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At the frontier of epigenetics of brain sex differences.

McCarthy MM, Nugent BM - Front Behav Neurosci (2015)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Maryland School of Medicine Baltimore, MD, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Sexual differentiation of brain and behavior. Sex differences in the brain are established early in development during a critical period. Feminization of the brain proceeds in the absence of exposure to elevated gonadal steroids during the critical period and masculinization occurs when the fetal testis begins production of androgens at the beginning of the critical period, the end of which is defined by the developmental stage at which exogenous administration of androgens to females is ineffective at switching brain development from feminization to masculinization. Gonadal hormones rise again in adulthood and promote sex differences in behavior by acting on a neural substrate that was organized differently in males and females. A central question in behavioral neuroendocrinology has been how early life exposure to androgens exerts an enduring influence on adult brain and behavior.
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Figure 1: Sexual differentiation of brain and behavior. Sex differences in the brain are established early in development during a critical period. Feminization of the brain proceeds in the absence of exposure to elevated gonadal steroids during the critical period and masculinization occurs when the fetal testis begins production of androgens at the beginning of the critical period, the end of which is defined by the developmental stage at which exogenous administration of androgens to females is ineffective at switching brain development from feminization to masculinization. Gonadal hormones rise again in adulthood and promote sex differences in behavior by acting on a neural substrate that was organized differently in males and females. A central question in behavioral neuroendocrinology has been how early life exposure to androgens exerts an enduring influence on adult brain and behavior.

Mentions: In addition to the variety of possible epigenetic changes noted above, there is also a need to separate and interpret findings by developmental state, sex (obviously), brain region and cell type. When considering brain sex differences all of these are fundamental, beginning with developmental stage. The principle drivers of sex differences are steroid hormones, which differ profoundly in males and females at some times of life and very little or not at all at other times of life. Early exposure to steroids has enduring effects and most brain sex differences are established during a critical developmental window, although the timing of the window may vary for different endpoints as well as for masculinization vs. feminization. For steroid-mediated masculinization of reproductive behavior, the beginning of the critical window is delineated by the onset of gonadal steroidogenesis by the testis of the fetal male (around embryonic day 18 in rats and mice) and the close is the developmental age at which a female brain is no longer sensitive to exogenously induced masculinization which is accomplished by steroid injection (Figure 1). In our rodent models this is about 1 week after birth. Thus the sensitive period is perinatal, i.e., both prior to and just after birth. In primates evidence to date suggests the process of brain sexual differentiation is largely prenatal although the exact parameters are difficult to firmly establish for the obvious reasons associated with work in humans and primates. The interested reader is referred to the following reviews for a more thorough discussion of the details of sexual differentiation (Arnold et al., 2003; De Vries, 2004; Morris et al., 2004; Forger, 2006; de Vries and Södersten, 2009; McCarthy et al., 2009b, 2012; McCarthy and Arnold, 2011; Shen et al., 2015).


At the frontier of epigenetics of brain sex differences.

McCarthy MM, Nugent BM - Front Behav Neurosci (2015)

Sexual differentiation of brain and behavior. Sex differences in the brain are established early in development during a critical period. Feminization of the brain proceeds in the absence of exposure to elevated gonadal steroids during the critical period and masculinization occurs when the fetal testis begins production of androgens at the beginning of the critical period, the end of which is defined by the developmental stage at which exogenous administration of androgens to females is ineffective at switching brain development from feminization to masculinization. Gonadal hormones rise again in adulthood and promote sex differences in behavior by acting on a neural substrate that was organized differently in males and females. A central question in behavioral neuroendocrinology has been how early life exposure to androgens exerts an enduring influence on adult brain and behavior.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543874&req=5

Figure 1: Sexual differentiation of brain and behavior. Sex differences in the brain are established early in development during a critical period. Feminization of the brain proceeds in the absence of exposure to elevated gonadal steroids during the critical period and masculinization occurs when the fetal testis begins production of androgens at the beginning of the critical period, the end of which is defined by the developmental stage at which exogenous administration of androgens to females is ineffective at switching brain development from feminization to masculinization. Gonadal hormones rise again in adulthood and promote sex differences in behavior by acting on a neural substrate that was organized differently in males and females. A central question in behavioral neuroendocrinology has been how early life exposure to androgens exerts an enduring influence on adult brain and behavior.
Mentions: In addition to the variety of possible epigenetic changes noted above, there is also a need to separate and interpret findings by developmental state, sex (obviously), brain region and cell type. When considering brain sex differences all of these are fundamental, beginning with developmental stage. The principle drivers of sex differences are steroid hormones, which differ profoundly in males and females at some times of life and very little or not at all at other times of life. Early exposure to steroids has enduring effects and most brain sex differences are established during a critical developmental window, although the timing of the window may vary for different endpoints as well as for masculinization vs. feminization. For steroid-mediated masculinization of reproductive behavior, the beginning of the critical window is delineated by the onset of gonadal steroidogenesis by the testis of the fetal male (around embryonic day 18 in rats and mice) and the close is the developmental age at which a female brain is no longer sensitive to exogenously induced masculinization which is accomplished by steroid injection (Figure 1). In our rodent models this is about 1 week after birth. Thus the sensitive period is perinatal, i.e., both prior to and just after birth. In primates evidence to date suggests the process of brain sexual differentiation is largely prenatal although the exact parameters are difficult to firmly establish for the obvious reasons associated with work in humans and primates. The interested reader is referred to the following reviews for a more thorough discussion of the details of sexual differentiation (Arnold et al., 2003; De Vries, 2004; Morris et al., 2004; Forger, 2006; de Vries and Södersten, 2009; McCarthy et al., 2009b, 2012; McCarthy and Arnold, 2011; Shen et al., 2015).

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Maryland School of Medicine Baltimore, MD, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus