What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues?
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The "four core genotypes" (FCG) model comprises mice in which sex chromosome complement (XX vs. XY) is unrelated to the animal's gonadal sex. The four genotypes are XX gonadal males or females, and XY gonadal males or females. The model allows one to measure (1) the differences in phenotypes caused by sex chromosome complement (XX vs. XY), (2) the differential effects of ovarian and testicular secretions, and (3) the interactive effects of (1) and (2). Thus, the FCG model provides new information regarding the origins of sex differences in phenotype that has not been available from studies that manipulate gonadal hormone levels in normal XY males and XX females. Studies of the FCG model have uncovered XX vs. XY differences in behaviors (aggression, parenting, habit formation, nociception, social interactions), gene expression (septal vasopressin), and susceptibility to disease (neural tube closure and autoimmune disease) not mediated by gonadal hormones. Some sex chromosome effects are mediated by sex differences in dose of X genes or their parental imprint. Future studies will identify the genes involved and their mechanisms of action.
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The four core genotypes mouse model has helped identify the influence of sex chromosomes on physical traits, such as obesity and food intake.
“the four core genotypes mouse model which incorporates mice with four different combinations of gonads and sex chromosomes [66, 67], has helped identify the influence of sex chromosomes on physical traits, such as obesity and food intake [68, 69].”
From Integrating Transwomen and Female Athletes with Differences of Sex Development (DSD) into Elite Competition: The FIMS 2021 Consensus Statement (2021) · cites this paper as [66]
The Introduction and section 5 describe the four core genotypes model and report sex-chromosome effects on several phenotypes. The copy does not report an effect on obesity or food intake; section 5.3 uses food as a reward in a habit-formation test, which is not a measure of intake. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGenes on sex chromosomes may interact with BPA.
“Another possibility is that genes on sex chromosomes may interact with BPA [58].”
From Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice (2011) · cites this paper as [58]
The Introduction discusses direct effects of X and Y genes, and section 7.2 discusses their possible effects on the brain and other tissues. Neither passage addresses an interaction with BPA; searches for “BPA” and “bisphenol” found no relevant passage in our copy. (LLM, conf=0.76)
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Sleep, rhythms, and the endocrine brain: influence of sex and gonadal hormones
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Mechanisms of sex disparities in influenza pathogenesis
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Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders
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Sex Differences in Spatial Cognition: Advancing the Conversation
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Etiologies underlying sex differences in autism spectrum disorders
Schaafsma, S. M., & Pfaff, D. W. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.03.006 · Cited by 178 · see citing works
Sex differences in mood disorders: Perspectives from humans and rodent models
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A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease
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Self-citationGestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice
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“Another possibility is that genes on sex chromosomes may interact with BPA [58].”
BackgroundSex Differences in Molecular and Cellular Substrates of Stress
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Burgoyne, P. S., & Arnold, A. P. (2016) · Biology of Sex Differences · doi:10.1186/s13293-016-0115-5 · Cited by 154 · see citing works
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Self-citationThe Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species
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Hormonal Programming Across the Lifespan
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“Both Tg XX Sry and Tg XY Sry genotypes display similar testosterone levels during adulthood [99].”
Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders
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Sex differences in androgen regulation of metabolism in nonhuman primates
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Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications
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- Authors
- Arnold, A. P., & Chen, X.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Arnold, Arthur P.
- Venue
- Frontiers in Neuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 30
- Issue
- 1
- Pages
- 1-9
- ISSN
- 0091-3022 (ISSN-L)
- PMC
- PMC3282561
- OpenAlex
- W2044615029
- Cited by
- 587
- References
- 89
- Citations by year
- 2026: 23 · 2025: 31 · 2024: 48 · 2023: 50 · 2022: 46 · 2021: 40 · 2020: 48 · 2019: 35 · 2018: 27 · 2017: 33 · 2016: 34 · 2015: 31 · 2014: 32 · 2013: 16 · 2012: 30
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Frontiers in Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH59268, R01MH059268)
- National Institute on Deafness and Other Communication Disorders (R01DC000217)
- National Institute of General Medical Sciences (R01GM059268)
- National Institute of Allergy and Infectious Diseases (AI/AR50839, AI070306, R21AI070306)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 41310)
- National Institute of Neurological Disorders and Stroke (NS045966, NS 043196, R01NS043196, R01NS045966)
- National Center for Complementary and Integrative Health (R24AT002681, AT002681)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Keywords
- sex chromosome complement, sex differences, gonadal sex, ovarian hormones, testicular hormones, sex differences in behavior, aggression, parenting, habit formation, nociception, social interaction, neural tube closure, autoimmune disease susceptibility, brain gene expression
- MeSH terms
- Aggression, Animals, Behavior, Animal, Brain, Female, Genotype, Male, Neural Tube Defects, Sex Characteristics, Sex Chromosome Aberrations, Sex Chromosomes, Disorders of Sex Development, Social Behavior, X Chromosome, Y Chromosome, Parenting, Sex Determination Processes, Models, Animal, Mice, Sex-Determining Region Y Protein
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