Mouse Models for Evaluating Sex Chromosome Effects that Cause Sex Differences in Non-Gonadal Tissues

The ability of nutrients to regulate specific metabolic pathways is often overshadowed by their role in basic sustenance. Consequently, the mechanisms whereby these nutrients protect against or promote a variety of acquired metabolic syndromes remains poorly understood. Premenopausal women are generally protected from the adverse effects of obesity despite having a greater proportion of body fat than men. Menopause is often associated with a transformation in body fat morphology and a gradual increase in the susceptibility to metabolic complications, eventually reaching the point where women and men are at equal risk. These phenomena are not explained solely by changes in food preference or nutrient intake suggesting an important role for the sex hormones in regulating the metabolic fate of nutrients and protecting against metabolic disease pathophysiology. Here, we discuss how differences in the acquisition, trafficking, and subceullular metabolism of fats and other lipid soluble nutrients in major organ systems can create overt sex-specific phenotypes, modulate metabolic disease risk, and contribute to the rise in obesity in the modern sedentary climate. Identifying the molecular mechanisms underpinning sex differences in fat metabolism requires the unravelling of the interactions among sex chromosome effects, the hormonal milieu, and diet composition. Understanding the mechanisms that give rise to sex differences in metabolism will help to rationalize treatment strategies for the management of sex-specific metabolic disease risk factors.

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Sex Differences in Ischemic Stroke Sensitivity Are Influenced by Gonadal Hormones, Not by Sex Chromosome Complement

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.186 ◽

2014 ◽

Vol 35 (2) ◽

pp. 221-229 ◽

Cited By ~ 66

Author(s):

Bharti Manwani ◽

Kathryn Bentivegna ◽

Sharon E Benashski ◽

Venugopal Reddy Venna ◽

Yan Xu ◽

...

Keyword(s):

Sex Differences ◽

Ischemic Stroke ◽

Sex Hormones ◽

Sex Chromosome ◽

Chromosome Complement ◽

Serum Testosterone ◽

Gonadal Hormones ◽

Epidemiologic Studies ◽

Artery Occlusion ◽

Male Mice

Epidemiologic studies have shown sex differences in ischemic stroke. The four core genotype (FCG) mouse model, in which the testes determining gene, Sry, has been moved from Y chromosome to an autosome, was used to dissociate the effects of sex hormones from sex chromosome in ischemic stroke outcome. Middle cerebral artery occlusion (MCAO) in gonad intact FCG mice revealed that gonadal males (XXM and XYM) had significantly higher infarct volumes as compared with gonadal females (XXF and XYF). Serum testosterone levels were equivalent in adult XXM and XYM, as was serum estrogen in XXF and XYF mice. To remove the effects of gonadal hormones, gonadectomized FCG mice were subjected to MCAO. Gonadectomy significantly increased infarct volumes in females, while no change was seen in gonadectomized males, indicating that estrogen loss increases ischemic sensitivity. Estradiol supplementation in gonadectomized FCG mice rescued this phenotype. Interestingly, FCG male mice were less sensitive to effects of hormones. This may be due to enhanced expression of the transgene Sry in brains of FCG male mice. Sex differences in ischemic stroke sensitivity appear to be shaped by organizational and activational effects of sex hormones, rather than sex chromosomal complement.

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Sex differences in mouse models of fear inhibition: Fear extinction, safety learning, and fear–safety discrimination

British Journal of Pharmacology ◽

10.1111/bph.14600 ◽

2019 ◽

Vol 176 (21) ◽

pp. 4149-4158 ◽

Cited By ~ 7

Author(s):

Jacob W. Clark ◽

Sean P.A. Drummond ◽

Daniel Hoyer ◽

Laura H. Jacobson

Keyword(s):

Sex Differences ◽

Mouse Models ◽

Fear Extinction

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Sex Differences in the Cerebellum and Frontal Cortex: Roles of Estrogen Receptor Alpha and Sex Chromosome Genes

Neuroendocrinology ◽

10.1159/000324402 ◽

2011 ◽

Vol 93 (4) ◽

pp. 230-240 ◽

Cited By ~ 37

Author(s):

Jean M. Abel ◽

Diane M. Witt ◽

Emilie F. Rissman

Keyword(s):

Estrogen Receptor ◽

Sex Differences ◽

Frontal Cortex ◽

Estrogen Receptor Alpha ◽

Sex Chromosome ◽

Receptor Alpha

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Sex differences in body fluid homeostasis: Sex chromosome complement influences on bradycardic baroreflex response and sodium depletion induced neural activity

Physiology & Behavior ◽

10.1016/j.physbeh.2015.08.010 ◽

2015 ◽

Vol 152 ◽

pp. 416-421 ◽

Cited By ~ 4

Author(s):

L. Vivas ◽

F.M. Dadam ◽

X.E. Caeiro

Keyword(s):

Sex Differences ◽

Neural Activity ◽

Body Fluid ◽

Sex Chromosome ◽

Chromosome Complement ◽

Sodium Depletion ◽

Fluid Homeostasis ◽

Body Fluid Homeostasis

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hebp3, a Novel Member of the Heme-Binding Protein Gene Family, Is Expressed in the Medaka Meninges With Higher Abundance in Females Due to a Direct Stimulating Action of Ovarian Estrogens

Endocrinology ◽

10.1210/en.2012-2000 ◽

2013 ◽

Vol 154 (2) ◽

pp. 920-930 ◽

Cited By ~ 7

Author(s):

Kiyoshi Nakasone ◽

Yoshitaka Nagahama ◽

Kataaki Okubo

Keyword(s):

Sex Differences ◽

Gene Family ◽

Protein Gene ◽

Sex Chromosome ◽

Binding Protein ◽

Heme Binding ◽

Teleost Brain ◽

Binding Protein Gene ◽

Heme Binding Protein ◽

The Brain

The brains of teleost fish exhibit remarkable sexual plasticity throughout their life span. To dissect the molecular basis for the development and reversal of sex differences in the teleost brain, we screened for genes differentially expressed between sexes in the brain of medaka (Oryzias latipes). One of the genes identified in the screen as being preferentially expressed in females was found to be a new member of the heme-binding protein gene family that includes hebp1 and hebp2 and was designated here as hebp3. The medaka hebp3 is expressed in the meninges with higher abundance in females, whereas there is no expression within the brain parenchyma. This female-biased expression of hebp3 is not attributable to the direct action of sex chromosome genes but results from the transient and reversible action of estrogens derived from the ovary. Moreover, estrogens directly activate the transcription of hebp3 via a palindromic estrogen-responsive element in the hebp3 promoter. Taken together, our findings demonstrate that hebp3 is a novel transcriptional target of estrogens, with female-biased expression in the meninges. The definite but reversible sexual dimorphism of the meningeal hebp3 expression may contribute to the development and reversal of sex differences in the teleost brain.

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Sex differences in gene expression and proliferation are dependent on the epigenetic modifier HP1γ

10.1101/563940 ◽

2019 ◽

Author(s):

Pui-Pik Law ◽

Ping-Kei Chan ◽

Kirsten McEwen ◽

Huihan Zhi ◽

Bing Liang ◽

...

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Sex Chromosome ◽

Chromosome Complement ◽

Autosomal Gene ◽

Sexually Dimorphic ◽

Heterochromatin Protein 1 ◽

Epigenetic Modifier ◽

Early Embryos ◽

Males And Females

SummarySex differences in growth rate in very early embryos have been recognized in a variety of mammals and attributed to sex-chromosome complement effects as they occur before overt sexual differentiation. We previously found that sex-chromosome complement, rather than sex hormones regulates heterochromatin-mediated silencing of a transgene and autosomal gene expression in mice. Here, sex dimorphism in proliferation was investigated. We confirm that male embryonic fibroblasts proliferate faster than female fibroblasts and show that this proliferation advantage is completely dependent upon heterochromatin protein 1 gamma (HP1γ). To determine whether this sex-regulatory effect of HP1γ was a more general phenomenon, we performed RNA sequencing on MEFs derived from males and females, with or without HP1γ. Strikingly, HP1γ was found to be crucial for regulating nearly all sexually dimorphic autosomal gene expression because deletion of the HP1γ gene in males abolished sex differences in autosomal gene expression. The identification of a key epigenetic modifier as central in defining gene expression differences between males and females has important implications for understanding physiological sex differences and sex bias in disease.

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Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex

10.1101/2021.09.01.458115 ◽

2021 ◽

Author(s):

Sarah R Ocanas ◽

Victor A Ansere ◽

Kyla B Tooley ◽

Niran Hadad ◽

Ana J Chucair-Elliott ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Sex Differences ◽

Sex Chromosomes ◽

Sex Chromosome ◽

Chromosome Complement ◽

Experimental Models ◽

Ctcf Binding ◽

Autosomal Gene ◽

Sex Effects

Sex differences in the brain as they relate to health and disease are often overlooked in experimental models. Many neurological disorders, like Alzheimer's disease (AD), multiple sclerosis (MS), and autism, differ in prevalence between males and females. Sex differences originate either from differential gene expression on sex chromosomes or from hormonal differences, either directly or indirectly. To disentangle the relative contributions of genetic sex (XX v. XY) and gonadal sex (ovaries v. testes) to the regulation of hippocampal sex effects, we use the "sex-reversal" Four Core Genotype (FCG) mouse model which uncouples sex chromosome complement from gonadal sex. Transcriptomic and epigenomic analyses of hippocampal RNA and DNA from ~12 month old FCG mice, reveals differential regulatory effects of sex chromosome content and gonadal sex on X- versus autosome-encoded gene expression and DNA modification patterns. Gene expression and DNA methylation patterns on the X chromosome were driven primarily by sex chromosome content, not gonadal sex. The majority of DNA methylation changes involved hypermethylation in the XX genotypes (as compared to XY) in the CpG context, with the largest differences in CpG islands, promoters, and CTCF binding sites. Autosomal gene expression and DNA modifications demonstrated regulation by sex chromosome complement and gonadal sex. These data demonstrate the importance of sex chromosomes themselves, independent of hormonal status, in regulating hippocampal sex effects. Future studies will need to further interrogate specific CNS cell types, identify the mechanisms by which sex chromosome regulate autosomes, and differentiate organizational from activational hormonal effects.

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