Conceptual frameworks and mouse models for studying sex differences in physiology and disease: Why compensation changes the game

Abstract

A sophisticated mechanistic understanding of physiology and disease requires knowledge of how sex-biasing factors cause sex differences in phenotype. In therian mammals, all sex differences are downstream of the unequal effects of XX vs. XY sex chromosomes. Three major categories of sex-biasing factors are activational and organizational effects of gonadal hormones, and sex chromosome effects operating outside of the gonads. These three types of effects can be discriminated from each other with established experimental designs and animal models. Two important mouse models, which allow conclusions regarding the sex-biasing effects of sex chromosome complement, interacting with gonadal hormone effects, are the Four Core Genotypes model and the XY* model. Chromosome Y consomic strains give information about the role of the Y chromosome. An important recent change in sexual differentiation theory is the increasing realization that sex-biasing factors can counteract the effects of each other, reducing rather than producing sex differences in phenotype. This change in viewpoint rationalizes a change in experimental strategies for dissecting sex chromosome effects. The overall goal is to understand the sexome, defined as the sum of effects of sex-biasing factors on gene systems and networks.

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

“…This interpretation follows the proposed hypothesis of the compensatory effect of the sex-biasing factors (De Vries, 2004), which has received increasing attention in the last years. Recently, Arnold (Arnold, 2014) incorporated the effect of sex chromosome complement in the developing brain as a mechanism to prevent or compensate for the potentially sex differentiating effects of gonadal hormone levels later in life. Thus, sex differences in brain aromatase expression in mouse embryos at E16, caused by sex chromosome factors, may prevent sex-differentiating effects of estradiol and DHT during the testosterone surge by the fetal testis at E17-18.…”

Epigenetics and sex differences in the brain: A genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice

“…The idea is that although sex differences may on average be small, in the aggregate these differences can cause functional effects. The sexome concept thus shifts attention from sex differences in single genes to whole-genome or gene network approaches (Arnold, 2014). Few such studies, however, have been conducted to date.…”

Of sex and determination: marking 25 years of Randy, the sex-reversed mouse

“…This 'four core genotype' model has now been used to explore the basis of many sex-specific differences, from neuroanatomy to food preferences. Moreover, it has led to a more general appreciation of how commonly such differences occur and their clinical importance (Arnold, 2014). Sry could itself have roles outside the gonad.…”