Sex differences in the response to oxidative and proteolytic stress

Abstract

Sex differences in diseases involving oxidative and proteolytic stress are common, including greater ischemic heart disease, Parkinson disease and stroke in men, and greater Alzheimer disease in women. Sex differences are also observed in stress response of cells and tissues, where female cells are generally more resistant to heat and oxidative stress-induced cell death. Studies implicate beneficial effects of estrogen, as well as cell-autonomous effects including superior mitochondrial function and increased expression of stress response genes in female cells relative to male cells. The p53 and forkhead box (FOX)-family genes, heat shock proteins (HSPs), and the apoptosis and autophagy pathways appear particularly important in mediating sex differences in stress response.

Keywords: Heat shock; Oxidative stress; Proteostasis; Sex differences; Sexual antagonistic pleiotropy; Sexual dimorphism.

Graphical abstract

Fig. 1

Sex determination and dosage compensation in Drosophila and human. The sex determination and dosage compensation pathways are outlined for Drosophila and human, with an emphasis on similarities. LncRNAs and the conserved PcG proteins (indicated in green font) function to regulate X-linked gene expression and dosage compensation in both species. Similarly, the conserved doublesex-related transcription factor (indicated in blue font) promotes male cell differentiation in both species. (A) In Drosophila males, the male-specific-lethal complex (MSL) interacts with lncRNA roX and PcG proteins to activate gene expression along the X chromosome, thereby contributing to dosage compensation. The double-sex (dsx) and fruitless (fru) gene transcripts splice in the default male mode, thereby yielding the male isoform of each transcription factor. These male isoforms of Dsx and Fru then direct male somatic cell differentiation. The steroid hormone ecdysone further regulates spermatogenesis. (B) In Drosophila females, the lncRNAs R1 and R2 interact with PcG proteins to activate expression of the Sex-lethal gene (Sxl). Sxl protein interacts with partner UNR to inhibit the translation of the male-specific lethal (MSL) subunit MSL2 (as indicated by red t-bar). Because the MSL complex is not formed, it does not activate X chromosome gene expression in the female, and this limited X chromosome gene expression contributes to dosage compensation. Sxl protein regulates splicing of the transformer (tra) gene, and the resultant Tra protein in turn regulates splicing of dsx and fru gene transcripts in the female mode, to produce the female isoform of each transcription factor. These female isoforms of Dsx and Fru then direct female somatic cell differentiation. Tra protein also acts through an unknown mechanism (indicated by question mark) to regulate additional gene expression and female somatic cell differentiation. The steroid hormone ecdysone further regulates oogenesis. (C) In human males, the SRY gene on the Y chromosome activates expression of the SOX9 gene. SOX9 activates DMRT1 and inhibits FOXL2, thereby shifting the balance in activity between these two mutually-antagonistic factors towards DMRT1. DMRT1 promotes male cell differentiation. Male cell differentiation yields greater production of male-biased hormones, including testosterone, which further promotes male cell differentiation and spermatogenesis. (D) In human females, the lncRNA Xist interacts with PcG proteins to inactivate gene expression in cis along one X chromosome (Xi, as indicated by curved red t-bar). On the other X chromosome, Xist is not expressed, and gene expression remains active (Xa). The balance of activity between DMRT1 and FOXL2 favors FOXL2, which in turn promotes female cell differentiation. Female cell differentiation yields greater production of female-biased hormones, including estrogens, which further promotes female cell differentiation and oogenesis. (E) In Drosophila, several X-linked genes show incomplete dosage compensation and female-biased expression. (F) In human females, numerous X-linked genes “escape” from X-inactivation to varying degree, resulting in female-biased expression (indicated by single asterisk). Additional X-linked genes show female-biased expression in certain studies, that may or may not be related to the X-inactivation mechanism (indicated by double asterisk). The genes presented are limited to examples that fall under the general functional categories “Ubiquitin/proteasome”, “Autophagy” and “Mitochondria/ROS/apoptosis”. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Cellular targets for estrogen function in response to oxidative and proteotoxic stress. In the ovary, the somatic follicle cells of maturing oocyte follicles produce the majority of circulating estrogens, of which 17β-estradiol is the most active, and here referred to as estrogen. In the target cell, estrogen binds to receptors ERα and ERβ, and the activated receptors directly activate membrane and cytoplasmic signaling cascades. These include the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/p38MAPK/PI3K/AKT cascade, which inactivates FOXO-family transcription factors, and the cAMP/PKA/CREB cascade which activates the CREB transcription factor. In addition, there is significant cross-talk between these signaling cascades and others regulated by estrogen, including p53, JNK and extracellular signal-regulated kinase (ERK). In the nucleus, ERα, ERβ, FOXO and CREB transcription factors activate expression of genes involved in regulation of apoptosis, proteostasis, redox state, and autophagy. Activated ERα and ERβ also translocate to the mitochondria where they activate expression of mitochondrial-encoded genes including cytochrome C, as well as interacting with components of the ETC. Estrogen also interacts directly with the mitochondrial membrane to modulate membrane microviscosity, and has been reported to act directly as an antioxidant to detoxify lipid peroxyradicals. Please see text for additional details.

Fig. 3

Summary of mammalian female advantage in cellular stress resistance. The major genetic and physiological features that contribute to the human female advantage in resistance to oxidative and proteotoxic stress are diagrammed. Arrow indicates activation, and t-bars indicate suppression. Please see text for additional details.