scholarly journals Evidence of Altered Brain Sexual Differentiation in Mice Exposed Perinatally to Low, Environmentally Relevant Levels of Bisphenol A

Endocrinology ◽  
2006 ◽  
Vol 147 (8) ◽  
pp. 3681-3691 ◽  
Author(s):  
Beverly S. Rubin ◽  
Jenny R. Lenkowski ◽  
Cheryl M. Schaeberle ◽  
Laura N. Vandenberg ◽  
Paul M. Ronsheim ◽  
...  
Keyword(s):  
Sex Differences ◽  
Bisphenol A ◽  
Brain Development ◽  
Sexual Differentiation ◽  
Female Offspring ◽  
Sexually Dimorphic ◽  
Critical Periods ◽  
Neuron Number ◽  
Brain Sexual Differentiation ◽  
Estrogenic Chemical

Humans are routinely exposed to bisphenol A (BPA), an estrogenic chemical present in food and beverage containers, dental composites, and many products in the home and workplace. BPA binds both classical nuclear estrogen receptors and facilitates membrane-initiated estrogenic effects. Here we explore the ability of environmentally relevant exposure to BPA to affect anatomical and functional measures of brain development and sexual differentiation. Anatomical evidence of alterations in brain sexual differentiation were examined in male and female offspring born to mouse dams exposed to 0, 25, or 250 ng BPA/kg body weight per day from the evening of d 8 of gestation through d 16 of lactation. These studies examined the sexually dimorphic population of tyrosine hydroxylase (TH) neurons in the rostral periventricular preoptic area, an important brain region for estrous cyclicity and estrogen-positive feedback. The significant sex differences in TH neuron number observed in control offspring were diminished or obliterated in offspring exposed to BPA primarily because of a decline in TH neuron number in BPA-exposed females. As a functional endpoint of BPA action on brain sexual differentiation, we examined the effects of perinatal BPA exposure on sexually dimorphic behaviors in the open field. Data from these studies revealed significant sex differences in the vehicle-exposed offspring that were not observed in the BPA-exposed offspring. These data indicate that BPA may be capable of altering important events during critical periods of brain development.

scholarly journals Sex differences in the gut microbiome–brain axis across the lifespan

2016 ◽  
Vol 371 (1688) ◽  
pp. 20150122 ◽  
Author(s):  
Eldin Jašarević ◽  
Kathleen E. Morrison ◽  
Tracy L. Bale
Keyword(s):  
Sex Differences ◽  
Brain Development ◽  
Cross Talk ◽  
Gut Microbiome ◽  
Disease Risk ◽  
Sexually Dimorphic ◽  
Risk And Resilience ◽  
Functional Potential ◽  
Bidirectional Communication ◽  
The Brain

In recent years, the bidirectional communication between the gut microbiome and the brain has emerged as a factor that influences immunity, metabolism, neurodevelopment and behaviour. Cross-talk between the gut and brain begins early in life immediately following the transition from a sterile in utero environment to one that is exposed to a changing and complex microbial milieu over a lifetime. Once established, communication between the gut and brain integrates information from the autonomic and enteric nervous systems, neuroendocrine and neuroimmune signals, and peripheral immune and metabolic signals. Importantly, the composition and functional potential of the gut microbiome undergoes many transitions that parallel dynamic periods of brain development and maturation for which distinct sex differences have been identified. Here, we discuss the sexually dimorphic development, maturation and maintenance of the gut microbiome–brain axis, and the sex differences therein important in disease risk and resilience throughout the lifespan.

Recipe for a sexually dimorphic brain: Ingredients include ovarian and testicular hormones

1998 ◽  
Vol 21 (3) ◽  
pp. 330-331 ◽  
Author(s):  
Diane F. Halpern
Keyword(s):  
Brain Development ◽  
Neural Activity ◽  
Sexual Differentiation ◽  
Ovarian Hormones ◽  
Sexually Dimorphic ◽  
Transient Effects ◽  
Measurement Issues ◽  
False Dichotomy ◽  
New Knowledge ◽  
The Brain

New knowledge about the sexual differentiation of the brain profoundly changes our understanding of basic topics in brain development such as the false dichotomy between long-lasting and transient effects of hormones on neural activity, the importance of ovarian hormones in brain development, the plasticity of neural structures throughout the life span, and the way measurement issues affect research conclusions.

scholarly journals Epigenetic Control of Sexual Differentiation of the Bed Nucleus of the Stria Terminalis

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4241-4247 ◽  
Author(s):  
Elaine K. Murray ◽  
Annie Hien ◽  
Geert J. de Vries ◽  
Nancy G. Forger
Keyword(s):  
Cell Death ◽  
Sex Differences ◽  
Sexual Differentiation ◽  
Cell Number ◽  
Histone Deacetylation ◽  
Postnatal Life ◽  
Sexually Dimorphic ◽  
Stria Terminalis ◽  
Bed Nucleus ◽  
Deacetylase Inhibitor

Abstract The principal nucleus of the bed nucleus of the stria terminalis (BNSTp) is larger in volume and contains more cells in male than female mice. These sex differences depend on testosterone and arise from a higher rate of cell death during early postnatal life in females. There is a delay of several days between the testosterone surge at birth and sexually dimorphic cell death in the BNSTp, suggesting that epigenetic mechanisms may be involved. We tested the hypothesis that chromatin remodeling plays a role in sexual differentiation of the BNSTp by manipulating the balance between histone acetylation and deacetylation using a histone deacetylase inhibitor. In the first experiment, a single injection of valproic acid (VPA) on the day of birth increased acetylation of histone H3 in the brain 24 h later. Next, males, females, and females treated neonatally with testosterone were administered VPA or saline on postnatal d 1 and 2 and killed at 21 d of age. VPA treatment did not influence volume or cell number of the BNSTp in control females but significantly reduced both parameters in males and testosterone-treated females. As a result, the sex differences were eliminated. VPA did not affect volume or cell number in the suprachiasmatic nucleus or the anterodorsal nucleus of the thalamus, which also did not differ between males and females. These findings suggest that a disruption in histone deacetylation may lead to long-term alterations in gene expression that block the masculinizing actions of testosterone in the BNSTp.

Sex differences in the serum concentrations of testosterone in mice and hamsters during their critical periods of neural sexual differentiation

1984 ◽  
Vol 100 (1) ◽  
pp. 7-11 ◽  
Author(s):  
S. F. Pang ◽  
F. Tang
Keyword(s):  
Sex Differences ◽  
Sexual Differentiation ◽  
Critical Period ◽  
Serum Levels ◽  
Serum Concentrations ◽  
Critical Periods ◽  
Minimum Concentration ◽  
Male And Female ◽  
Dose Dependent ◽  
Circulating Levels

ABSTRACT Male and female mice and hamsters were decapitated 1–5 days after birth and serum concentrations of testosterone determined by radioimmunoassay. In the two species studied, serum levels of testosterone in male pups were significantly (P <0·05) higher than those obtained in female neonates. This lends support to the hypothesis that circulating levels of testosterone play an important role in the process of neural sexual differentiation in rodents. Moreover, the sex differences in serum concentrations of testosterone in neonatal rodents together with the detectable levels of testosterone in female neonates may suggest that androgenization is a dose-dependent phenomenon. Alternatively, they may indicate that a minimum concentration of the steroid must be present for androgenization to occur during the critical period of neural sexual differentiation and that this 'threshold' is exceeded in male but not in female rodents. J. Endocr. (1984) 100, 7–11

Effects of aroclor 1254 on the expression of the KAP3 gene and reproductive function in rats

2007 ◽  
Vol 19 (4) ◽  
pp. 539 ◽  
Author(s):  
Chae Kwan Lee ◽  
Han Seung Kang ◽  
Ju Ran Kim ◽  
Byung Ju Lee ◽  
Jong Tae Lee ◽  
...  
Keyword(s):  
Sexual Differentiation ◽  
Reproductive Function ◽  
Female Rats ◽  
Mrna Levels ◽  
Critical Periods ◽  
Control Groups ◽  
Control Male ◽  
Control Female ◽  
Male Control ◽  
Brain Sexual Differentiation

The present study investigated the effects of aroclor 1254 (A1254) on the expression of the kinesin superfamily associated protein 3 (KAP3) gene in F1 rat brain during brain sexual differentiation and puberty. In addition, the effects of A1254 on reproductive function were examined. The KAP3 gene is involved in the neurogenesis and synaptogenesis of sexual differentiation in rats and also during puberty. In the present study, pregnant Sprague–Dawley rats each received a daily dose of A1254 (0, 10, 50 mg kg–1) dissolved in 1.0 mL corn oil by gavage, from gestational Day (GD) 8 to postnatal Day (PD) 21. The mRNA levels of the KAP3 gene in hypothalamic tissues were analysed by northern blot hybridisation during the critical periods of brain sexual differentiation (GD18 and PD5) and puberty (PD28). Variables affecting reproduction in F1 female rats, such as vaginal opening (VO), vaginal oestrus (VE) and oestrous cyclicity, were recorded. Depending on the sex and A1254 exposure (control or 50 mg kg–1 day–1), F1 rats were divided into three mating groups, namely control male–control female, control male–A1254-treated female and A1254-treated male–control female. During the critical periods of brain sexual differentiation (GD18, PD5) and puberty (PD28), KAP3 mRNA levels were significantly reduced in A1254-treated fetal and pubertal rat brains relative to those of control groups. In A1254-treated F1 female rats, VO and VE were delayed, the percentage of irregular oestrous cycles was increased and the duration of the oestrous cycle was extended in a dose-dependent manner compared with control groups. Treatment with a high dose of A1254 significantly impaired the reproductive function of both male and female F1 rats, including mating and pregnancy indices and the number of live fetuses. These data suggest that A1254 disrupts transcriptional regulation of the KAP3 gene in fetal and pubertal rat brains and that these effects may be related to A1254-induced abnormal brain sexual differentiation and lowered reproductive function in F1 rats.

scholarly journals Neuroendocrine-Immune Crosstalk Shapes Sex-Specific Brain Development

Endocrinology ◽  
2020 ◽  
Vol 161 (6) ◽  
Author(s):  
Sheryl E Arambula ◽  
Margaret M McCarthy
Keyword(s):  
Sex Differences ◽  
Brain Development ◽  
Sexual Differentiation ◽  
Gonadal Hormones ◽  
Neuroimmune System ◽  
Overwhelming Evidence ◽  
Brain Structure And Function ◽  
New Research ◽  
And Function ◽  
The Brain

Abstract Sex is an essential biological variable that significantly impacts multiple aspects of neural functioning in both the healthy and diseased brain. Sex differences in brain structure and function are organized early in development during the critical period of sexual differentiation. While decades of research establish gonadal hormones as the primary modulators of this process, new research has revealed a critical, and perhaps underappreciated, role of the neuroimmune system in sex-specific brain development. The immune and endocrine systems are tightly intertwined and share processes and effector molecules that influence the nervous system. Thus, a natural question is whether endocrine-immune crosstalk contributes to sexual differentiation of the brain. In this mini-review, we first provide a conceptual framework by classifying the major categories of neural sex differences and review the concept of sexual differentiation of the brain, a process occurring early in development and largely controlled by steroid hormones. Next, we describe developmental sex differences in the neuroimmune system, which may represent targets or mediators of the sexual differentiation process. We then discuss the overwhelming evidence in support of crosstalk between the neuroendocrine and immune systems and highlight recent examples that shape sex differences in the brain. Finally, we review how early life events can perturb sex-specific neurodevelopment via aberrant immune activation.

scholarly journals Sexual Differentiation in the Neonate: Rodent vs. Primate Comparisons

1989 ◽  
Vol 8 (5) ◽  
pp. 971-979
Author(s):  
Jeanne M. Manson
Keyword(s):  
Gender Identity ◽  
Sexual Differentiation ◽  
Reproductive Tract ◽  
Mammalian Species ◽  
External Genitalia ◽  
First Trimester ◽  
Female Offspring ◽  
Gonadal Hormones ◽  
Strong Impact ◽  
Critical Periods

There are some similarities and differences in the process of sexual differentiation during development in rodents and primates. The most obvious difference is in the timing of the critical periods for morphogenesis of the reproductive tract and sexual differentiation of the central nervous system (CNS). In primates these events occur late in the first trimester while in rodents they occur in the perinatal period. The gonadal hormones involved in morphogenesis of the male reproductive tract are identical for all mammalian species studied. Testosterone is the androgen that induces differentiation of the seminal vesicles, vas deferens, and epididymis, while dihydrotestosterone (DHT) promotes differentiation of the external genitalia, urethra, and prostate. Estrogens, derived from aromatization of testosterone, are the proximal determinants of male sexual differentiation of the CNS in rodents. In nonhuman primates, however, a nonaromatizable androgen, DHT, produces the same effect as testosterone on sexually differentiated behaviors in female offspring. Studies of male patients with 5α-reductase deficiency have suggested that maturation of male gender identity and psychosexual behavior in humans is critically dependent on testosterone but not on normal levels of DHT in prenatal and prepubertal life. Gender identity does not appear to be unalterably fixed in humans until the time of puberty and even at this and later times environmental factors have a strong impact.

Actions of Peripubertal Gonadal Steroids in the Formation of Sexually Dimorphic Brain Regions in Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (6) ◽  
Author(s):  
Masahiro Morishita ◽  
Ryoma Koiso ◽  
Shinji Tsukahara
Keyword(s):  
Sex Differences ◽  
Immunohistochemical Analysis ◽  
Brain Regions ◽  
Sexually Dimorphic ◽  
Stria Terminalis ◽  
Neuron Number ◽  
Bed Nucleus ◽  
Action Mechanisms ◽  
Sexually Dimorphic Nucleus ◽  
Immunohistochemical Analyses

Abstract The calbindin-sexually dimorphic nucleus (CALB-SDN) and calbindin-principal nucleus of the bed nucleus of the stria terminalis (CALB-BNSTp) show male-biased sex differences in calbindin neuron number. The ventral part of the BNSTp (BNSTpv) exhibits female-biased sex differences in noncalbindin neuron number. We previously reported that prepubertal gonadectomy disrupts the masculinization of the CALB-SDN and CALB-BNSTp and the feminization of the BNSTpv. This study aimed to determine the action mechanisms of testicular androgens on the masculinization of the CALB-SDN and CALB-BNSTp and whether ovarian estrogens are the hormones that have significant actions in the feminization of the BNSTpv. We performed immunohistochemical analyses of calbindin and NeuN, a neuron marker, in male mice orchidectomized on postnatal day 20 (PD20) and treated with cholesterol, testosterone, estradiol, or dihydrotestosterone during PD20-70, female mice ovariectomized on PD20 and treated with cholesterol or estradiol during PD20-70, and PD70 mice gonadectomized on PD56. Calbindin neurons number in the CALB-SDN and CALB-BNSTp in males treated with testosterone or dihydrotestosterone, but not estradiol, was significantly larger than that in cholesterol-treated males. Noncalbindin neuron number in the BNSTpv in estradiol-treated females was significantly larger than that in cholesterol-treated females. Gonadectomy on PD56 had no significant effect on neuron numbers. Additionally, an immunohistochemical analysis revealed the expression of androgen receptors in the CALB-SDN and CALB-BNSTp of PD30 males and estrogen receptors-α in the BNSTpv of PD30 females. These results suggest that peripubertal testicular androgens act to masculinize the CALB-SDN and CALB-BNSTp without aromatization, and peripubertal ovarian estrogens act to feminize the BNSTpv.

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