A “Four Core Genotypes” rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases

Abstract

Background: We have generated a rat model similar to the Four Core Genotypes mouse model, allowing comparison of XX and XY rats with the same type of gonad. The model detects novel sex chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype. Methods: XY rats were produced with an autosomal transgene of Sry, the testis-determining factor gene, which were fathers of XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females that have XX and XY progeny with ovaries. These groups can be compared to detect sex differences caused by sex chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Results: We have measured numerous phenotypes to characterize this model, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Numerous phenotypes previously found to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development. Conclusion: The results establish a powerful new model to discriminate sex chromosome and gonadal hormone effects that cause sexual differences in rat physiology and disease.

Sex differences in acute early life stress‐enhanced fear learning in adult rats

“…Future studies are needed to determine whether organizational effects of gonadal steroid hormones and/or sex chromosome gene expression differences contribute to the increased female vulnerability in aELS‐induced fear learning in adulthood. One compelling approach to addressing this question would be to use the four‐core genotype rat or mouse model, where chromosomal sex (XX vs. XY) and gonadal hormone status (ovaries vs. testes) are independently manipulated to yield four experimental groups (Arnold & Chen, 2009; Arnold et al., 2023; Quinn et al., 2007). Prior to behavioral testing, the animals can be gonadectomized to eliminate any potential influence of circulating gonadal steroid hormones.…”

Sex Differences In The Interaction Between Alcohol And mTORC1

“…Sex chromosome genes have garnered attention in recent years for their potential roles in driving sex-specific differences in behavior and susceptibility to various conditions. Research involving mouse models with differing sex chromosome complements (XX, XY) and gonadal sex such as the four Core Genotypes mice has provided valuable insights (Corre, Friedel et al 2016, Arnold 2020, Ghosh, Chen et al 2021, Arnold, Chen et al 2023, Cioffi, Grassi et al 2024.…”

“…These models allowed scientists to differentiate the impacts of sex chromosomes themselves from the influence of gonadal hormones (Corre, Friedel et al 2016, Ghosh, Chen et al 2021, Arnold, Chen et al 2023, Cioffi, Grassi et al 2024. Using these models, Sneddon et al showed in a recent study that chromosomal sex plays a role in shaping the development of binge-like alcohol consumption and aversion-resistance drinking in females (Sneddon, Rasizer et al 2022, Sneddon, Masters et al 2023.…”

“…Sex chromosome genes have garnered attention in recent years for their potential roles in driving sex-specific differences in behavior and susceptibility to various conditions. Research involving mouse models with differing sex chromosome complements (XX, XY) and gonadal sex such as the four Core Genotypes mice has provided valuable insights (Corre, Friedel et al 2016, Arnold 2020, Ghosh, Chen et al 2021, Arnold, Chen et al 2023, Cioffi, Grassi et al 2024). These models allowed scientists to differentiate the impacts of sex chromosomes themselves from the influence of gonadal hormones (Corre, Friedel et al 2016, Ghosh, Chen et al 2021, Arnold, Chen et al 2023, Cioffi, Grassi et al 2024).…”

“…Research involving mouse models with differing sex chromosome complements (XX, XY) and gonadal sex such as the four Core Genotypes mice has provided valuable insights (Corre, Friedel et al 2016, Arnold 2020, Ghosh, Chen et al 2021, Arnold, Chen et al 2023, Cioffi, Grassi et al 2024). These models allowed scientists to differentiate the impacts of sex chromosomes themselves from the influence of gonadal hormones (Corre, Friedel et al 2016, Ghosh, Chen et al 2021, Arnold, Chen et al 2023, Cioffi, Grassi et al 2024). Using these models, Sneddon et al showed in a recent study that chromosomal sex plays a role in shaping the development of binge-like alcohol consumption and aversion-resistance drinking in females (Sneddon, Rasizer et al 2022, Sneddon, Masters et al 2023).…”