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Review
. 2020 Apr:120:104691.
doi: 10.1016/j.yhbeh.2020.104691. Epub 2020 Jan 31.

Sexual differentiation of brain and other tissues: Five questions for the next 50 years

Arthur P Arnold  1
Affiliations
Review

Sexual differentiation of brain and other tissues: Five questions for the next 50 years

Arthur P Arnold. Horm Behav. 2020 Apr.

Abstract

This paper is part of the celebration of the 50th anniversary of founding of the journal Hormones and Behavior, the official journal of the Society for Behavioral Neuroendocrinology. All sex differences in phenotypic development stem from the sexual imbalance in X and Y chromosomes, which are the only known differences in XX and XY zygotes. The sex chromosome genes act within cells to cause differences in phenotypes of XX and XY cells throughout the body. In the gonad, they determine the type of gonad, leading to differences in secretion of testicular vs. ovarian hormones, which cause further sex differences in tissue function. These current ideas of sexual differentiation are briefly contrasted with a hormones-only view of sexual differentiation of the last century. The multiple, independent action of diverse sex-biasing agents means that sex-biased factors can be synergistic, increasing sex differences, or compensatory, making the two sexes more equal. Several animal models have been fruitful in demonstrating sex chromosome effects, and interactions with gonadal hormones. MRI studies of human brains demonstrate variation in brain structure associated with both differences in gonadal hormones, and in the number of X and Y chromosomes. Five unanswered questions are posed as a challenge to future investigators to improve understanding of sexual differentiation throughout the body.

Keywords: Compensation; Sex chromosomes; Sex differences; Sexual differentiation; X chromosome; Y chromosome.

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Figures

Figure 1.
Figure 1.
A schematic diagram illustrating sex-biasing influences of sex chromosomes and gonadal hormones, which act independently and interdependently on cells in diverse tissues. Because different sex-biasing factors can work together or in opposition, their effect can be to make or reduce sex differences in emergent phenotypes. From (Arnold, 2019b), reprinted with permission of Elsevier.
Figure 2.
Figure 2.
An illustration of a sex chromosome effect on body weight in mice, which is thought to be caused in part by sex chromosome effects on feeding behavior (Chen et al., 2012; Chen et al., 2015). A. In Four Core Genotypes (FCG) mice, the four different groups do not differ in body weight at weaning (day 21). After puberty, at day 45, gonadal male (M) mice weigh more than gonadal female (F) mice (‡ p<0.000001), and XX mice weigh more than XY mice (* p<0.05). Ten months after mice are gonadectomized at 75 days of age, XX mice weigh more than XY († p<0.0001), and gonadal females weigh more than males (** p<0.01), an effect that is more prominent in gonadal females than males (interaction * p<0.05). B. In mice from the XY* model, nine months after gonadectomy at 75 days, mice with two X chromosome weigh more than those with one X chromosome (‡ p<0.000001), irrespective of gonadal sex. Modified from (Chen et al., 2012).
Figure 3.
Figure 3.
In an MRI study of brains of 5-25 year old humans, groups differed in the number and type of sex chromosomes. The left graph represents effect-size deviations of brain volumes relative to XY males. An increase in number of X chromosomes was associated with a reduction in total brain volume (TBV), cortical volume (CV), and surface area (SA), but not cortical thickness (CT). An increase in number of Y chromosomes was associated with an increase in all four variables. The right graph shows standardized effect-size estimates (± 95% confidence interval) for addition of one X or one Y chromosome on each anatomic dependent variable. From (Raznahan et al., 2016), by permission of Oxford University Press.
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