from XY embryos. This effect was also independent of gonadal sex. The expression of other steroidogenic molecules, estrogen receptor-α and androgen receptor was not influenced by sex chromosomes. In conclusion, sex chromosomes determine sex dimorphisms in aromatase expression and regulation in the developing mouse brain.

“Brain sex differentiation” in teleosts: Emerging concepts with potential biomarkers

“Brain sex differentiation” in teleosts is a contentious topic of research as most of the earlier reports tend to suggest that gonadal sex differentiation drives brain sex differentiation. However, identification of sex-specific marker genes in the developing brain of teleosts signifies brain–gonadal interaction during early sexual development in lower vertebrates. In this context, the influence of gonadotropin-releasing hormone (GnRH)–gonadotropin (GTH) axis on gonadal sex differentiation, if any requires in depth analysis. Presence of seabream (sb) GnRH immunoreactivity (ir−) in the brain of XY Nile tilapia was found as early as 5days post hatch (dph) followed by qualitative reduction in the preoptic area-hypothalamus region. In contrast, in the XX female brain a steady ir− of sbGnRH was evident from 15dph. Earlier studies using sea bass already implied the importance of hypothalamic gonadotropic axis completion during sex differentiation period. Such biphasic pattern of localization was also seen in pituitary GTHs using heterologous antisera in tilapia. However, more recent analysis in the same species could not detect any sexually dimorphic pattern using homologous antisera for pituitary GTHs. Detailed studies on the development of hypothalamo–hypophyseal–gonadal axis in teleosts focusing on hypothalamic monoamines (MA) and MA-related enzymes demonstrated sex-specific differential expression of tryptophan hydroxylase (Tph) in the early stages of developing male and female brains of tilapia and catfish. The changes in Tph expression was in agreement with the levels of serotonin (5-HT) and 5-hydroxytryptophan in the preoptic area-hypothalamus. Considering the stimulatory influence of 5-HT on GnRH and GTH release, it is possible to propose a network association between these correlates during early development, which may bring about brain sex dimorphism in males. A recent study from our laboratory during female brain sex development demonstrated high expression of tyrosine hydroxylase in correlation with catecholamine levels, brain aromatase and its related transcription factors such as fushi tarazu factor 1, Ftz-f1 and fork head box protein L2, foxl2. Taken together, gender differences in the levels of various transcripts provide new perspectives on brain sex differentiation in lower vertebrates. Sexually dimorphic or differentially expressing genes may play an essential role at the level of brain in response to gonadal differentiation, which might consequentially or causatively respond to gonadal sex.

The Effects of Perinatal Androgen Deprivation on Sexual Motivation in Male Rats

Testosterone and its metabolites—estrogen and dihydrotestosterone— are involved in the brain sex differentiation during the perinatal period by binding to androgen receptors (AR) or estrogen receptors (ER). However, in the presence of flutamide (FLU), testosterone that is metabolized to estrogen will only bind to ER. Blockade of AR using FLU during the perinatal period could alter the levels of estrogen, which in turn, may modulate the sex differentiation of the brain. This study tested perinatal androgen deprivation on estrogen levels and in turn, its effects on sexual motivation paradigm in male rats.Animals (N=37) were divided into two groups: Group 1 received FLU (20 mg/kg; SC) during perinatal period (prenatal day 4 ‐ postnatal day 4) and Group 2 served as control. On postnatal day 65, these groups were divided into 3 subgroups (injected 5 days/week x 7 weeks): A. finasteride (20 mg/kg, SC), an α‐reductase inhibitor, B. letrozole (2 mg/kg, SC), an aromatase inhibitor and C. vehicle. Each male rat had a choice of approaching a cage containing a gonadally‐intact female or an ovariectomized (OVX) rat for 20 minutes. The movement of the male rat was video‐tracked by Any‐Maze. In addition, serum estrogen levels were measured using ELISA.Animals receiving FLU not only had high serum estrogen levels, but also exhibited no preference for the gonadally‐intact or the OVX female. On the other hand, the control‐vehicle group spent more time with the gonadally‐intact than the OVX rat. These results suggest that perinatal androgen deprivation in male rats results in high levels of estrogen and lack of sexual motivation towards gonadally‐intact female rats.

The Effects of Perinatal Androgen Deprivation on Locomotor Activity in Male Rats

Testosterone and its metabolites—estrogen and dihydrotestosterone— are involved in the brain sex differentiation during the perinatal period by binding to androgen receptors (AR) or estrogen receptors (ER). However, in the presence of flutamide (FLU), testosterone that is metabolized to estrogen will only bind to ER. Blockade of AR using FLU during the perinatal period could alter the levels of estrogen, which in turn, may modulate the sex differentiation of the brain. This study tested perinatal androgen deprivation on estrogen levels and, in turn, its effects on locomotor activity in male rats.Long‐Evans rats (N=37) were divided into two groups: Group 1 received FLU (20 mg/kg; SC) during perinatal period (prenatal day 4 ‐ postnatal day 4) & Group 2 served as control. On postnatal day 65, these groups were divided into 3 subgroups (injected 5 days/week x 7 weeks): A. finasteride (20 mg/kg, SC), an α‐reductase inhibitor, B. letrozole (2 mg/kg, SC), an aromatase inhibitor and C. vehicle.Open Field (OF) Paradigm: Each animal was tested every week in an OF apparatus where the rat was allowed to explore the OF for 6 minutes. The time spent in the center of the field was compared with the time spent in the periphery using Any‐Maze. In addition, serum estrogen levels were measured using ELISA.Animals receiving FLU not only had high serum estrogen levels but also showed increased locomotor activity by spending significantly more time in the center field. These results suggest that perinatal androgen deprivation results in high levels of estrogen that may contribute to their willingness to explore freely.

The Effects of Perinatal Androgen Deprivation on Body Weight and Spatial Working Memory in Male Rats

Testosterone and its metabolites—estrogen and dihydrotestosterone— are involved in the brain sex differentiation during the perinatal period by binding to androgen receptors (AR) or estrogen receptors (ER). However, in the presence of flutamide, testosterone that is metabolized to estrogen will only bind to ER. Blockade of AR using flutamide during the perinatal period could affect the levels of estrogen, which in turn, may modulate the sex differentiation of the brain. Any such change in estrogen levels is expected to alter memory. This study tested perinatal androgen deprivation on estrogen levels and in turn, its effects on spatial working memory (SWM) in male rats. Long- Evans rats (N=37) were divided into two groups: Group 1 was administered flutamide (20 mg/kg; SC) during perinatal period (prenatal day 4 - postnatal day 4), Group 2 served as control. On postnatal day 65, these groups were divided into 3 subgroups:A. finasteride (FIN; 20 mg/kg, SC), an α-reductase inhibitor, B. letrozole (2 mg/kg, SC), an aromatase inhibitor and C. vehicle (VEH) and injected 5 days/week x 7 weeks. Prior to performing Radial Arm Maze Test to assess their SWM, animals were placed on a 60 % food restriction. Subsequently, serum estrogen levels were measured using ELISA. Animals from Group 1-FIN and -VEH exhibited greater choice accuracy in locating arms with food suggesting improved SWM. Moreover, Group 1 showed a significant increase in body weight compared to Group 2 as well as higher serum estrogen levels implying a relationship between body weight, memory and estrogen.

Mapping plasticity: Sex/gender and the changing brain

Abstract There is a consensus in the neuroscientific literature that brains are either male or female, and that ‘brain sex’ is a fixed, immutable trait. Feminist critics have challenged this idea, raising questions, for example, about brain plasticity (the role of sociocultural factors in the emergence and endurance of brain structure and function). However, neuroscientific studies of sex/gender differences still rarely consider these factors. This paper discusses brain plasticity as a shared point of interest for the neurosciences and feminist theory. Plasticity arguments resonate strongly with longstanding feminist arguments about the interaction of nature and nurture, the embodiment of social practices, and the performative nature of gender. However, whether it is appropriate and productive for feminist theory to approach the gendered subject as a plastic, cerebral subject is up for discussion. This paper explores these different dimensions. I pay detailed attention to the concern that plasticity arguments can corroborate the idea of brain sex as effectively as they can undermine it. Depending on how broadly one defines plasticity, the focus of research can be on ‘the plasticity of sex differences’ or on ‘sex differences in plasticity’. I conclude that a traditional definition of plasticity, according to which the brain is largely stable, conserves the idea of brain sex. However, the alternative ‐ framing the brain as fundamentally and infinitely plastic ‐ also raises concerns.

Effects of bisphenol A and fadrozole exposures on cyp19a1 expression in the Murray rainbowfish, Melanotaenia fluviatilis.

Several endocrine-disrupting chemicals (EDCs) have been attributed to the alteration of reproduction in fish through disrupting endogenous sex steroidogenic pathways including aromatisation of androgens to oestrogen by CYP19 aromatase. Here we investigate this hypothesis in adult male and female Melanotaenia fluviatilis by examining the mRNA expression of cyp19a1 isoforms after exposure for ≤96 h to two EDCs with contrasting modes of action: one a weak oestrogen mimic, bisphenol A [BPA (100 or 500 μg/L)], and the other a nonsteroidal aromatase inhibitor, fadrozole [FAD (10 or 50 µg/L)]. The results suggest that BPA did not affect cyp19a1a expression significantly at both concentrations, whereas 50 µg/L of FAD significantly upregulated its expression in ovary. In contrast, BPA exposures increased expression of cyp19a1b in brain of both males and females, whilst FAD had contrasting effects in brain: It increased in males but decreased in females. Similar contrasting responses of cyp19a1b were induced by BPA in gonads: upregulation in ovary and downregulation in testis. FAD did not have a significant effect on gonadal expression of cyp19a1b. Collectively, the results suggest that BPA and FAD can disrupt cyp19a1b activity more readily than can cyp19a1a, albeit with contrasting effects in either a tissue- or sex-specific context that is conceivably consistent with their (BPA and FAD) opposing modes of action. Enhanced spatial and temporal sensitivity of cyp19a1b compared with cyp19a1a suggests that brain sex of fish is more susceptible to disruption by environmental pollutants such as BPA and FAD. Therefore, we propose that the response of cyp19a1b in brain tissue of M. fluviatilis is a more suitable indicator of oestrogenic pollution in the aquatic environment.

A Starring Role for Microglia in Brain Sex Differences

Microglia, the resident innate immune cells in the brain, have long been understood to be crucial to maintenance in the nervous system, by clearing debris, monitoring for infiltration of infectious agents, and mediating the brain’s inflammatory and repair response to traumatic injury, stroke, or neurodegeneration. A wave of new research has shown that microglia are also active players in many basic processes in the healthy brain, including cell proliferation, synaptic connectivity, and physiology. Microglia, both in their capacity as phagocytic cells and via secretion of many neuroactive molecules, including cytokines and growth factors, play a central role in early brain development, including sexual differentiation of the brain. In this review, we present the vast roles microglia play in normal brain development and how perturbations in the normal neuroimmune environment during development may contribute to the etiology of brain-based disorders. There are notable differences between microglia and neuroimmune signaling in the male and female brain throughout the life span, and these differences may contribute to the vast differences in the incidence of neuropsychiatric and neurological disorders between males and females.