1. Animal models for studying sex differences
Arthur P. Arnold, PhD
Department of Integrative Biology & Physiology
Lab of Neuroendocrinology of the Brain Research Institute
University of California, Los Angeles (UCLA)
UCLA
FCG
LNE

2. Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019
What causes sex differences in physiology and disease? = F M
Possible answers: Gonadal hormones
Sex chromosomes
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

3. Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

4. Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019
Endocrinology 2005
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

5. XXF XXM XYF XYM “Four Core Genotypes” (FCG) Mice
Paul Burgoyne and Robin Lovell-Badge
Make gonadal determination independent
of sex chromosome complement
to compare XX and XY mice with the same type of gonads
XXF
XXM
XYF
XYM
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

6. Sry WT XY male Y-linked Sry is testis-determining.
Sry “moved” to Chromosome 3.
This version of Chrom3 becomes testis-determining.
“Four Core Genotypes” (FCG) Mice
2 kinds of sperm: X or Y -
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019
4 kinds of sperm: X or XSry or Y or YSry

7. Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019
“Four Core Genotypes” Model
XY-(Sry+) father x XX mother
genome
gonads
abbreviation
X X
XXF
offspring:
X Y-
XYF
X X(Sry+)
XXM
X Y-(Sry+)
XYM
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

8. Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019
Sex chromosome complement
Four core genotypes
Sry+
Gonadal
type
Sry-
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

9. Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019
FCG
phenotypes
horm
XX=XY /
investigators no
yes
Xuqi Chen et al.
2008
neural tube closure defects
Midbrain dopamine neurons in vitro
yes
yes
Laura Carruth et al.
2002
XX female
XY female
yes
yes
Rhonda Voskuhl lab,
UCLA
autoimmune disease
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

10. Hormonal and sex chromosome effects on body weight and adiposity5 10 15 20 25 12 F M 11 7
body weight (g) XX XY 9 * 16 17 13 40 35 30
day 21
day 45
5 months
after GDX
Chen et al.
PLoS Genet. 2012
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

11. Interaction of sex hormones and sex chromosomes
chow (low fat diet)
Chen et al.
PLoS Genet. 2012
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

12. Mice with two X chromosomes are heavier and fatter
XY* Model:
Mice with two X chromosomes are heavier and fatter
than mice with one X chromosome
Chen et al.
PLoS Genet. 2012;8(5):e
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

13. Inherent sex differences in the genome
lead to several types of cellular inequality.
Arnold AP. Trends Genet (2):55-61
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

14. Human X chromosome: Escape from X inactivation
23% of X genes are expressed higher in F than M.
PAR
NPX
F>M
tissues
M>F
X genes
Red X escapees are potential drivers of sex differences in cell phenotypes.
Tukiainen T et al.
Landscape of X chromosome inactivation across human tissues. Nature :
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

15. Where to get sex chromosome mice
1. Ask me.
2. FCG C57BL/6J: Jackson Lab
3. XY* C57BL/6J: UCDavis MMRRC
4. FCG and XY* on different strain backgrounds: Arnold Lab
5. X escapee floxed and knockouts: Gene KO consortia, Arnold lab
6. Transgenes for X escapees and Y gametologs: UCDavis MMRRC
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

16. Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019
UCLA
Metabolism
Lab of Karen Reue
Jenny Link
Cardiovascular
Lab of Mansoureh Eghbali
Jingyuan Li, Soban Umar,
Christine Cunningham
Sex chromosome trisomies, etc.
Lab of Eric Vilain
Negar Ghahramani, Tuck Ngun
Behavior & Cognition
Lab of David Jentsch
Shawn Aarde
Autoimmune Disease: Rhonda Voskuhl
Systems Biology: Jake Lusis
Feeding Behavior:
Yvette Taché
Crick Institute, London
Paul Burgoyne
Robin Lovell-Badge
Arnold Lab
Xuqi Chen
Yuichiro Itoh
Shayna Williams-Burris
Shawn Aarde
Mariam Barseghyan
Jessy Martinez
Kathy Kampf
Rebecca McClusky
Maureen Ruiz-Sundstrom
Ryan Mackie
Haley Hrncir
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019

17. Support: thank you! NICHD, ORWH, NIDDK, NHLBI, NINDS, NIMH, NIDCD, OD
Society for Women’s Health Research
UCLA Iris Cantor Center, CURE, Center for Neurobiology of Stress, Parkinson’s Center
Arthur Arnold, "Sex and Gender Differences in Aging" June 6-7, 2019